Acta Orthopaedica Volume 91, Issue 1 by Acta

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Element of success in joint replacement

Vol. 91, No. 1, 2020 (pp. 1–120)

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Volume 91, Number 1, February 2020

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Vol. 91, No. 1, 2020

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Acta Orthopaedica

ISSN 1745-3674

Vol. 91, No. 1, February 2020 Editorial AI ethics, accountability, and sustainability: revisiting the Hippocratic oath Consensus hip, knee. ERAS Consensus statement for perioperative care in total hip replacement and total knee replacement surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations Hip Only 8% of major preventable adverse events after hip arthroplasty are filed as claims: a Swedish multi-center cohort study on 1,998 patients Higher early proximal migration of hemispherical cups with electrochemically applied hydroxyapatite (BoneMaster) on a porous surface compared with porous surface alone: a randomized RSA study with 53 patients Fixation, sex, and age: highest risk of revision for uncemented stems in elderly women — data from 66,995 primary total hip arthroplasties in the Norwegian Arthroplasty Register Outpatient total hip or knee arthroplasty in ambulatory surgery center versus arthroplasty ward: a randomized controlled trial Changes in health-related quality of life are associated with patient satisfaction following total hip replacement: an analysis of 69,083 patients in the Swedish Hip Arthroplasty Register The neck–shaft angle: an update on reference values and associated factors Postoperative mortality after a hip fracture over a 15-year period in Denmark: a national register study Is there a weekend effect after hip fracture surgery? A study of 74,410 hip fractures reported to the Norwegian Hip Fracture Register Risk of reoperation within 12 months following osteosynthesis of a displaced femoral neck fracture is linked mainly to initial fracture displacement while risk of death may be linked to bone quality: a cohort study from Danish Fracture Database Knee Comparison of the 10-year outcomes of cemented and cementless unicompartmental knee replacements: data from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man Patients report inferior quality of care for knee osteoarthritis prior to assessment for knee replacement surgery – a cross-sectional study of 517 patients in Denmark The Forgotten Joint Score-12 in Swedish patients undergoing knee arthroplasty: a validation study with the Knee Injury and Osteoarthritis Outcome Score (KOOS) as comparator Weight and height separated provide better understanding than BMI on the risk of revision after total knee arthroplasty: report of 107,228 primary total knee arthroplasties from the Swedish Knee Arthroplasty Register 2009–2017 No effect of cognitive behavioral patient education for patients with pain catastrophizing before total knee arthroplasty: a randomized controlled trial Fracture epidemiology Incidence of distal ulna fractures in a Swedish county: 74/100,000 person-years, most of them treated non-operatively 20-year trends of distal femoral, patellar, and proximal tibial fractures: a Danish nationwide cohort study of 60,823 patients Aseptic loosening, rat model Mechanical instability induces osteoclast differentiation independent of the presence of a fibrous tissue interface and osteocyte apoptosis in a rat model for aseptic loosening Information to authors (see http://www.actaorthop.org/)

L Felländer-Tsai

T W Wainwright, M Gill, D A Mcdonald, R G Middleton, M Reed, O Sahota, P Yates, and O Ljungqvist

M Magnéli, M Unbeck, B Samuelsson, C Rogmark, O Rolfson, M Gordon, and O Sköldenberg

P B Jørgensen, H Daugaard, S S Jakobsen, M Lamm, K Søballe, and M Stilling

H Dale, S Børsheim, T B Kristensen, A M Fenstad, J-E Gjertsen, G Hallan, S A Lie, and O Furnes

C Husted, K Gromov, H K Hansen, A Troelsen, B B Kristensen, and H Husted G S Ray, P Ekelund, S Nemes, O Rolfson, and M Mohaddes

48 53 58

C S Fischer, J-P Kühn, H Völzke, T Ittermann, D Gümbel, R Kasch, L Haralambiev, R Laqua, P Hinz, and J Lange O Gundel, L C Thygesen, I Gögenur, and S Ekeloef

A Boutera, E Dybvik, G Hallan, and J-E Gjertsen

A M Nyholm, H Palm, H Sandholdt, A Troelsen, K Gromov, and DFDB collaborators

H R Mohammad, G S Matharu, A Judge, and D W Murray

L H Ingelsrud, E M Roos, K Gromov, S S Jensen, and A Troelsens

S Heijbel, J E Naili, A Hedin, A W-Dahl, K G Nilsson, and M Hedström

E A Sezgin, A W-Dahl, L Lidgren, And O Robertsson

S Birch, M Stilling, I Mechlenburg, and T B Hansen

104

M Moloney, S Farnebo, and L Adolfsson

109

V Vestergaard, A B Pedersen, P T Tengberg, A Troelsen, and H M Schrøder

115

R V Madsen, D Nam, J Schilcher, A Dvorzhinskiy, J P Sutherland, F M Bostrom, and A Fahlgren

Thank you, reviewers! Acta Orthopaedica thanks all reviewers for their work with manuscripts during year 2019. We depend on your work to keep and increase the quality of Acta. Your effort is much appreciated!

Aamodt, Arild Adami, Johanna Adolfsson, Lars Evert Ali, Abdulemir Andersen, Thomas Arndt, Toni Atroshi, Isam Backteman, Torsten Basso, Trude Bauer, Thomas Berg Breen, Anne Berg, Hans E Bergh, Kåre Bernhoff, Karin Bisseling, Pepijn Bobak, Peter Bodén, Henrik Boeckstyns, Michel E H Bohm, Eric Richard Bos, Pieter K Bosker, Bart Breusch, Steffen Brisby, Helena Brismar, Harald Brismar, Torkel Brix, Michael Brouwer, Reinoud W Buchholz, Ines Busch, Vincent Buttaro, Martin Bülhoff, Matthias Böhler, Nikolaus Clarius, Michael Colaris, J W Conway, Janet D Cordero-Ampuero, José Court-Brown, Charles Crawford, Ross W Crawford, Scott Creutzfeldt, Johan Dale, Håvard Dalsgaard, Hanne L de Steiger, Richard N Degreef, Ilse Ding, Ming Dolatowski, Filip C

Drogset, Jon Olav Egund, Niels Ekholm, Carl Ekström, Wilhelmina H G Enocson, Anders Eriksen, Erik Fink Exner, Ulrich Fakler, Johannes K M Flivik, Gunnar Frihagen, Frede Furnes, Ove Garland, Anne Gehmert, Sebastian Geijer, Mats Gerdhem, Paul Gerdin Wärnberg, Martin Gillam, Marianne Hansen Gjertsen, Jan-Erik Goodman, Stuart Barry Goosen, Jon Gordon, Max Gottliebsen, Martin Graves, Stephen Ellis Gromov, Kirill Gudnason, Asgeir Gustafson, Pelle Hamilton, David F Hansen, Torben Bæk Hardes, Jendrik Hedin, Hanne Hedström, Margareta Heesterbeek, Petra Henricson, Anders Hole, Randi Holm Ingelsrud, Lina Hooper, Gary Hozack, William Husted, Henrik Hägglund, Gunnar Ilchmann, Thomas Issa, Kimona Jerrhag, Daniel Johansen, Antony Johansson, Torsten Johnsen, Lars Gunnar Jürisson, Mikk

Jämsen, Esa Kambhampati, Srinivas B S Kaptein, Bart L Kehlet, Henrik Keller, Johnny Kendrick, Ben J L Kennedy, Oran Kjærsgaard-Andersen, Per Knutson, Kaj Koivu, Helka Kold, Søren Kopylov, Philippe Koskinen, Seppo Koster, Lennard Kraus, Tanja Kristensen, Pia Kjær Kärrholm, Johan Laaksonen, Inari Lange, Jeppe Larsen, Morten Schultz Lazarinis, Stergios Lenguerrand, Erik Li, Yan Liavaag, Sigurd Liddle, Alexander David Louwerens, Jan Willem Lundberg, Arne Lundström, Claes Maasalu, Katre Madanat, Rami Madsen, Jan Erik Malchau, Henrik Mann, Kenneth Mathijssen, Nina Mattila, Ville McNally, Martin Meermans, Geert Merckoll, Else Miettinen, Hannu Millis, Michael Brian Mohaddes, Maziar Monsen, Tor Johan Moppett, Iain Morken, Gunnar Moseley, Colin F Muir, Dawson

Mukka, Sebastian Mulders, Marjolein A M Mäkelä, Keijo T Mäkinen, Tatu Märtson, Aare Möller, Hans Naili, Josefine E Narayanan, Unni Nelissen, Rob Nemeth, Banne Nieminen, Jyrki Nieuwenhuijse, Marc J Niinimäki, Tuukka Nijhof, Marc Nilsson, Kjell G Nolte, Peter O´Donnell, Richard Olgun, Z Deniz Olsen, Bo Sanderhoff Ovaska, Mikko Overgaard, Soeren Overgaard, Søren Page, Richard Parsch, Klaus Dieter Parvizi, Javad Pedersen, Alma B. Petersen, Klaus Kjær Petersen, Kristian Kjær Pijls, Bart G Pontén, Eva Magdalena Pronk, Yvette Rahme, Hans Ranstam, Jonas Rasmussen, Jeppe Vejlgaard

Ravn, Christen Reito, Aleksi Ricksten, Sven-Erik Robertsson, Otto Rogmark, Cecilia Rolfson, Ola Romijn, Marc Gerard Rosengren, Björn E D Rutz, Erich Ryd, Leif Röhrl, Stephan Maximilian Røise, Olav Sadoghi, Patrick Saini, Rajkumar Salomonsson, Björn Sayed-Noor, Arkan S Scheer, Johan Scherman, Peter Schreurs, B Willem Sierra, Rafael Sinikumpu, Jaakko Skråmm, Inge Sköldenberg, Olof Smolders, José M H Smulders, Katrijn Soininvaara, Tarja Solberg, Lene Bergendal Soriano, Alex Stark, André Stefánsdóttir, Anna Strömberg, Joakim Teeter, Matthew Terjesen, Terje Toksvig-Larsen, Sören

Troelsen, Anders Trovik, Clement Stig Tsagozis, Panagiotis Tönnesen, Hanne van der Pluijm, Marco van der Weegen, Walter van Enst, Annefloor van Steenbergen, Liza N van Susante, JLC Vehmeijer, Stephan Verhaar, Jan A N Vetti, Nils Viberg, Bjarke Virolainen, Petri Vliet Vlieland, Thea von Schewelov, Thord Vos, Dagmar Isabella W-Dahl, Annette Wagner, Christof Warwick, David Weidenhielm, Lars Weiss, Rüdiger J Wensaas, Anders Westberg, Marianne Whitehouse, Michael Richard Wiig, Ola Wikman, Agneta Wilcke, Maria Willigenburg, Nienke Wolf, Sebastian I Wolterbeek, Nienke Wright, Timothy Wyat, Michael Charles Zijlstra, Wierd P

Acta Orthopaedica 2020; 91 (1): 1–2

Editorial

AI ethics, accountability, and sustainability: revisiting the Hippocratic oath Artificial intelligence (AI) embedded in healthcare technologies creates opportunities and great expectations. However, new interactions between man and machine arise and must be addressed (Lancet 2017). Unfortunately, medical education and training at all levels lag behind the advancement of technology. New knowledge in healthcare and medicine emerges so rapidly that when newly graduated doctors have completed their specialist training, much knowledge has already become obsolete. In order to ensure quality and patient safety and to benefit from the positive opportunities that AI-based technology creates, new insights, investments, and focus are pivotal. When new technologies enter the medical and healthcare stage, physician training must ensure that these are used in a safe, effective, and evidence-based manner. In orthopedics and traumatology, the potential for more efficient and precise diagnostics with AI-based image interpretation has been widely identified. However, in medicine in general AI is often mentioned as a gray area and thus requires special attention in order to ensure ethics, fairness, accountability, and sustainability. The availability and trust in medical decision support tools based on AI is increasing, despite the fact that education and training in how these potentially black boxes function is lagging behind. The initially somewhat restrictive attitude in the healthcare sector is now undergoing rapid expansion. Large amounts of data are considered the new “gold” and are being embraced by stakeholders at all levels in healthcare and medicine. This pinpoints the need for education, as well as critical scrutiny and discussion of the ethical implications regarding data management and AI in healthcare and medicine. Recent media reports of data breaches on a number of social media platforms have shed light on these emerging challenges. When designing algorithms for decision support, measurements, references, and validation must be carefully defined in collaboration with medical experts. Systematic monitoring and validation of the algorithms in close collaboration with experts is also necessary. Bias and confounders must be managed because the origin of data on which the algorithms are based can lead to erroneous interpretations and potential damage (Box). From an ethical perspective, understanding, insight, and transparency regarding potential self-learning and automated decision support tools are necessary before they can be commercialized and scaled up (Larsson 2018). The level of explainability and transparency required for the responsible physician

Examples of unintended consequences or misuse of AI • Ethnic bias in apps using face recognition for detection of genetic disorders • Machine learning applications in image databases that not only reproduce but reinforce gender bias • Ethnic bias in algorithm-based practices for predicting recidivism in crime • Unethical and questionable AI-based marketing practices based on user data • Misinterpretations of surroundings or data leading to fatal accidents in AI-based navigation systems/robotics/autonomous vehicles

to trust the increasingly autonomous decision support tools must also be defined. Transparency is necessary for regulation of commercial AI products in order for them to be able to receive appropriate learning feedback, but also to meet society’s need for accountability when new products lead to potential unintentional, unwanted, or unexpected outcomes. Responsibility and accountability must be discussed and clarified. There must be no doubt about who should be held accountable when AI represents a third party besides the responsible physician and the patient in healthcare. Is AI as a partner and member of the healthcare team feasible in clinical decision-making and execution of tasks? A couple of examples highlighting the challenges to applied AI in the healthcare sector are applications intended for patients and doctors as well as robotics and systems collecting big data while they are used. A clear ethical dilemma may arise if the user is unable to understand or interpret the user instructions and product description. Even though there is great potential for efficiency and scalability by creating these kinds of platforms in healthcare, there is a risk of bias and confounders, as well as unintentional use and interpretation of data. The risk of under-use, misuse, and overuse are potentially serious matters in terms of accountability and ethics. The balance between access to data and the right to privacy The large amounts of data required to develop AI create value conﬂicts between regulation and laws that protect the integrity of both patient and physician information—an important part of medical ethics—and the access to large amounts of data that the development of AI tools requires. We must also be able to ask the

© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of the Nordic Orthopedic Federation. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI 10.1080/17453674.2019.1682850

question and discuss how much consideration should be given to patients and physicians when their information is released to train AI. Tension at the crossroads of innovation and individual integrity may evolve. Ethics has always been a central part of both medical science and healthcare practice. A new chapter in relation to new technology and AI is undoubtedly needed. Pure enthusiasm, bounty hunting, and the notion of value creation must not challenge the interests of patient and physician integrity. The frequently paraphrased line in the Hippocratic oath “I will abstain from all intentional wrong-doing and harm” must be revisited. Unintentional harm definitely must not be overlooked.

Acta Orthopaedica 2020; 91 (1): 1–2

Li Felländer-Tsai Division of Orthopaedics and Biotechnology, CLINTEC, Karolinska Institutet, Sweden Email: Li.Tsai@ki.se

Editorial: Artificial intelligence in health care: within touching distance. Lancet 2017; 390: 2739. Larsson, S. Algorithmic governance and the need for consumer empowerment in data-driven markets. Internet Policy Review 2018; 7(2). doi: 10.14763/2018.2.791

Acta Orthopaedica 2020; 91 (1): 3–19

Consensus statement for perioperative care in total hip replacement and total knee replacement surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations Thomas W WAINWRIGHT 1,2, Mike GILL 3, David A MCDONALD 4,5, Robert G MIDDLETON 1,2,6, Mike REED 7,8, Opinder SAHOTA 9,10, Piers YATES 11, and Olle LJUNGQVIST 12 1 Orthopaedic Research Institute, Bournemouth Univesity, Bournemouth, UK; 2 The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, UK; 3 Golden Jubilee National Hospital, Glasgow, Scotland; 4 Scottish Government, Glasgow, Scotland; 5 Nursing, Midwifery and Allied Health Professions Research Unit, Glasgow Caledonian University, Glasgow, Scotland; 6 Poole Hospital NHS Foundation Trust, Poole, UK; 7 Northumbria Healthcare NHS Foundational Trust, Northumbria, UK; 8 Health Sciences, University of York, York, UK; 9 Nottingham University Hospital, Nottingham, UK; 10 Nottingham University, Nottingham, UK; 11 University of Western Australia, Perth, Australia; 12 Örebro University, Örebro, Sweden Correspondence: twainwright@bournemouth.ac.uk Submitted 2019-03-04. Accepted 2019-09-16.

Background and purpose — There is a large volume of heterogeneous studies across all Enhanced Recovery After Surgery (ERAS®) components within total hip and total knee replacement surgery. This multidisciplinary consensus review summarizes the literature, and proposes recommendations for the perioperative care of patients undergoing total hip replacement and total knee replacement with an ERAS program. Methods — Studies were selected with particular attention being paid to meta-analyses, randomized controlled trials, and large prospective cohort studies that evaluated the efficacy of individual items of the perioperative treatment pathway to expedite the achievement of discharge criteria. A consensus recommendation was reached by the group after critical appraisal of the literature. Results — This consensus statement includes 17 topic areas. Best practice includes optimizing preoperative patient education, anesthetic technique, and transfusion strategy, in combination with an opioid-sparing multimodal analgesic approach and early mobilization. There is insufficient evidence to recommend that one surgical technique (type of approach, use of a minimally invasive technique, prosthesis choice, or use of computer-assisted surgery) over another will independently effect achievement of discharge criteria. Interpretation — Based on the evidence available for each element of perioperative care pathways, the ERAS® Society presents a comprehensive consensus review, for the perioperative care of patients undergoing total hip replacement and total knee replacement surgery within an ERAS® program. This unified protocol should now be further evaluated in order to refine the protocol and verify the strength of these recommendations.

Over the last 15 years, the systematic implementation of an evidence-based perioperative care protocol (“fast-track” or “enhanced recovery pathway”), such as that developed by the Enhanced Recovery After Surgery (ERAS) Society, has shown that hospital length of stay and complications can be reduced for a number of surgical procedures (Ljungqvist et al. 2017). For total hip (THR) and total knee replacement surgery (TKR), high-volume models have reduced length of stay from 4–10 days to 1–3 days, and outpatient surgery is possible for around 15% of patients in unselected cohorts within a socialized health systems (den Hartog et al. 2013, Kehlet 2013, Khan et al. 2014, Aasvang et al. 2015, Gromov et al. 2017). Given the proven benefit to both the patient and the healthcare system, ERAS protocols have been published for rectal, urological, pancreatic, gastric, breast, and reconstructive surgery, head and neck cancer surgery, bariatric, and liver surgery (Cerantola et al. 2013, Nygren et al. 2012, Lassen et al. 2012, Melloul et al. 2016, Mortensen et al. 2014, Thorell et al. 2016, Dort et al. 2017, Temple-Oberle et al. 2017). In Denmark, hip and knee replacement surgery has since year 2009 been coordinated nationally across select highvolume centers, adopting and developing a unified perioperative protocol, and a basis for research that has advanced the knowledge base for elective hip and knee replacement (Kehlet 2013). In the United Kingdom (UK), a national enhanced recovery partnership program ran between 2009 and 2011 with the aim to spread the best practice developed for hip and knee replacement based on work from UK high-volume centers (Wainwright and Middleton 2010, Malviya et al. 2011, McDonald et al. 2012). However, despite these efforts and previous narrative reviews on fast-track/enhanced recovery protocols for THR and TKR (Ibrahim et al. 2013a, 2013b;

Sprowson et al. 2013), a systematic and evidence-based guideline has not been produced. The present work brought together a group of ERAS experts to interpret the evidence using the GRADE system for rating quality of evidence and strength of recommendations (Guyatt et al. 2008). The scope of these guidelines includes only the perioperative period, with evidence examined on the ability of different interventions to reduce perioperative stress, maintain and support homeostasis and physiological function, and importantly accelerate the achievement of discharge criteria, including minimizing complications. Whilst the site of replacement is an independent factor for recovery, wherever possible we have prioritized procedure level evidence and applied critical analysis to studies that have included both THR and TKR. This article represents the efforts of the ERAS Society (http://www.erassociety.org) to present an updated and expanded consensus review of perioperative care for hip and knee replacement based on current evidence.

Methods Development of consensus recommendations A panel of experts in total hip replacement and total knee replacement was convened. This working group comprised surgeons, a physician, an anesthetist, and physiotherapists. A nursing perspective was also incorporated through the consideration and inclusion of qualitative nursing-specific literature (Specht et al. 2015, 2016). Previous ERAS Society guidelines were reviewed and used as a methodological template (Gustafsson et al. 2013). The panel was asked to advise on appropriate topics to be included in the guidelines, with final decisions being made by the lead authors (TW, OL). Once agreed, topics were allocated to authors, depending on each individual’s expertise. The final paper was agreed upon by all authors. Literature search and study selection Search terms were created using MESH terms and key words, and searches were carried out using the Bournemouth University MySearch interface (Bournemouth University), which includes Medline, CINAHL, Science Direct, PsycINFO, and Cochrane Database of Systematic Reviews databases. Whilst ERAS has evolved over the last 10–15 years, for completeness the peer-reviewed and English-language literature was systematically reviewed from January 1966 to October 2018. We appreciate that evidence from ERAS studies is evolving at a fast rate and so future studies may impact on findings; however, the recommendations presented are considered to reflect evidence at the time of writing (January 2019). Preoperative, surgical, anesthetic and analgesia, postoperative, and rehabilitation topics were searched. Reference lists of eligible articles were also reviewed for other relevant studies. Key words included “hip replacement,” “hip arthroplasty,” “knee replacement,” “knee arthroplasty,” “hip prosthesis,” “knee

Acta Orthopaedica 2019; 2020; 91 (1): 3–19

Table 1. GRADE system for rating quality of evidence (Guyatt et al. 2008) Evidence level

Definition

High quality Moderate quality Low quality Very low quality

Further research unlikely to change confidence in estimate of effect Further research likely to have important impact on confidence in estimate of effect and may change the estimate Further research very likely to have important impact on confidence in estimate of effect and likely to change the estimate Any estimate of effect is very uncertain

prosthesis,” and additional keywords were added depending on the topic. The authors screened titles and abstracts to identify potentially relevant articles, and reference lists of eligible articles were hand-searched for relevant studies. Systematic reviews, meta-analyses, randomized controlled trials, and non-randomized trials were considered for each topic, unless there were few papers identified, in which case all papers were screened. Qualitative studies were also considered in specific areas, where “hands on” experience of ERAS was described. We consider that although these do not qualify as high-level evidence, they provide valuable evidence on issues such as how patients perceive the ERAS pathway, and the role that nurses play. We carefully reviewed the final literature selected, and any discrepancies were resolved through group consensus. Studies in ERAS or fast-track set-ups showing improvements in the achievement of discharge criteria, or reducing length of stay, or having a positive effect on complications were targeted. Quality assessment and data analyses The overall quality of evidence was assessed using criteria developed by the Centre for Evidence Based Medicine at Oxford, England. Possible levels of evidence included “high” (i.e., systematic reviews, meta-analyses, or robust randomized controlled trials), “moderate” (i.e., smaller randomized controlled trials or prospective cohort data), or “low” (i.e., retrospective data). In line with ERAS guidelines for other surgical procedures (Gustafsson et al. 2013) the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system was used to evaluate the quality of evidence and recommendations (Tables 1 and 2, Guyatt et al. 2008). Recommendations are made based on whether the evidence level is high, medium, low, or very low quality, and the strength of the recommendation is based on the balance between desirable and undesirable effects. As with other ERAS working groups (Cerantola et al. 2013, Gustafsson et al. 2013), a GRADE evaluation may result in a strong recommendation even when based on low-quality data, if the risk of harm is negligible. Conversely, a weak recommenda-

Acta Orthopaedica 2020; 91 (1): 3–19

Table 2. GRADE system for rating strength of recommendations (Guyatt et al. 2008) Recommendation strength Definition Strong Weak

When desirable effects of intervention clearly outweigh the undesirable effects, or clearly do not When trade-offs are less certain—either because of low-quality evidence or because evidence suggests desir able and undesirable effects are closely balanced

tion may result from high-quality data. Any disagreements in the assessment of quality of evidence and grading of recommendation statements were resolved through consensus discussions. We were judicious when providing strong recommendations in areas where there was weak procedure-specific evidence. This was to ensure that new non-evidenced based traditions within ERAS were not created, when previous work in ERAS for THA and TKA has cautioned against this (Husted et al. 2014).

Evidence base and recommendations—ERAS items Preoperative information education and counselling Preoperative patient education has not been shown to independently affect postoperative outcomes, such as accelerating the achievement of discharge criteria, but it has been found to reduce preoperative anxiety across a number of systematic reviews (Bergin et al. 2014, Jordan et al. 2014, Louw et al. 2013), including a Cochrane review (McDonald et al. 2014). However, the conclusions of these reviews may be flawed due to the heterogeneity of the pooled studies. There is a strong need for properly designed randomized and controlled studies that are sufficiently powered, performed in ERAS settings, and allow for discrimination between outcome parameters. Further information on what type of information should be given, at what point, by whom, and, for example, whether it should it be graded between younger active, older active, and older sedentary patients is required. Whilst strong specific evidence may be lacking to recommend preoperative education and counselling, qualitative studies detailing the patient perspective highlight the importance of patients getting the right information and support (Specht et al. 2016). Preoperative education is also unlikely to cause harm and is delivered in differing forms within all established hip and knee replacement ERAS centers. This means that it is a strongly recommended component. Summary/recommendation—Preoperative patient education is recommended Evidence level—Low Recommendation grade—Strong

Preadmission patient optimization Optimizing preoperative risk factors, such as smoking, alcohol consumption, anemia, nutritional and metabolic status, and low physical activity, that may lead to complications or a prolonged length of stay, could potentially benefit a large proportion of hip and knee replacement patients (Hansen et al. 2012). In the ERAS specific literature, preoperative screening and intervention has helped reduce the number of patients with delayed recovery (Hansen et al. 2012). The effect of specific individual factors on ERAS outcomes is considered below. Smoking cessation The risk of an increased length of stay and other early postoperative complications for patients who smoke has been found to be reduced within established ERAS pathways (Jorgensen and Kehlet 2013). However, the association between current and former smoking and a substantially higher risk of postoperative complications and mortality post-surgery has level 1 evidence (Singh 2011). There is level 2 evidence across surgical studies to show that referral to a smoking cessation program 4 weeks preoperatively is associated with fewer complications, especially wound-related problems (Moller et al. 2002, Mills et al. 2011, Mak et al. 2014, Thomsen et al. 2014). Summary/recommendation—4 weeks or more smoking cessation is recommended before hip and knee replacement Evidence level—High Recommendation grade—Strong Alcohol A large retrospective study found that hip and knee replacement patients who misused alcohol had a longer length of stay and were more likely to have medical and surgery related complications (Best et al. 2015). However, whilst this risk of a longer length of stay and other early postoperative complications may be less for patients on exemplar hip and knee replacement ERAS pathways (Jorgensen and Kehlet 2013), in line with evidence from other surgical procedures and public health recommendations, alcohol cessation interventions before surgery should be utilized to reduce complications in patients with high alcohol intake (Oppedal et al. 2012). Summary/recommendation—Alcohol cessation programs are recommended before hip and knee replacement Evidence level—Low Recommendation grade—Strong Anemia Preoperative anemia is associated with an increased risk of transfusion, length of stay, infection, morbidity, and readmission rates (Kehlet 2013, Munoz et al. 2014), with the prevalence in elective hip and knee surgery reported as ranging from 15–39% (Spahn 2010).

RCTs and cohort studies of interventions such as preoperative iron or erythropoietin therapy and postoperative retransfusion of salvaged cells in general report a statistically significant and clinically relevant reduction in allogeneic blood transfusion (Munoz et al. 2014, Theusinger el al. 2014). Algorithm-led preoperative anemia screening in established ERAS centers has also been associated with reduced RBC transfusion, readmission, critical care admission, length of stay, and costs (Pujol-Nicolas et al. 2017). The cause of the anemia must also be investigated and managed. Summary/recommendations—Preoperative anemia should be identified, investigated, and corrected prior to hip and knee replacement. Evidence level—High Recommendation grade—Strong Preoperative physiotherapy Preoperative physiotherapy (including exercise programs) has been proposed as an intervention to expedite discharge (Carli and Zavorsky 2005). However, whilst preoperative physiotherapy may slightly improve early postoperative pain and function, the effects of the intervention in isolation remain too small to be considered clinically important and do not accelerate achievement of discharge criteria or shorten length of hospital stay (Wang et al. 2016). In addition, 1–2 day length of stay for unselected patients and outpatient surgery for hip and knee replacement has been achieved without preoperative physiotherapy (Gromov et al. 2017). Several reviews of RCTs of variable quality indicate little clinical benefit from preoperative physiotherapy (Wang et al. 2016, Moyer et al. 2017, Chen et al. 2018). There is emerging work examining the addition of nutrition therapy and psychological preparation to exercise regimes, in a concept called prehabilitation. These programs have shown improvements to recovery in general surgical procedures (Carli and Scheede-Bergdahl 2015). However, procedure specific studies in hip and knee replacement are needed before recommendation, and the effect may only be seen in specific patient groups, such as elderly and frail patients, patients with special needs or multiple comorbidities, patients with psychiatric diseases, and patients not currently able to achieve discharge on the day of surgery (Bandholm et al. 2018). Summary/recommendation—Current evidence does not support preoperative physiotherapy as an essential intervention Evidence level—Moderate (for not recommending) Recommendation grade—Strong Preoperative fasting Recent anesthetic guidelines indicate that the intake of clear fluids until 2 hours before surgery does not increase gastric content, reduce gastric fluid pH, or increase complication rates. Therefore, the intake of clear fluids until 2 hours before the

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induction of anesthesia as well as a 6-hour fast for solid food is recommended (Smith et al. 2011). To facilitate this, specific guidelines should be provided to each individual patient depending on their time of surgery and place on the operating list. Summary and recommendation—Intake of clear fluids until 2 hours before the induction of anesthesia, and a 6-hour fast for solid food is recommended Evidence level—Moderate Recommendation grade—Strong Preoperative carbohydrate treatment Carbohydrate loading has been shown to reduce insulin resistance in various surgical procedures including orthopedic surgery (Nygren 2006, Awad et al. 2013). Meta-analysis data suggest shorter length of stay after major abdominal surgery but not in hip and knee replacement (Smith et al. 2014). In hip replacement, some small RCTs show positive effects on preoperative hunger and nausea, and postoperative pain (Harsten et al. 2012) as well as on glucose metabolism (Soop et al. 2004) and insulin resistance (Nygren et al. 1999), while others show no effect (Ljunggren and Hahn 2012). Whilst carbohydrate loading may improve patient well-being perioperatively (Harsten et al. 2012), outpatient surgery (Gromov et al. 2017) and routine 1–2-day length of stay on unselected patients (Aasvang et al. 2015) is achievable without carbohydrate loading. Therefore, the current evidence does not support the routine use of carbohydrate loading; however, future research may elicit benefits for more elderly and frail patients, and patients with multiple comorbidities. Summary/recommendation—In hip and knee replacement carbohydrate loading may improve patient well-being and metabolism, but it has not been shown to accelerate the achievement of discharge criteria or reduce complications, and so it is not currently recommended as an essential routine intervention Evidence level—Moderate (for not recommending) Recommendation grade—Strong Pre-anesthetic medication Sedative or anxiolytic drugs may be used to promote patient comfort and/or facilitate the successful completion of technical procedures such as spinal anesthesia. However, their use is not universal and side effects may include postoperative sedation. There are minimal data available (for or against) to support the preoperative use of sedative or anxiolytic medication to reduce anxiety and accelerate the achievement of discharge criteria (Moiniche et al. 2002). If indicated, short-acting sedative drugs may be used by the clinician to facilitate successful completion of technical procedures, but routine administration of sedatives to reduce anxiety preoperatively should be avoided.

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Summary and recommendation—The routine administration of sedatives to reduce anxiety preoperatively is not recommended Evidence level—Low Recommendation grade—Strong Standardized anesthetic protocol A core component of hip and knee replacement ERAS pathways is a standardized anesthetic protocol. However, the components of these protocols differ, and a lack of methodological quality, reporting detail, and homogeneity of outcome measures makes direct comparison of techniques in ERAS settings difficult (Kehlet and Aasvang 2015). The use of general versus central neuraxial anesthesia In general, large multi-center cohorts of exemplar ERAS hip and knee replacement pathways favor neuraxial techniques over general anesthesia, and this change in practice has been at the core of established ERAS pathways (McDonald et al. 2012, Khan et al. 2014). Large epidemiological studies (albeit in non-ERAS set ups) show that central neuraxial anesthesia is independently associated with better outcomes compared with general anesthesia (Memtsoudis et al. 2013). Conversely, emerging research from 2 single-center RCTs in established ERAS centers has questioned whether the reduced cardiopulmonary and thromboembolic complications associated with neuraxial techniques (Harsten et al. 2013, 2015b are as relevant in an ERAS set up. A modern general anesthetic was compared with a traditional high dose of neuraxial anesthesia (bupivacaine 0.5% 3 mL), and no clinically relevant differences in functional recovery, length of stay, urinary complications, and mobilization were found. However, further studies are needed to compare modern general anesthetic and neuraxial anesthesia practices. General anesthesia may also reduce urinary bladder dysfunction, and rare but potentially severe neurological complications (Kehlet and Aasvang 2015). Future multi-center RCTs are required to further compare the safety issues and potential differences in postoperative morbidity between the 2 anesthetic techniques with specific emphasis on detailing the components of each technique, e.g., type of spinal. Summary and recommendations—Modern general anesthesia and neuraxial techniques may both be used as part of multimodal anesthetic regimes Evidence level—Moderate (modern general anesthesia), moderate (neuraxial techniques) Recommendation grade—Strong Spinal (intrathecal) opioids There has been considerable interest in the use of opioids as an addition to local anesthetic in spinal anesthesia for hip and knee replacement. Whilst spinal opioids have been shown to

lower pain scores and analgesic use (Cole et al. 2000), they increase the risk of urinary retention, pruritus, and respiratory depression (Gehling and Tryba 2009, Fernandez et al. 2014). Side effects may be avoided when lower doses are used, however, any superior effect on pain is then lost compared to alternative techniques such as local infiltrative analgesia (LIA) in knee replacement (Andersen and Kehlet 2014). Therefore, despite the analgesic benefits, the potential for unwanted side effects such as respiratory depression, postoperative nausea and vomiting, and pruritus does not support the routine use of spinal opioids. Summary and recommendations—Spinal opioids are not recommended for routine use Evidence level—Moderate Recommendation grade—Strong Epidurals Lumbar epidurals have been accepted as providing favorable analgesia postoperatively for lower limb surgery. However, there are potential side effects that delay recovery and these include hypotension, urinary retention, pruritus, and motor blockade. Also, serious complications such as permanent nerve damage are rare, but remain a concern (Choi et al. 2003, Rawal 2012). Alternative means of postoperative analgesia are now more effective and commonly used after uncomplicated knee or hip replacement. Summary and recommendations—Epidural analgesia is not recommended for routine use in hip and knee replacement because of the potential for adverse effects which delay recovery Evidence level—High (analgesic efficacy), moderate (negative safety and side-effect profile) Recommendation grade—Strong Use of local anesthetics for nerve blocks and infiltration analgesia Local infiltration analgesia (LIA) has an advantage over nerve blocks, because it produces no motor blockade. This can allow for earlier safe ambulation with a reduction in the side effects associated with both nerve blocks and epidural analgesia, where hypotension and urinary retention can cause additional problems. Concerns with LIA have been raised regarding potential risks of local anesthetic toxicity, wound healing, and infection (McCartney and McLeod 2011). However, several reports have demonstrated that toxic levels do not appear to be reached using techniques described (Affas et al. 2011, Brydone et al. 2015). Several case series with long-term follow-up also demonstrate no increased risk of joint infection when using LIA compared with previous published data (Malviya et al. 2011, McDonald et al. 2012, 2016).

A review of the literature on LIA in total hip and knee replacement concludes that there is little evidence to support using this technique in hip replacement either intraoperatively or with a postoperative wound infusion catheter technique, as long as multimodal, oral non-opioid analgesia is given (Andersen and Kehlet 2014). For knee replacement, metaanalysis data support the intraoperative use of LIA (Yun et al. 2015), but not wound catheter administration postoperatively (Andersen and Kehlet 2014). There are no firm data suggesting one method of infiltration or a specific combination of drugs and dosage over another in LIA. There are several nerve block techniques that may be used. Femoral nerve blockade has been compared and reviewed against epidurals and PCAs with advantages such as reducing the risk of hypotension and the use of opioids (Fowler et al. 2008, Paul et al. 2010, Chan et al. 2014). However, the main problem is its negative effect on mobilization (Kandasami et al. 2009, Ilfeld et al. 2010, Sharma et al. 2010). Whilst femoral nerve block is an effective analgesic technique following knee replacement, concerns remain regarding the impact on muscle function and early mobilization, with an increased risk of falls (Sharma et al. 2010). The Hunter Canal block is an alternative to the femoral nerve block and is proposed to offer better preserved quadriceps muscle strength and mobilization ability in the 48 hours post-surgery (Jaeger et al. 2013, Perlas et al. 2013). However, conclusive data showing superiority has not been proven in established ERAS pathways. The addition of a sciatic nerve block to the postoperative analgesic regimen following hip and knee replacement has not been found to provide substantial benefit (Paul et al. 2010) over any of the other alternative local techniques or the use of no local technique when assessed as part of a multimodal opioid-sparing analgesic regime. Summary and recommendations—LIA is recommended for knee replacement but not for hip replacement within a multi-modal opioid sparing regime. Nerve block techniques provide equal analgesia; however, when compared with LIA prolonged motor blockade may limit early and safe mobilization. Nerve blocks are therefore not recommended as an essential ERAS component Evidence level for LIA in knee replacement—High Recommendation grade—Strong Postoperative nausea and vomiting Postoperative nausea and vomiting (PONV) is distressing for patients and can lead to notable patient morbidity and an associated prolonged length of hospital stay. In general, female gender, a past history of motion sickness or PONV, and being a non-smoker are all risk factors for PONV (Apfel et al. 1999). Several classes of first-line medications are available: dopamine (D2) antagonists (e.g., droperidol), serotonin (5HT3)

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antagonists (e.g., ondansetron), and corticosteroids (e.g., dexamethasone). Studies have shown that combinations of the drugs enhance their efficacy (Eberhart et al. 2002, Apfel et al. 2004). Therefore, in patients with 1 to 2 risk factors a combination of 2 drugs is often recommended, and, in patients with higher risk, three drugs in combination. If rescue treatment is required despite prophylaxis, drugs from classes not yet used should be employed (Gan et al. 2014). Summary and recommendation—Evidence supports the use of screening for and multimodal PONV prophylaxis and treatment for patients undergoing hip and knee replacement Evidence level—Moderate Recommendation grade—Strong Prevention of perioperative blood loss—tranexamic acid Hip and knee replacement has been associated with pronounced blood loss (Liu et al. 2011), which, traditionally, has been healed by blood transfusion. However, its use carries risks including transfusion reaction, disease transmission, coagulopathy, renal failure, deep infection, and death (Juelsgaard et al. 2001). Studies are also required to evaluate the optimal transfusion triggers, especially in high-risk patients, where a lack of data has prevented inclusion in recent transfusion guidelines (Munoz et al. 2017, 2018). Historically, it has been shown to add to the cost of an operation and increase hospital stay (Newman et al. 1997). Decreasing blood loss and thus need for transfusion at the intraoperative stage may be achieved using combined local and systemic tranexamic acid, as this stops the breakdown of fibrin clot by inhibiting activation of plasminogen, plasmin, and tissue plasminogen activator. Studies have found it to be both efficient and safe (Rajesparan et al. 2009, Husted et al. 2010, 2014, Henry et al. 2011) despite previous concerns of an increased risk of venous thromboembolic events; and recent RCTs and metaanalyses support combined systemic and/or intra-articular administration (Nielsen et al. 2016, Shang et al. 2016, Zhang et al. 2017). Summary and recommendation—Tranexamic acid is recommended to reduce perioperative blood loss and the requirement for postoperative allogenic blood transfusion Evidence level—High Recommendation grade—Strong Multimodal analgesia Combining oral analgesics of different classes and with different modes of action has been shown to yield additive pain relief (Ong et al. 2010). This is an effective way of limiting the use of opioids perioperatively and thereby avoiding their wellknown side effects. In addition, prolonged opioid use in and after surgery is a leading risk factor for longer term addiction

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and so should be avoided (Clarke et al. 2014). The use of multimodal non-opioid oral analgesia is one of the cornerstones of exemplar ERAS hip and knee replacement pathways (McDonald et al. 2012, Khan et al. 2014). Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay. Optimal pain management is a prerequisite of ERAS and alternative analgesic drugs (such as glucocorticoids and ketamine) have been described for hip and knee replacement. Simple systemic techniques such as the addition of a highdose preoperative glucocorticoid to multimodal regimes have been shown to be safe and effective in knee and hip replacement (Mathiesen et al. 2008, Lunn et al. 2011). However, there is a need for further data on dosage use in hip replacement patients and in at-risk groups such as high-pain responders. Paracetamol Paracetamol is regularly prescribed perioperatively and within ERAS pathways. It reduces pain and morphine consumption over a 24-hour period in patients undergoing both hip and knee replacement (Sinatra et al. 2005). Although not specific to hip and knee replacement, paracetamol has been shown to reduce PONV if given prophylactically before surgery or arrival in the postoperative care unit and this correlated with a reduction in pain scores but not postoperative opioid use (Apfel et al. 2013). Paracetamol can reduce acute postoperative pain, has a favorable side-effect profile, and is a core component of multimodal analgesia in all exemplar hip and knee ERAS pathways. Summary and recommendations—The routine use of paracetamol is recommended Evidence level—Moderate Recommendation grade—Strong Non-steroidal anti-inflammatory drugs (NSAIDs) Studies have shown that NSAIDs decrease pain and reduce supplemental analgesic (opioid) use following hip and knee replacement (Buvanendran et al. 2003, Huang et al. 2008). Level 1 evidence of postoperative analgesia following knee replacement determined that NSAIDs should be recommended for their analgesic and opioid-sparing effects (Fischer et al. 2008). NSAIDs are a central tenant of multimodal analgesia in exemplar hip and knee replacement ERAS pathways, and there is evidence from a randomized controlled trial that indicates no increase in perioperative blood loss, and accompanying reduction in pain (Meunier et al. 2007. However, individual patient risk should be assessed including the potential for bleeding complications, gastroduodenal ulcer history, cardiovascular morbidity, aspirin-sensitive asthma, and renal and hepatic function. Due to their side-effect profile, judicious use and appropriate patient selection is required. It should also be noted that the avoidance of NSAIDs postoperatively due to the risk of prosthetic loosening is an unsubstantiated fear that prevents patients from receiving evidence-based multimodal

analgesia including NSAIDs (Husted et al. 2014). Additionally, it is important to avoid inappropriate use of NSAIDs in patients with pre-existing kidney disease (Bjerregaard et al. 2016b). Summary and recommendations—The routine use of NSAIDS is recommended for patients without contraindications Evidence level—High Recommendation grade—Strong Gabapentinoids Several meta-analyses have suggested that gabapentinoids may reduce postoperative opioid consumption, pruritus, and nausea following total hip and knee replacement surgery, and improve sleep, and indeed gabapentinoids have been included in exemplar peer-reviewed ERAS cohorts (Malviya et al. 2011). However, there is a lack of evidence as to whether such drugs reduce pain (Lunn et al. 2015, Han et al. 2016a, 2016b, Hamilton et al. 2016, Zhai et al. 2016, Mao et al. 2016, Petersen et al. 2018b), and so gabapentinoids are not recommended. Summary and recommendation—Gabapentinoids are not currently recommended as an adjunct in a multimodal analgesia regime although further studies are indicated Evidence level—Moderate (for not recommending) Recommendation grade—Strong The use of supplemental opioid analgesia ERAS programs emphasize the desire to minimize the use of opioids postoperatively and utilize alternative forms of analgesia. Nevertheless, their use when required is routinely reported in exemplar ERAS centers (Husted 2012). The efficacy of opioids in reducing pain scores after surgery is well established. However, concerns remain regarding side effects including drowsiness, respiratory depression, nausea and vomiting, pruritus, urinary retention, and potential risk of long-term addiction. Currently, opioid analgesics are used if needed within the immediate postoperative period. They can be used to enable a smooth transition from peripheral techniques (e.g., LIA or PNBs) to non-opioid analgesia. The choice of opioid and method of delivery has been debated. Several studies investigated the use of controlled-release (CR) oxycodone following hip and knee replacement. Equivalency of analgesic effect has been demonstrated (Rothwell et al. 2011), and CR oxycodone has been associated with shorter hospital length of stay and better tolerance compared with PCA regimes (de Beer et al. 2005). Furthermore, by removing the required IV access and connection to a PCA pump, patients are more readily able to function independently (e.g., dress/shower/ambulate) and achieve the desired discharge criteria, which reduces the need for supervision to assist with movement of equipment that can adequately be replaced with oral medication. Therefore,

it is strongly recommended that the use of such pumps is limited in the routine arthroplasty surgical population. Summary and recommendation—ERAS programs seek to minimize the use of opioids. However, opioids such as oxycodone may be used when required as part of a multimodal approach Evidence level—High Recommendation grade—Strong Maintaining normothermia The National Institute for Clinical Excellence (NICE) recommends the pre-warming of patients and to maintain the active warming of all adults undergoing surgery throughout the intraoperative phase (NICE 2016). Multiple series suggest that normothermia should be targeted as part of the anesthetic care of hip and knee replacement patients. There are many methods described to conserve body temperature, including pre-warming and humidification of anesthetic gases, warming IV and irrigation fluids, and forced air-warming blankets and devices. However, the use of forced air-warming is not recommended as there is evidence that this is associated with an increased risk of infection (McGovern et al. 2011, Koc et al. 2017). In addition, the ambient temperature should be at least 21°C while the patient is exposed prior to active warming starting (NICE 2016). Summary and recommendations—Normal body temperature should be maintained peri- and postoperatively through pre-warming and the active warming of patients intraoperatively Evidence level—High Recommendation grade—Strong Antimicrobial prophylaxis Infection after hip and knee replacement is a serious complication that can be difficult to treat (Zimmerli et al. 2004). There is currently no universal internationally defined guideline for antibiotic/antiseptic prophylaxis for hip and knee replacement, with differing national and local policies in existence (Voigt et al. 2015). However, a recent consensus paper does present recommendations for type, timing, dosing, and repetition of antimicrobials (Aboltins et al. 2019). In a meta-analysis of total joint arthroplasty, antibiotic prophylaxis reduced the absolute risk of wound infection by 8% and the relative risk by 81% compared with no prophylaxis (p < 0.001). No other comparison showed a statistically significant difference in clinical effect (AlBuhairan et al. 2008). Antibiotic-loaded bone cement may reduce infection rates after joint replacement. The evidence is more robust in hip compared with knee replacement (Engesaeteret al. 2006, Dale et al. 2009, Bohm et al. 2014). A recent systematic review and meta-analysis concluded that there is a paucity of well-con-

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ducted trials, and evidence of the protective effect is insufficient to recommend routine use in knee replacement (Hinarejos et al. 2015). Additional research into the role of antibiotic-loaded bone cement may also address concerns regarding patient safety, risk of antibiotic-resistant microorganisms, and increased cost. Summary and recommendations—Patients should receive systemic antimicrobial prophylaxis in accordance with local policy and availability Evidence level—Moderate Recommendation grade—Strong Antithrombotic prophylaxis treatment Hip and knee replacement may be associated with deep venous thrombosis (DVT) and pulmonary embolism (PE), which can lead to post-thrombotic syndrome (PTS) or death (Husted et al. 2010). Evidence-based guidelines from the American College of Chest Physicians (ACCP) for DVT prophylaxis (FalckYtter et al. 2012) suggest a minimum of 10 to 14 days’ antithrombotic prophylactic use for patients undergoing hip and knee replacement. Comparatively, national guidelines, such as those made by NICE in the UK, advocate early mobilization, and the use of chemoprophylaxis for 28 days for hip replacement and 14 days for knee replacement postoperatively (NICE 2018). However, many of the data behind these recommendations are from older studies with traditional care pathways with less focus on early mobilization. More recent guidelines from the European Society of Anaesthesiology (Venclauskas et al. 2018) focus on day surgery and ERAS pathways, and take and provide recommendations for thromboprophylaxis in ambulatory or fast-track surgery derived from personal and procedure risk factors. This tailored approach is consistent with the protocols presented in the large Danish observational studies of hip and knee replacement patients on ERAS pathways, where the incidence of thromboembolic events has been found to be substantially lower compared with historical figures. This has led to the abandonment of routine prophylaxis in favor of selective treatment in Denmark (Husted et al. 2010, Jorgensen et al. 2013, Jorgensen and Kehlet 2016). A subsequent recent large observational study on 17,582 patients has confirmed the safety of in-hospital only prophylaxis for those patients staying less than 5 days in hospital, and highlighted that further studies are needed to define optimal prophylaxis for highrisk patients and those who stay in hospital longer than 5 days (Petersen et al. 2018a). Summary and recommendations—Patients should be mobilized as soon as possible post-surgery and receive antithrombotic prophylaxis treatment in accordance with local policy Evidence level—Moderate Recommendation grade—Strong

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Perioperative surgical factors Surgical technique There is a multitude of literature reporting that the use of specific surgical techniques and approaches can accelerate the achievement of discharge criteria. Studies are conflicting and there is no strong evidence to illustrate the isolated effect of any one approach against another (Aggarwal et al. 2019, Jia et al. 2019). In a comprehensively reported and inclusive cohort series of ERAS outpatient hip and knee replacement surgery, all hip replacements were performed using a standard posterolateral approach with standard prosthesis, and all knee replacements were performed with a standard medial parapatellar approach with a standard prosthesis (Gromov et al. 2017). However, for example other studies on hip replacement have demonstrated success in same day discharge when adopting the direct anterior approach (Goyal et al. 2017, Berend et al. 2018), and conversely the posterior approach has been found to have a lower overall complication rate compared to the anterior approach (Aggarwal et al. 2019). Therefore, at present insufficient evidence exists to recommend that one surgical technique (type of approach, use of a minimally invasive technique, prosthesis choice, or use of computer navigation or robot) over another will independently effect achievement of discharge criteria within an ERAS set-up. Summary and recommendation—There is no conclusive evidence that choice of surgical approach accelerates the achievement of discharge criteria. Therefore no recommendation can be given Evidence level—High Recommendation grade—Strong Use of tourniquet for knee replacement Tourniquet use in knee replacement is used with the aim to reduce bleeding. However, studies show that it does not reduce total blood loss and its use may cause swelling and impair early functional recovery (Li et al. 2009, Smith and Hing 2010). Studies have also found an increased risk of thrombosis and wound complication with tourniquet use, and no evidence of a better quality of cementation (Prasad et al. 2007, Husted et al. 2014, Zhang et al. 2014, Liu et al. 2017). No difference has been found in preserving knee-extension strength between surgeries with or without a tourniquet for patients on an ERAS pathway (Harsten et al. 2015a); although studies on standard care pathways have found differences in strength after surgery in favor of no tourniquet (Dennis et al. 2016, Guler et al. 2016) . Summary and recommendation—The routine use of a tourniquet is not recommended Evidence level—Moderate Recommendation grade—Strong Drainage Level 1 evidence does not support the routine use of drains

because they do not have any positive effect on the aims of their intended use such as for wound infections, hematomas, and healing complications (Parker et al. 2007, Quinn et al. 2015, Zhang et al. 2018). They have not been used in proven and welldocumented hip and knee ERAS pathways (Husted et al. 2014), with no increase in complications, and their use may in fact increase blood loss and transfusion rate (Kelly et al. 2014). Summary and recommendation—The routine use of surgical drains is not recommended for hip and knee replacement Evidence level—Moderate Recommendation grade—Strong Perioperative fluid management Recent advances in perioperative care have reduced the length of time that patients are nil by mouth prior to and following surgery. This has enabled rapid return of gastrointestinal function, particularly after major abdominal operations (NICE 2017). Maintaining fluid balance is, therefore, a prominent component of general surgical ERAS pathways. However, due to limited intraoperative blood and fluid loss and the early intake of postoperative oral fluids, the term “effective fluid management” remains ambiguous in lower limb primary replacement. We are aware of only 1 study on fluid management on an ERAS pathway for total knee replacement (Holte et al. 2007), which found that liberal fluid management, when compared with restrictive fluid management, may lead to hypercoagulability and a reduction in vomiting, with no differences found for postoperative hypoxemia, exercise capacity, recovery variables, or length of stay. There have been limited investigation of intraoperative techniques such as goal directed fluid therapy in hip and knee replacement. However, large observational studies in ERAS hip and knee settings have highlighted that acute kidney injury is most often due to pre-existing kidney disease and postoperative hypotension, indicating that an increased focus on perioperative fluid management is important in the perioperative care of patients with pre-existing kidney disease (Bjerregaard et al. 2016b). Care should be taken to detect and avoid electrolyte imbalance including hyponatremia (Sah 2014). Intravenous fluids should be judiciously used with the aim of providing routine maintenance fluids to meet insensible losses, to maintain normal status of body fluid compartments and enable renal excretion of waste products (NICE 2017). Routine maintenance provision should nearly always be a short-term measure and postoperative intravenous fluids discouraged in favor of early oral intake. Summary and recommendation—It is recommended that intravenous fluids should be used judiciously and postoperative intravenous fluids discouraged in favor of early oral intake Evidence level—Moderate Recommendation grade—Strong

Urinary catheter use Urinary catheters have been used routinely for longer surgical procedures to monitor urinary output and guide fluid resuscitation (Huang et al. 2015). However, their use has been questioned due to improved blood-saving and anesthetic practices. Studies have found no benefit in the use of an indwelling catheter when compared with no catheter or intermittent catheterization (Balderi and Carli 2010, Huang et al. 2015). Additionally, a low incidence of serious renal and urological complications has been found following hip and knee replacement surgery for patients on an ERAS pathway (Bjerregaard et al. 2016a). Therefore, the evidence indicates that the routine use of urinary catheters should be avoided. Postoperatively, a large RCT performed in an ERAS pathway has also demonstrated that a catheterization threshold of 80 0mL compared with 500 mL significantly reduced the need for postoperative urinary catheterization, without increasing urological complications (Bjerregaard et al. 2016b). Summary and recommendation—The routine use of urinary catheters is not recommended and when used they should be removed as soon as the patient is able to void, ideally within 24 hours after completion of surgery. A catheterization threshold of 800 mL should be used to reduce the need for postoperative urinary catheterization Evidence level—Moderate Recommendation grade—Strong Postoperative nutritional care No studies have investigated the direct association of early feeding or postoperative nutritional supplementation with the accelerated achievement of discharge criteria. However, return to normal food intake is considered an essential component of ERAS protocols in order to achieve return to normal behaviors. Early return to normal diet is a central component of all exemplar ERAS pathways, with units encouraging patients to eat and drink as soon as they feel able. Summary and recommendation—An early return to normal diet is recommended and should be promoted Evidence level—Low Recommendation grade—Strong Early mobilization Patients should be mobilized as soon as possible following surgery. Outpatient surgery is now established for 13–15% of unselected patients, and patients are routinely discharged on the first and second postoperative day (Gromov et al. 2017) establishing early mobilization as essential. This is supported by level 1 evidence that early mobilization reduces length of stay (Guerra et al. 2015). This counteracts the long-recog-

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nized adverse physiological effects associated with prolonged bed rest such as increased insulin resistance, muscle atrophy, reduced pulmonary function, impaired tissue oxygenation, and increased risk of thromboembolism (Harper and Lyles 1988). Summary and recommendation—Patients should be mobilized as early as they are able to in order in order to facilitate early achievement of discharge criteria Evidence level—Strong Recommendation grade—Strong Criteria-based discharge A feature of exemplar hip and knee replacement ERAS pathways is that patients are discharged directly to their home and that objective discharge criteria are used. These criteria clearly define the requirements for going home from hospital, and are typified by including elements such as the ability to dress independently, the ability to get in and out of bed, the ability to sit and rise from a chair/toilet, the ability to be independent with personal care, and independent mobilization with walker/ crutches, and the ability to walk > 70 m with crutches (Husted et al. 2011, Scott et al. 2013). Summary and recommendation—Objective discharge criteria should be used to facilitate patient discharge directly to their home Evidence level—Low Recommendation grade—Strong Continuous improvement and audit The continual review of clinical practice and outcomes is a critical component of ongoing quality improvement in healthcare. Experience from other ERAS procedures indicates that the relative effectiveness of audit and feedback is likely to be greater when baseline adherence to recommended practice is low (Gustafsson et al. 2011). Compliance with ERAS processes has been found to be lower than expected in other procedures, with large studies in colorectal surgery reporting compliance levels of around 60% (ERAS Compliance Group 2015). Therefore, an audit process that incorporates data collection, and the reviewing of one’s practices against ongoing gathering of evidence (performed either in-house or by others) is an important factor in ERAS pathways (Ljungqvist et al. 2017). Experience from other procedures indicates that the 4 main roles of an internal or external audit cycle are to: (1) measure clinical outcomes (such as length of stay, readmissions, and complications); (2) measure non-clinical outcomes (such as economics, and patient satisfaction/experience); (3) measure process compliance with ERAS components; and (4) maintain the concept as dynamically as possible (including new available evidence and modifying the multimodal concept).

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Table 3. Summary of recommended interventions for the perioperative care of hip and knee replacement Evidence Number Item Recommendation level

Recommendation grade

1 Preoperative information, Patients should routinely receive preoperative education Low education and counseling 2 Preoperative optimization 4 weeks’ or more smoking cessation is recommended prior to surgery. Smoking: High Alcohol cessation programs are recommended for alcohol abusers Alcohol: Low Anemia should be actively identified, investigated, and corrected High preoperatively 3 Preoperative fasting Clear fluids should be allowed up to 2 h and solids up to 6 h hours Moderate prior to induction of anesthesia 4 Standard anesthetic protocol General anesthesia and neuraxial techniques may both be used as General part of multimodal anesthetic regimes anesthesia: moderate neuraxial techniques: Moderate 5 Use of local anesthetics for Within a multimodal opioid-sparing analgesic regimen, the routine LIA in knee infiltration analgesia and use of LIA is recommended for knee replacement but not for hip replacement: nerve blocks replacement High Nerve block techniques have not shown clinical superiority over LIA 6 Postoperative nausea and Patients should be screened for and given multimodal PONV Moderate vomiting prophylaxis and treatment 7 Prevention of perioperative Tranexamic acid is recommended to reduce perioperative blood High blood loss loss and the requirement for postoperative allogenic blood transfusion 8 Perioperative oral analgesia A multimodal opioid-sparing approach to analgesia should be adopted Paracetamol: The routine use of paracetamol and NSAIDs is recommended for Moderate patients without contraindications NSAIDS: High 9 Maintaining normothermia Normal body temperature should be maintained peri- and postoperatively High 10 Antimicrobial prophylaxis Patients should receive systemic antimicrobial prophylaxis Moderate 11 Antithrombotic prophylaxis Patients are at increased risk of VTE and should undergo pharmacologic Moderate treatment and mechanical prophylaxis in line with local policy 12 Perioperative surgical factors There is no conclusive evidence that choice of surgical approach High accelerates the achievement of discharge criteria Therefore no recommendation can be given 13 Perioperative fluid management Fluid balance should be maintained to avoid over- and under-hydration Moderate 14 Postoperative nutritional care An early return to normal diet should be promoted Low 15 Early mobilization Patients should be mobilized as early as they are able in order to Moderate facilitate early achievement of discharge criteria 16 Criteria-based discharge Team-based functional discharge criteria should be used to facilitate Low patient discharge directly to their home 17 Continuous improvement Routine internal and/or external audit of process measures, clinical Low and audit outcomes, cost effectiveness, patient satisfaction/experience, and changes to the pathway is recommended

Summary and recommendation—Routine internal and/or external audit of process measures, clinical outcomes, costeffectiveness, patient satisfaction/experience, and changes to the pathway is recommended Evidence level—Low Recommendation grade—Strong

Comment This document outlines the recommendations of the ERAS Society for the perioperative management of patients undergoing hip and knee replacement surgery, and summary details

Strong Strong Strong

Strong Strong

Strong

Strong Strong Strong Strong Strong Strong Strong Strong

Strong Strong Strong Strong Strong

are provided in Table 3. It is based on the best available evidence as judged by these authors, which demonstrates that when using an ERAS pathway unselected patients can be routinely discharged from hospital 0–3 days following surgery, with no increased effect on morbidity or mortality (Aasvang et al. 2015, Gromov et al. 2017). These guidelines are an important document in summarizing the large volume of heterogeneous studies across all ERAS components within hip and knee replacement surgery. The aim is to provide a starting point for implementation for teams new to ERAS, and as a point of reflection for experienced ERAS teams to examine their current practice. These

guidelines, and the testing of their implementation, as has been performed in other ERAS procedures, will hopefully allow us to consolidate consensus within the evidence base, and generate new evidence, through systematic prospective data collection and through clinical trials. Future work should focus on reaching the goal of the “pain and risk free” hip and knee replacement. In order to do this, we will need to better understand the pathophysiological mechanisms of recovery, and the potential to optimize postdischarge functional outcomes (Wainwright and Kehlet 2019). This will be important because, for some of the ERAS components, there is a strong need for properly designed randomized controlled studies that are sufficiently powered, performed in ERAS settings, and that allow for discrimination between outcome parameters. With length of stay now reduced to between 0 and 3 days, post-discharge markers of recovery will become increasing important in order to discriminate interventions. More specifically, work is still required in order to understand how to reduce the inflammatory response postoperatively; how to further reduce pain; how to reduce impairment of physical activity and improve function quicker postoperatively; how to better identify patients at high risk of complications owing to psychiatric disorders, chronic renal failure, and orthostatic intolerance; anemia and transfusion thresholds; postoperative urine retention and urinary bladder catheterization; and how to improve sleep (Wainwright and Kehlet 2019). Intertwined with this will be the need for further research on the feasibility of same-day surgery, and the type (e.g., exercise therapy, cryotherapy, electro-neuromuscular stimulation), timing and duration of physiotherapy post-discharge (Bandholm et al. 2018, Wainwright and Kehlet 2019). Funding This study received no funding and was completed independently. Conflicts of interest TW—Consulting contracts with: Medtronic, ZimmerBiomet. Department/research funding from: ZimmerBiomet, Stryker, Lima Corporate. MG—No relevant conflicts of interest. DM—No relevant conflicts of interest. RM—Consulting contracts with: Stryker, ZimmerBiomet. Department/research funding from: ZimmerBiomet, Stryker, Lima Corporate. MR—Speakers’ Bureau: Heraeus, ZimmerBiomet, Stryker. Research funding: Heraeus Medical GMHB, ZimmerBiomet, 3M, Curetis GMHB, Vifor Pharma, Schuelke. Other financial/material support: Stryker, ZimmerBiomet, Heraeus, Biocomposites, Aquilant, Depuy, Smith & Nephew, Bone and Joint Infection Registry. OS—No relevant conflicts of interest. PY—Consulting contracts with: DepuySynthes, Zimmer, Global, Palacos, Corin, Matortho. Designer for: MatOrtho,

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Global Orthopaedics, Zimmer, Synthes, Corin. Department/research funding from: DepuySynthes, Zimmer, Global, Smith & Nephew, Stryker, Matortho. OL—Co-founder of and Chairman of the Executive Committee of the ERAS Society. Founder and shareholder in Encare AB, Advisor to Nutricia, NL; Advanced Medical Nutrition, Can. Speaker’s honoraria and travel support from Nutricia, Fresenius-kabi, BBraun, Merck, Medtronic, and Baxter.

TW conceived and designed the study. TW, MG, OL, DM, RGM, MR, OS, and PY all contributed to data collection and manuscript writing. All authors provided critical input on the manuscript. Acta thanks Henrik Husted and Stephan Vehmeijer for help with peer review of this study.

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Only 8% of major preventable adverse events after hip arthroplasty are filed as claims: a Swedish multi-center cohort study on 1,998 patients Martin MAGNÉLI 1, Maria UNBECK 2, Bodil SAMUELSSON 1, Cecilia ROGMARK 3, Ola ROLFSON 4, Max GORDON 1, and Olof SKÖLDENBERG 1 1 Department

of Clinical Sciences at Danderyd Hospital, Division of Orthopaedics, Karolinska Institutet, Stockholm; 2 Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm; 3 Department of Clinical Sciences Malmö, Lund University Clinical and Molecular Osteoporosis Research Unit, Malmö; 4 Department of Orthopaedics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden Correspondence: martin.j.magneli@gmail.com Submitted 2018-09-13. Accepted 2019-09-21

Background and purpose — Hip arthroplasty is one of the most performed surgeries in Sweden, and the rate of adverse events (AEs) is fairly high. All patients in publicly financed healthcare in Sweden are insured by the Mutual Insurance Company of Swedish County Councils (Löf). We assessed the proportion of patients that sustained a major preventable AE and filed an AE claim to Löf. Patients and methods — We performed retrospective record review using the Global Trigger Tool to identify AEs in a Swedish multi-center cohort consisting of 1,998 patients with a total or hemi hip arthroplasty. We compared the major preventable AEs with all patient-reported claims to Löf from the same cohort and calculated the proportion of filed claims. Results — We found 1,066 major preventable AEs in 744 patients. Löf received 62 claims for these AEs, resulting in a claim proportion of 8%. 58 of the 62 claims were accepted by Löf and received compensation. The claim proportion was 13% for the elective patients and 0.3% for the acute patients. The most common AE for filing a claim was periprosthetic joint infection; of the 150 infections found 37 were claimed. Interpretation — The proportion of filed claims for major preventable AEs is very low, even for obvious and serious AEs such as periprosthetic joint infection.

In Sweden, cemented total hip arthroplasty was the 7th most performed surgery in 2016 (SPOR 2016), and over 20,000 are performed every year (Kärrholm et al. 2017). High-volume surgeries may generate a considerable number of adverse events (AEs). The AE rate following elective total hip arthroplasty ranges from 4.1% to 10% (Huddleston et al. 2012, Bohl et al. 2016, Richards et al. 2018). The Swedish Patient Injury Act states that all healthcare providers are obliged to have insurance covering AEs (Swedish Parliament 2010). Additionally, providers are obliged to urgently inform patients who sustain an AE about their right to claim compensation (Swedish Parliament 2010). All publicly financed Swedish healthcare and most privately financed, regardless of whether the provider is public or private, is insured by Löf (“Landstingens Ömsesidiga Försäkringsbolag”, “the Mutual Insurance Company of Swedish County Councils”). Patients who sustain an AE have the right to file a claim to Löf. The claim is assessed by experts at Löf and if the insurance terms are fulfilled, the patient will receive compensation. It is a non-fault insurance system, and there is no legal consequence for either the individual caregiver, or the healthcare provider. Orthopedics is the specialty with the largest amount (28%, n = 1,492) of accepted AEs that received compensation in 2016 (Löf 2016). Considering the high number of hip arthroplasties and the incidence of AEs, there is reason to suspect that too few patients file insurance claims after AEs. We assessed the proportion of patients who sustained a major preventable AE and filed a claim for compensation to Löf.

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Methods Study design This is a national multi-center cohort study on data from medical records, insurance records and register data. It is part of a larger study on AEs after hip arthroplasty named VARA (Validation of Register Data after Hip Arthroplasty) (Magnéli et al. 2019). The exposure was major preventable AEs following hip arthroplasty within 90 days and the outcome was accepted claims to Löf. Setting All patients aged 18 and older who received either a hemior total hip arthroplasty in 1 of 4 major county councils in Sweden (Stockholm, Skåne, Västra Götaland, and Västerbotten) during 2009–2011 and reported to the Swedish Hip Arthroplasty Register (SHAR) were eligible for inclusion in this study. The surgeries were performed in 24 different hospitals (6 university hospitals, 5 central county hospitals, 7 county hospitals, and 6 private hospitals reimbursed by the county councils). Almost all hip arthroplasties in Sweden are publicly financed and the patients are thereby insured by Löf. We included patients with both elective and acute surgeries. Study size and participants The sample size was calculated for the VARA project, a project designed to validate a Swedish instrument for measuring AEs after hip arthroplasty. We used a weighted sample for increasing the chance of selecting patients with an AE, thereby avoiding excess record review. 20 different selection groups for acute and elective arthroplasties were created as follows (Table 1, see Supplementary data). 1. We constructed 3 arbitrary groups dividing patients on lengths of primary stay in percentiles divided as 0–55%, 56–80%, and 81–100%. The 3 groups were further divided based on whether there was an ICD-10 code (WHO 2017) indicating an AE in the National Patient Register (NPR) (Table 2, see Supplementary data). Overall, 6 groups were generated. 2. A selection was made for patients who had readmissions in the NPR. The readmission groups were divided in readmission within 2–30 days and within 31–90 days after surgery. The 2 groups were further divided based on whether there was an ICD-10 code indicating an AE in the NPR, generating 4 groups. This sampling process was repeated for both acute and elective patients, which resulted in 20 selection groups. Data sources We recruited the study cohort from the SHAR that also supplied data on the primary surgeries. The completeness of the register is approximately 98% (Kärrholm et al. 2017). We received the dates and type of clinic on all admissions and unplanned outpatient visits at the hospitals from the NPR.

This data were used to track all admissions to be reviewed. The NPR has had total national coverage since 1987 (Ludvigsson et al. 2011, Socialstyrelsen 2016). We linked data on the primary surgery from the SHAR to the NPR using the Swedish personal identity number as a unique identifier. With the crossed-linked dataset, we generated a timeline for each patient and tracked all their admissions and acute outpatient visits at hospitals across Sweden. Medical records from the different hospitals were either reviewed on location in various electronic medical record systems or obtained on paper copies. We reviewed claims data on location at Löf using the organization’s claims handling software. Definitions, inclusion and exclusion criteria We defined the index admission as the time from patient arrival on the ward to discharge from the ward or the following geriatric or rehabilitation ward. We defined an AE as suffering, physical harm or disease, and death related to the index admission that was not an inevitable consequence of the patient’s disease or treatment. A preventable AE was an event that could have been prevented if adequate actions had been taken during the patient’s contact with healthcare (SFS 2010:659, Swedish Parliament 2010). AEs related to both acts of omission and commission were included. The inclusion period for all AEs was from the index admission to 90 days postoperatively. We excluded all planned outpatient care and primary care visits. We reviewed 5,422 admissions in 69 hospitals. We included only AEs that were related to index admission. We excluded AEs that were caused during the care for other AEs. Review process The review process has been described in detail in a previous article (Magnéli et al. 2019). We used the Swedish adaptation of the Global Trigger Tool (GTT) (Griffin and Resar 2009), called the Markörbaserad journalgranskning (Sveriges Kommuner och Landsting 2012), a retrospective record review method for identifying AEs. The GTT is a well-studied method that identifies more AEs than other methods (Naessens et al. 2009, Classen et al. 2011). A study-specific manual was created and included all alterations for the GTT. GTT consists of a 2-stage review process. The first reviewers screened the record searches for any of the 38 predefined triggers indicating a potential AE. In stage 2 the reviewers performed an assessment of potential AEs identified via the triggers and deemed whether they met the inclusion criteria of an AE. The identified potential AEs were assessed regarding causality using a 4-point Likert scale and only included the AEs that were assessed to be caused by the healthcare (those classified as 3 or 4). The severity of the AEs was assessed and classified using a version of the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) index (National Coordinating Council for Medication Error and Reporting and Prevention 2001). We included categories

E–I. AEs that scored 3 or 4 on the preventability 4-point Likert scale were defined as preventable AEs. The preventable AEs that scored F or more on the NCC MERP index were defined as major preventable AEs. We performed double review of 6% of the records to assess the agreement of the reviewers in the stage 1 review. We evaluated whether at least 1 trigger or potential AE was identified in the record, whether the record was to be forwarded to secondary review, whether they found the same specific event, and whether this event was a potential AE. Patient insurance According to the Patient Injury Act (Swedish Parliament 2010), the patient has the right to receive compensation if there is predominant probability that the AE was caused by 1 of the following: 1. examination, care, treatment, or similar action provided that the injury could be avoided either by another embodiment of the chosen procedure or by selecting another available procedure which, according to a retrospective assessment, would have satisfied the need for care in a less risky manner; 2. malfunction of a medical device or a medical device used for the examination, care, treatment or similar action or improper handling thereof; 3. incorrect or delayed diagnosis; 4. transmission of infectious agent that led to infection in connection with examination, care, treatment, or similar action; 5. accidents in connection with examination, care, treatment, or similar action or during transport or in connection with fire or other damage to care facilities or equipment; 6. ordering or dispensation of medicines in violation of regulations or instructions. When examining entitlement to compensation pursuant to the 1st subparagraphs 1 and 3, the standard of action shall apply that applies to an experienced specialist or other experienced professional in the specific field. Löf Löf receives approximately 16,000 claims per year and compensates approximately 40% of those (Löf 2016). Filing a claim is free of charge. Before 2017, the claim to Löf must have been made within 3 years after the AE was noticeable. Löf can compensate for loss of income, other expenses, pain and suffering, and medical invalidity. All assessments are on the individual patient; therefore, the range of compensation, even for the same type of AE, is wide, and study includes too few patients to draw conclusions on compensation levels for different AEs. The experts at Löf uses guidelines from Insurance Sweden in their decision making (Insurance Sweden 2013). A reviewer (MM) performed the review of Löf’s records (> 5 years after the last surgery in the study and exceeding the 3-year limit for filing claims) and recorded type of injury,

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reimbursement, and level of disability caused by the AE. All assessments on the claims were made by the experts at Löf and the reviewer only recorded their assessments. Statistics We excluded the non-preventable AEs, because only preventable AEs can be accepted as claims by Löf and also chose to only include the major preventable AEs (NCC MERP index of F or more). We included the claims for AEs within 90 days following surgery that were filed during the 3-year time limit to file claims. We defined confidence intervals (CI) at 95%. We calculated the claim proportion in the study population with a customized bootstrap function that works as follows: the dataset consists of patient id, sample group (1–20), whether the patient had filed a claim or not and whether the patient had a major preventable AE or not. In each sample group the same number of patients in the group were sampled with replacements. In each group we calculated the filed claim proportion (number of filed claims/number of major preventable AEs). This was multiplied by the group proportion (size of the corresponding group in the study population/study population). The rate times proportion for all 20 groups was summed and this is the point estimate for the claim proportion in the study population. This procedure corresponds to 1 bootstrap repetition and it was repeated 20,000 times. The mean of the samples was the final point estimate and the confidence interval was calculated by using the 2.5th and 97.5th percentiles. For the acute and the elective, the corresponding 10 sample groups were used and for all patients the groups were pooled. The proportion ratio was the mean of the elective patients/mean of the acute patients. We used R (v. 3.5.1; R Project for Statistical Computing, https://www.r-project.org/) for all analyses. Ethics, funding, and potential conflicts of interest Ethical approval was provided by the Regional Ethics Committee of Gothenburg (516-13 and T732-13). The head of each respective unit granted permission for data access for the reviewers. This study was funded by institutional grants from the Karolinska Institutet, Department of Clinical Sciences, Danderyd Hospital, from the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, and from Löf. None of the authors have any conflicts of interest to disclose.

Results Flow of patients and descriptive data From the eligible population of 21,774 patients identified in the SHAR, 2,000 patients were included in the study (Figure). 2 patients were excluded from the cohort resulting in 1,998 patients. One did not have an available medical record, and the other did not have hip arthroplasty and was presumed to be a faulty registration in the register. We found 2,116 AEs of dif-

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Table 5. All claims and corresponding found AEs

Study population n = 21,774

Type of AE

Study cohort n = 2,000 Excluded (n = 2): – missing medical record, 1 – not hip arthroplasty, 1 Final cohort n = 1,988 AEs found during record review n = 2,116

Claims to Löf n = 68 Excluded, debut after the study’s inclusion period (n = 6): – periprosthetic joint infections, 4 – dislocations, 2

Major preventable AEs n = 1,066 (in 744 patients)

Claims to Löf (n = 62): – declined, 4 – accepted, 58

Number Accepted Identified Compenof claims claim AEs sation n = 62 n = 58 n = 750 mean (€)

Periprosthetic joint infections 37 36 150 5,350 Drop foot and peripheral nerve lesions 9 9 16 5,930 Dislocations 6 6 274 2,780 Pressure ulcers, all categories 1 1 190 4,440 Falls causing fractures 1 1 41 1,100 Perioperative fractures or tissue damage 2 1 33 5,710 Difference in leg length 2 1 20 6,840 Falls causing wounds 1 1 18 620 Implant related AEs a 1 1 7 20,190 Compartment syndrome 1 1 1 100 Numbness in arms 1 0 0 0 AEs = adverse events. a Including loosening of implant.

Patient inclusion and exclusions. Table 3. Demographics for the different groups. Values are frequency (%) unless otherwise specified

Factor

All patients N = 1,998

Claim group n = 61

AE group n = 744

No AE group n = 1,254

Age, median range Female Male Elective surgery Acute surgery) Total arthroplasty Hemiarthroplasty

77 18–100 1,250 (63) 748 (37) 1,331 (67) 667 (33) 1,422 (71) 576 (29)

69 18–88 35 (57) 26 (43) 56 (92) 5 (8) 57 (93) 4 (7)

78 18–99 458 (62) 286 (38) 470 (63) 274 (37) 497 (67) 247 (33)

76 18–100 792 (63) 462 (37) 861 (69) 393 (31) 925 (74) 329 (26)

AE = adverse event.

All patients Acute patients Elective patients Elective/acute ratio

Factor

No PJI patients n = 1,848

PJI patients n = 150

Claim group n = 36

Age, median range Female Male Acute surgery Elective surgery Total arthroplasty Hemiarthroplasty

77 18–100 1,167 (63) 681 (37) 631 (34) 1,217 (66) 1,307 (71) 541 (29)

76 37–97 83 (55) 67 (45) 36 (24) 114 (76) 115 (77) 35 (23)

72 37–88 20 (56) 16 (44) 4 (11) 32 (89) 32 (89) 4 (11)

No claim group n = 114 77 45–97 63 (55) 51 (45) 32 (28) 82 (72) 83 (73) 31 (27)

PJI = periprosthetic joint infection.

Table 4. Proportion of filed claims (%) for major preventable AEs Factor

Table 6. Demographics of PJI patients. Values are frequency (%) unless otherwise specified

Proportion CI 8 0.3 13 46

1–15 0.1–0.6 1–40 2–267

AEs = adverse events. CI = 95% confidence interval limit.

ferent severity in 1,171 (59%) patients. Of these, 1,605 (76%) AEs in 975 (49%) patients were classified as preventable, and 1,066 (50%) in 744 (37%) patients were deemed to be major preventable. There were 144 claims from the patients in the study cohort and 68 of these concerned AEs following hip arthroplasties

included in this study. 1 claim was not detected by the record review. 6 claims were excluded from the analysis due to their debut after the study’s inclusion period (4 periprosthetic joint infections [PJIs] and 2 dislocations). 4 patients had their claims declined by Löf because they were not deemed to be preventable AEs, resulting in a 58/62 proportion of accepted claims. The declined claims included a PJI due to hematogenous spread, a perioperative fracture, pain and numbness of the hands, and a lengthening of the operated leg. Remaining for analysis were 58 claims from 57 patients. The claim patients were younger and consisted of mostly planned surgery patients and total hip arthroplasty patients (Table 3). Main results 8% of the patients who sustained a major preventable AE filed a claim with Löf (Table 4). The ratio between the proportion of elective patients/proportion of acute patients was 46.

The total sum of the reimbursement was €296,090, with a mean of €5,220 (range 100–33,860; median = 3,190). The mean grade of disability was 5% (0–40; median = 3) (Table 5). The most common AE type that resulted in a claim was PJI. The PJI patients who filed a claim were younger and consisted of more elective patients, but there was no difference in sex (Table 6). The mean compensation for the 35 PJIs with available compensation data was €5,350 (range 380–33,860, median = 3,430). The mean grade of disability for the PJI patients was 6% (0–40, median = 2.5).

Discussion In this cohort study on 1,998 patients undergoing acute and elective hip arthroplasty, we found that only 8% of the 744 patients who sustained a major preventable AE filed a claim with Löf. PJI was the most common AE for filing claims. The proportion of filed claims was almost 50 times higher for the elective patients compared with the acute. In our earlier paper (Magnéli et al. 2019) we found that the 30 days’ incidence of major preventable AEs was more than double for acute patients, compared with the elective (21% vs. 10%). Despite this, only 5 of 62 claims concerned acute surgeries. 58 of the 62 claims were accepted by Löf, suggesting that only obvious AE claims are filed. Strengths and limitations A major strength of this study is the large study cohort and the use of a thorough method for measuring AEs. The study also includes both total and hemiarthroplasties as well as acute and elective surgery, which have not been studied before. This provides a better understanding of the numbers of AEs claimed. The use of a weighted sample is practical for accumulating high numbers of AEs in a study, but the rates have to be adjusted according to the group weights to represent the proportion in the population. This study includes a wide range of detected AEs of different severity. Many of the minor AEs in the study would likely not result in an accepted claim by Löf. However, the proportion of filed claims for PJI, arguably a severe AE, was only 1 in 4. Interpretation and generalizability Similar to our findings, a recent Swedish study by Kasina et al. (2018) revealed that 25% of the PJIs after total hip arthroplasty filed a claim and that 96% of the claims were accepted by Löf. Helkamaa et al. (2016) studied filed claims after total hip arthroplasty in Finland, which has a similar patient insurance program to that in Sweden, and found that 44% were accepted, a considerably lower rate than the Swedish studies. The difference in claims proportion between the acute and elective patients can probably be explained by the fact that

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these are 2 completely different patient groups and the age difference (median 84 vs. 73) might lead to lower capacity to assimilate information about Löf and act upon it. PJI was the most common AE for filing a claim. Löf will almost always approve PJI claims. If we hypothesize that all PJIs identified in our study would have been deemed as preventable AEs by Löf, the remaining 114 (76%) PJIs would have received compensation had they filed a claim. Hypothetically, this corresponds to approximately €600,000 of unexploited compensation in this study alone. The incidence rates for PJI are 0.9% after total hip arthroplasty (Lindgren et al. 2014) and 5–6% for hemiarthroplasty (de Jong et al. 2017, Guren et al. 2017). In 2015, over 16,000 total hip arthroplasties and 4,200 hemiarthroplasties were performed in Sweden, which would hypothetically generate 350 to 396 PJIs per year, with 263 to 297 of these not filing a claim. This would correspond to €1.4– 1.6 million of unexploited compensation each year. Conclusion The proportion of filed claims for major preventable AEs following hip arthroplasty is very low in Sweden. This is true even for obvious and serious AEs such as periprosthetic joint infection. The proportion of filed claims is higher for elective than acute patients. Whether the healthcare system fails to inform patients about their right to claim for compensation or the patients are informed but choose not to file a claim is unknown. Supplementary data Tables 1 and 2 are available as supplementary data in the online version of this article, http://dx.doi.org/10.1080/17453674. 2019.1677382 MM collected, analyzed, and interpreted the data and contributed to the drafting of the work. MU contributed to the design of the study, monitored the study, contributed to the drafting of the work, and revised the manuscript critically. BS collected data and critically revised the manuscript. CR contributed to the design of the study and the drafting of the work and revised the manuscript critically. OR contributed to the design of the study and critically revised the manuscript. MG and OS contributed to the design of the study; collected, analyzed, and interpreted the data; contributed to the drafting of the work; and revised the manuscript critically. Acta thanks Pieter K Bos and Kim Lyngby Mikkelsen for help with peer review of this study.

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Griffin F, Resar R. IHI Global Trigger Tool for measuring adverse events, 2nd ed. Cambridge, MA: Institute for Healthcare Improvement; 2009. Guren E, Figved W, Frihagen F, Watne L O, Westberg M. Prosthetic joint infection—a devastating complication of hemiarthroplasty for hip fracture. Acta Orthop 2017; 88(4): 383–9. Helkamaa T, Hirvensalo E, Huhtala H, Remes V. Patient injuries in primary total hip replacement. Acta Orthop 2016; 87(3): 209–17. Huddleston J I, Wang Y, Uquillas C, Herndon J H, Maloney W J. Age and obesity are risk factors for adverse events after total hip arthroplasty. Clin Orthop Relat Res 2012; 470(2): 490–6. Insurance Sweden. Medicinsk Invaliditet—skador 2013 [Medical Invalidity—2013][Internet]. Stockholm: svensk Försäkring; 2013. [cited 2018 Dec 18]. Available at: http://www.svenskforsakring.se/globalassets/medicinska-tabellverk/medicinska-tabellverk/medicinsk_invaliditet_skador_ rev_jan2014.pdf Kasina P, Enocson A, Lindgren V, Lapidus L J. Patient claims in prosthetic hip infections: a comparison of nationwide incidence in Sweden and patient insurance data. Acta Orthop 2018; 89(4): 394–8. Kärrholm K, Lindahl H, Malchau H, Mohaddes M, Nemes S, Rogmark C, Rolfson O. The Swedish Hip Arthroplasty Register: Annual Report 2016 [Internet]. The Swedish Hip Arthroplasty Register: Gothenburg; 2017. [cited 2018 Sep 13]. Available from: https://registercentrum.blob.core.windows.net/shpr/r/Annual-Report-2016-B1eWEH-mHM.pdf Lindgren V, Gordon M, Wretenberg P, Kärrholm J, Garellick G. Deep infection after total hip replacement: a method for national incidence surveillance. Infect Control Hosp Epidemiol 2014; 35(12): 1491–6. Löf. Anmälningar till Löf 2016 [Claims to Löf 2016] [Internet]. Stockholm: Landstingens ömsesidiga försäkringsbolag; 2016. [cited 2018 Sep 13]. Available at: http://lof.se/wp-content/uploads/Statistik-2016-Hela-Sverige. pdf Löf. If you are injured in the Swedish healthcare system [Internet]. Stockholm: Landstingens ömsesidiga försäkringsbolag; 2018. [cited 2018 Sep 13]. Available at: https://lof.se/wp-content/uploads/If-you-are-injured-inthe-Swedish-healthcare-system.pdf Ludvigsson J F, Andersson E, Ekbom A, Feychting M, Kim J-L, Reuterwall C, Heurgren M, Olausson P O. External review and validation of the Swedish national inpatient register. BMC Public Health 2011; 11:450. Magnéli M, Unbeck M, Rogmark C, Rolfson O, Hommel A, Samuelsson B, Schildmeijer K, Sjöstrand D, Gordon M, Sköldenberg O. Validation of adverse events after hip arthroplasty: a Swedish multi-centre cohort study. BMJ Open 2019; 9(3): e023773.

Naessens J M, Campbell C R, Huddleston J M, Berg B P, Lefante J J, Williams A R, Culbertson R A. A comparison of hospital adverse events identified by three widely used detection methods. Int J Qual Health Care 2009; 21(4): 301–7. National Coordinating Council for Medication Error, Reporting and Prevention. NCC MERP Index for Categorizing Medication Errors [Internet]. National Coordinating Council for Medication Error, Reporting and Prevention, 2001. [cited 2018 Sep 13]. Available at: https://www.nccmerp.org/ sites/default/files/indexBW2001-06-12.pdf Richards M, Alyousif H, Kim J-K, Poitras S, Penning J, Beaulé P E. An evaluation of the safety and effectiveness of total hip arthroplasty as an outpatient procedure: a matched-cohort analysis. J Arthroplasty 2018;3 3(10): 3206-10. SPOR. SPOR Årsrapport 2016-01-01 – 2016-12-31 [Annual report, the Swedish Perioperative Register 2016] [Internet]. SPOR [Swedish Perioperative Register], 2016. [cited 2018 Sep 13]. Available from: http://www.spor.se/ wp-content/uploads/2017/10/Årsrapport-SPOR-2016_v2.0_final_170926. pdf Socialstyrelsen. The national patient register [Internet]. Stockholm: Socialstyrelsen [National Board of Health and Welfare]; 2016. [cited 2018 Sep 13]. Available at: https://www.socialstyrelsen.se/SiteCollectionDocuments/information-in-the-national-patient-register.pdf Sveriges kommuner och landsting. Markörbaserad Journalgranskning—för att identifiera och mäta skador i vården [Marker based record review to identify and measure harm in healthcare] [Internet]. Stockholm: Sveriges Kommuner och Landsting [Swedish Association of Local Authorities and Regions]; 2012. [cited 2018 Sep 18]. Available from: https://webbutik.skl. se/bilder/artiklar/pdf/7164-847-1.pdf?issuusl=ignore Swedish Parliament. Patientskadelag [Patient Injury Act] (SFS 1996:799) [Internet]. Stockholm: Socialdepartementet [Ministry of Health and Social Affairs]; 1996. [cited 2018 Sep 13]. Available at: http://www.riksdagen. se/sv/dokument-lagar/dokument/svensk-forfattningssamling/patientskadelag-1996799_sfs-1996-799 Swedish Parliament. Patientsäkerhetslag [Patient Safety Act] (SFS 2010:659) [Internet]. Stockholm: Socialdepartementet [Ministry of Health and Social Affairs]; 2010. [cited 2018 Sep 13]. Available from: https://www.riksdagen.se/sv/dokument-lagar/dokument/svensk-forfattningssamling/patientsakerhetslag-2010659_sfs-2010-659 WHO. ICD - ICD-10-CM - International Classification of Diseases, Tenth Revision, Clinical Modification [Internet]. Geneva: World Health Organization; 2017. [cited 2018 Sep 13]. Available at: https://www.cdc.gov/nchs/ icd/icd10cm.htm

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Higher early proximal migration of hemispherical cups with electrochemically applied hydroxyapatite (BoneMaster) on a porous surface compared with porous surface alone: a randomized RSA study with 53 patients Peter Bo JØRGENSEN 1,2, Henrik DAUGAARD 3, Stig Storgaard JAKOBSEN 1, Martin LAMM 1, Kjeld SØBALLE 1,2 and Maiken STILLING 1,2 1 Department

of Orthopedic Surgery, Aarhus University Hospital, Aarhus, 2 Department of Clinical Medicine, Aarhus University, Aarhus, 3 Department of Orthopaedic Surgery, Gentofte Hospital, Hellerup, Denmark Correspondence: pbjr@clin.au.dk Submitted 2019-04-08. Accepted 2019-09-22.

Background and purpose — BoneMaster (BM) is an electrochemically deposited hydroxyapatite (HA) implantcoating, which is evenly distributed, thin, and quickly resorbed. It is designed to stimulate osseointegration and early implant stability and alleviate longer-term HA-induced third-body polyethylene wear. This study evaluates early cup migration and functional outcomes of cementless porouscoated hemispherical cups with or without BM. Patients and methods — In a patient-blinded, randomized, controlled trial 53 patients at mean 64 years (55–75) with coxarthritis were operated with an Exceed cup (Zimmer Biomet) and Bi-Metric stem (Zimmer Biomet) with porous and BM coating (PBM) or with porous coating alone (P). Follow-ups were performed postoperatively and at 3, 6, 12, and 24 months. Effect measures were cup migration measured with RSA and PROMs. Results — At 6-month follow-up, proximal cup migration in the PBM group (0.09 mm, 95% CI 0.02–0.20) was higher than in the P group (0.25 mm, CI 0.15–0.35). At 1and 2-year follow-up, cup migration in all 6 degrees of freedom was similar between groups (p > 0.2). From before surgery to 2-year follow-up, Oxford Hip Score (OHS) increased by 17 points (CI 14–20). Hip disability and Osteoarthritis Outcome Score (HOOS) increased in all sub-scores, but was more pronounced for PBM cups compared with P cups in the Symptoms sub-score (p = 0.04). Interpretation — Contrary to expectations, PBM cups had higher early migration than P cups. At 2-year follow-up, migration was similar between groups. There seems to be no early benefit of BM coating on acetabular cups.

Aseptic loosening remains one of the most common reasons for cup revision. In Denmark up to 86% of cups are cementless and 35% of these are coated with hydroxyapatite (HA) (DHR 2016). Plasma-sprayed HA coating results in better bony ingrowth and early implant fixation in experimental studies (Soballe et al. 1992, Daugaard et al. 2010). However, clinical results have not truly been able to show superior cementless cup fixation with HA over porous coating at midterm (Rohrl et al. 2004, Valancius et al. 2013) or long-term (Otten et al. 2016, Lazarinis et al. 2017). Plasma-sprayed HA applies coating in a line-of-sight, which may reduce the microstructure in the porous coating. Electrochemical application of HA is a new technique resulting in a thinner coating layer with better topographic structure and distribution as compared with plasma-sprayed HA. Electrochemically applied HA may stimulate early implant osseointegration and is resorbed within a few months (Daugaard et al. 2010). Therefore, it may not contribute to polyethylene wear. The osteoconductive properties of electrochemical HA coating have been validated in experimental studies (Wang et al. 2006, Daugaard et al. 2010) and clinically on a femoral stem using RSA (Boe et al. 2011, Flatoy et al. 2016) in accordance with the guidelines for phased introduction (Nelissen et al. 2011). The suggested thresholds for proximal cup migration are 0.2 mm (at risk) and 1.0 mm (unacceptable), and for every 1 mm of proximal migration the risk of later revision increases by 10% (Pijls et al. 2012). We evaluated the effect of electrochemically applied HA coating on early cup migration and functional outcomes using porous coated Exceed cups (Zimmer Biomet, Warsaw, IN, USA). We hypothesized that cementless Exceed ABT cups with electrochemically applied HA coating would have supe-

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ENROLLMENT

Assessed for eligibility n = 82 Excluded (n = 29): – met exclusioncriteria, 17 – declined, 6 – not treated with hip arthroplasty, 2 – other, 4 Randomized n = 53 ALLOCATION

Allocated to PBM cups (n = 28)

Allocated to P cups (n = 25) Received allocated intervention (n = 25)

Received allocated intervention (n = 28)

FOLLOW-UP

Table 1. Baseline characteristics, mean (95% CI) Baseline demographics N Age Men/women T-score OHS-score HOOS Pain Symptoms ADL Sport QoL

P cups 25 65 (63–67) 11 / 14 –0.3 (–0.8 to 0.2) 27 (23–30) 48 (43–57) 45 (40–55) 57 (46–63) 38 (26–43) 38 (30–42)

PBM cups 28 64 (62–66) 14 / 14 –0.8 (–1.2 to –0.4) 22 (19–25) 36 (31–45) 28 (28–42) 39 (37–50) 13 (13–26) 22 (17–29)

Lost to follow-up (n = 1): – died between 1 and 2 years, 1

Lost to follow-up (n = 0)

ANALYSIS

Analyzed at endpoint (n = 23) Excluded from RSA analysis (n = 2): – inadequate RSA-marker configuration, 2

Analyzed at endpoint (n = 27) Excluded from RSA analysis (n = 0)

rior or equal early fixation compared to identical cups without hydroxyapatite coating.

Patients and methods Study design In this patient-blinded, randomized controlled trial, 82 patients were assessed for eligibility between January 2013 and March 2015. Randomization was done in the theater within blocks of 10 patients (5 porous [P], and 5 porous with BoneMaster [PBM]) by drawing concealed labels from sequentially numbered closed envelopes. We obtained written consent of 56 patients who met the inclusion criteria; non-osteoporotic by a pre-op dual energy X-ray absorptiometry (DEXA) scan, age 55–75 years, and severe coxarthrosis (Figure 1, Table 1). Criteria of exclusion were: other diseases of affected hip than primary coxarthrosis at time of inclusion, secondary osteoarthritis, neuromuscular or vascular condition in lower extremity, arthroplasties of other lower-extremity joints, BMI at time of inclusion ≥ 35 or < 18.5, rheumatoid and similar arthritis, metabolic bone disease, reduced kidney function, previous treatment of skeleton with radiation therapy, pharmaceuticals that effect calcium–phosphorus metabolism and bone density, alcohol abuse, medication abuse, and psychological instability. Sample size A sample size calculation indicated 23 patients per group based on a clinically relevant difference in migration of 0.6 mm (SD 0.6) with a power of 90% and alpha set to 0.05 (Charnley 1982). To balance postoperative dropout, we aimed for 25 patients per group. To balance for exclusions during the inclusion period, we continued inclusion per block random-

Figure 1. Consort flow chart

ization until there were minimum 25 patients in each group, and in total 53 patients in the study. Implants 25 patients received a cementless Exceed cup (Exceed ABT RingLoc-x shell) size 50-62 mm, and a cementless Bi-Metric stem (Zimmer Biomet). Cup and stem were treated with plasma-spray porous titanium coating with a porosity of 45% and an average pore size of 250 µm (range, 100–1,000 µm), providing a scratch fit (Lindgren et al. 2018). Another 28 patients received similar porous coated Exceed cups (Exceed ABT RingLoc-x shell) size 50–62 mm and Bi-Metric stem (Zimmer Biomet), both with an additional electrochemically applied HA coating (BoneMaster, Zimmer Biomet). The BoneMaster coating consisted of 70% crystalline HA with a thickness of 5 µm and with a 2.0 Ca/P ratio. The amorphous phase in the coating was primarily amorphous calcium phosphate (ACP) but also β-tricalcium phosphate (TCP). All patients received cobalt-chromium-molybdenum modular femoral heads, size 36 mm (1 patient had a size 32), and an E1 highly cross-linked UHMWPE liner (Zimmer Biomet). Surgery All patients were operated at Aarhus University Hospital, Denmark. Preoperative planning was done with the AGFA OT3000 digital templating software (Agfa-Gevaert NV, Mortsel, Belgium) and calibrated digital radiographs. All procedures used a posterolateral approach and the acetabulum was under-reamed by 1 mm in all patients. During surgery 6–8 1-mm tantalum beads were inserted into the periprosthetic pelvic bone. Preoperatively, patients received 1.5 g cefuroxime intravenously as antimicrobial prophylaxis, and 1 dose of tranexamic acid 10 mg/kg IV. Postoperatively patients received 1 dose of tranexamic acid IV and 3 doses of 1.5 g

cefuroxime IV within the first 24 hours. Postoperatively, the patients were mobilized with full weight-bearing and walking aids as needed, using a “fast track” protocol. Radiostereometric analysis RSA recordings were performed on a standard RSA system with 2 synchronized ceiling-fixed roentgen tubes (Arco-Ceil/ Medira; Santax Medico, Aarhus, Denmark) angled toward each other at 40°. The radiographs were digital (Fuji CR, image size 35 x 43) and stored in DICOM file-format without compression. During the study the RSA equipment was replaced with a newer direct digital dedicated stereo X-ray system, AdoraRSA suite (Nordic X-ray Technique, Aarhus, Denmark) with CXDI-70C wireless detectors (Canon, Tokyo, Japan). X-ray tubes remained at a 40-degree angle and a uniplanar carbon calibration box (Box 24, Medis Specials, Leiden, Netherlands) was used for all recordings. RSA recordings were obtained by experienced radiographers and analyses were performed by the same blinded investigator (PBJ) using CAD surface implant models (Zimmer Biomet) with Model-Based RSA 4.1 (RSAcore, Leiden, The Netherlands). The maximum rigid body error was set to 0.35 mm and the condition number (CN) at 200. The mean CN was 99.8 (95% CI 89.9–109.6). 4 patients (2 in each group) with CN between 150 and 200 had a sufficient and non-linear bone model as judged by visual evaluation, and were kept in the analyses to maintain power. 1 patient with CN above 200 and 1 patient with only 2 markers were excluded from the RSA data. 2 patients had inadequate marker-configuration; 1 had inferior marker position and the other had only 2 visible markers. These patients were removed from the RSA analysis but contributed with patient-reported outcomes. 2 patients received new liners and femoral heads due to instability (PBM 3 days after primary operation) and recurrent dislocation of the hip (P 16 months after primary operation). These patients continued in the study. RSA precision When accepting condition numbers higher than 150 validation of precision becomes essential (Valstar et al. 2005). Precision calculations were based on double RSA examinations recorded at 6-month follow-up (on both RSA systems) (Table 2). Radiographs and DEXA scans Preoperative DEXA scans of the lumbar spine and dual hip region were performed using the 2 fan-beam GE Lunar iDXA with Encore software version 13 (Minneapolis, MN, USA). Patients with a T-score below –2.5 on hip or lumbar spine were defined as osteoporotic according to WHO criteria and excluded. Standard anterior-posterior and medio-lateral hip radiographs were recorded postoperatively and at 2-year follow-up. Cup position was measured by 1 experienced hip surgeon (KS) using the known diameter of the femoral head to calibrate and

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avoid magnification errors. Radiolucent lines of 1 mm or more were described according to DeLee and Charnley (1976). Patient-reported and clinical outcomes Patient-reported outcomes were hip disability and osteoarthritis outcome score (HOOS) and Oxford hip score (OHS). HOOS were recorded in 5 subscales (pain, symptoms, ADL, sport, and quality of life) and have been validated for use in patients receiving total hip arthroplasty (Paulsen et al. 2012). Outcome was evaluated in each subscale giving from 0 (worst) to 100 (best) points. OHS was evaluated on a scale from 0 (worst) to 48 (best) points. Postoperative complications were recorded at the 2-year follow-up. Statistics The RSA dataset consisted of signed cup migrations along and rotations about the 3 orthogonal axes (x, y, z), total translation (TT = sqrt(Tx2 + Ty2 + Tz2)), total rotation (TR = sqrt(Rx2 + Ry2 + Rz2)) and maximum total point motion (MTPM). All migration measures were normally distributed as evaluated on q–q plots and hence presented as mean and 95% confidence intervals (CI) and were tested using Student’s t-test. Due to the non-normal nature of summed RSA data (TT, TR, and MTPM) the Mann–Whitney U-test was used for statistical testing of those. Changes in HOOS and OHS were normally distributed as evaluated on q–q plots and tested using Student’s t-test, 1- and 2-year group comparisons were done with the Mann–Whitney U-test. Sub-analysis of proximal migration was performed comparing patients dichotomized on normal bone quality (T score > –1) and osteopenia (T score < –1). Statistics were calculated using Stata/IC version 13.0 (StataCorp, College Station, TX, USA) and the significance level was set at 0.05. Ethics, registration, funding, and potential conflicts of interest The study was approved by the Data Protection Agency (1-1602-175-11) and the Central Denmark Regions Committee on Biomedical Research Ethics (M-20110224) and was performed in agreement with the Helsinki II declaration. The study was registered at ClinicalTrials.gov (NCT02311179). Zimmer Biomet supported the study financially but had no influence on the manuscript or publication. The authors have no conflicts of interest.

Results RSA results Proximal migration was 0.16 mm (CI 0.02–0.30) higher for PBM coated cups (0.25 mm CI 0.15–0.35) compared with P coated cups (0.09 CI –0.02–0.20) at 6-month follow-up. From

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Proximal migration (mm) 0.5

Proximal migration, P cups (mm)

Proximal migration, PBM cups (mm)

1.0

0.5

Proximal migration (mm) 0.5

Osteopenia Normal BMD

PBM cups P cups

–0.5

Months after index operation

Figure 2. Mean proximal migration (CI) with limit for safe 2-year migration (red line).

–0.5

Months after index operation

–0.5

Months after index operation

Figure 3. Individual y-migration. Dashed lines are limits of agreement.

1-year follow-up to 2-year follow-up, the proximal migration was 0.0 mm (CI –0.06 to 0.06) for P-coated cups and 0.0 mm (CI –0.05 to 0.04) for PBM-coated cups. At 2-year followup, 8 P-coated cups and 10 PBM-coated cups had a proximal migration exceeding the precision limit of 0.2 mm, and the mean 2-year proximal cup migration was 0.09 mm (CI –0.02 to 0.20) for P-coated cups and 0.2 mm (CI 0.10–0.30) for PBM-coated cups. We found no statistically significant difference in proximal migration between the groups at 1-year follow-up (p = 0.2) and at 2-year follow-up (p = 0.2). At 3-month follow-up, we found a statistically significant difference in y-rotation (p = 0.03). Based on preoperative DEXA scan, 21 patients had osteopenia (T-score < –1) and 29 patients had normal bone quality (T-score > –1). The ratio of normal BMD/osteopenia was 15/8 in the P-coated group and 13/14 in the PBM- coated group. Proximal cup migration was 0.09 mm (CI –0.06 to 0.24) higher for osteopenic patients compared with patients with normal BMD at 6-month follow-up, although this difference was not statistically significant (p = 0.2) (Figure 4). Further RSA results are presented in Figures 2, 3 and 4, and in Tables 2 and 3. Radiographic results Radiographic evaluation revealed a mean inclination of 42°(CI 40–43) and mean anteversion of 20° (CI 18–21) with no statistically significant difference between groups (p > 0.3). Only 1 patient (PBM) had a radiolucent line of more than 1 mm (1.03 mm) in zone 3 evaluated on 2-year radiographs. This patient had an early migration of the cup of 0.3 mm medially and 0.3 mm proximally at 3-month follow-up, and stabilized hereafter. Patient-reported and clinical outcomes At 2-year follow-up OHS reached a median value of 46 points (7–48). OHS showed clinically relevant improvement in self-perceived hip function for both groups from baseline to 2-year follow-up of 17 points (CI 14–20) with no statistically significant difference between groups (p = 0.1). Similarly,

HOOS, P cups

HOOS, PBM cups 100

40 Pain Symptoms ADL Sport/Rec QoL

Figure 4. Mean proximal migration (CI) dependent on bone mineral density with limit for safe 2-year migration (red line).

100

Months after index operation

Pain Symptoms ADL Sport/Rec QoL

Months after index operation

Figure 5. Median HOOS (0–100). Oxford Hip Score (0–48) 50

Months after index operation

Figure 6. Oxford Hip Score in a box plot. The line tags the median, the box tags the interquartile range (IQR). Whiskers indicate the most extreme value within upper/lower quartile ±1.5×IQR.

HOOS increased significantly in all groups from baseline to 2-year follow-up (p < 0.001). PBM-coated cups had a greater increase in HOOS symptoms score than P-coated cups (p = 0.04). However, the difference of 14 points (CI 27–50) was not considered clinically relevant (Paulsen et al. 2014). At 1-year and 2-year follow-up, there were no statistically significant differences between the groups in any HOOS category or OHS (p > 0.5) (Figures 5 and 6).

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but there was no statistically significant difference between groups at 2-year follow-up.

Table 3. Migration, mean (95% CI)

P cups, n = 23

PBM cups, n = 27

Translations, mm x-axis (+medial/–lateral) 3 months –0.05 (–0.16 to 0.06) 0.01 (–0.14 to 0.16) 6 months –0.01 (–0.17 to 0.15) –0.03 (–0.17 to 0.11) 1 year –0.06 (–0.22 to 0.11) 0.02 (–0.15 to 0.18) 2 years –0.00 (–0.12 to 0.12) –0.02 (–0.19 to 0.16) y-axis (+proximal/–distal) 3 months 0.10 (–0.01 to 0.21) 0.20 (0.11 to 0.30) 6 months 0.09 (–0.02 to 0.20) 0.25 (0.15 to 0.35) a 1 year 0.09 (–0.03 to 0.22) 0.20 (0.10 to 0.30) 2 years 0.09 (–0.02 to 0.20) 0.20 (0.10 to 0.30) z-axis (+anterior/–posterior) 3 months 0.09 (–0.02 to 0.21) –0.02 (–0.17 to 0.13) 6 months 0.12 (–0.00 to 0.24) –0.01 (–0.20 to 0.17) 1 year 0.19 (0.05 to 0.33) 0.05 (–0.13 to 0.23) 2 years 0.12 (–0.03 to 0.26) 0.08 (–0.11 to 0.28) Rotations, degrees x-axis (+anterior/–posterior tilt) 3 months –0.04 (–0.52 to 0.44) 0.03 (–0.30 to 0.36) 6 months –0.09 (–0.63 to 0.45) 0.04 (–0.32 to 0.41) 1 year 0.24 (–0.26 to 0.75) –0.15 (–0.55 to 0.24) 2 years 0.15 (–0.40 to 0.71) 0.02 (–0.35 to 0.40) y-axis (+internal/–external rotation) 3 months –0.32 (–0.82 to 0.18) 0.33 (–0.04 to 0.71) a 6 months –0.30 (–0.87 to 0.27) 0.23 (–0.24 to 0.70) 1 year 0.14 (–0.55 to 0.82) –0.12 (–0.63 to 0.39) 2 years –0.02 (–0.58 to 0.53) 0.27 (–0.28 to 0.82) z-axis (+increased/–decreased inclination) 3 months 0.05 (–0.30 to 0.39) –0.17 (–0.54 to 0.19) 6 months –0.11 (–0.48 to 0.26) –0.19 (–0.59 to 0.20) 1 year –0.32 (–0.78 to 0.14) –0.13 (–0.57 to 0.32) 2 years –0.15 (–0.54 to 0.25) –0.20 (–0.65 to 0.25) Maximum total point movement b 3 months 0.94 (0.74 to 1.20) 1.01 (0.85 to 1.20) 6 months 1.05 (0.81 to 1.38) 1.19 (0.97 to 1.47) 1 year 1.16 (0.91 to 1.47) 1.28 (1.05 to 1.57) 2 years 1.16 (0.94 to 1.43) 1.38 (1.14 to 1.67) Total translation b 3 months 0.36 (0.29 to 0.46) 0.42 (0.33 to 0.54) 6 months 0.40 (0.30 to 0.53) 0.52 (0.41 to 0.66) 1 year 0.47 (0.38 to 0.58) 0.52 (0.41 to 0.66) 2 years 0.41 (0.32 to 0.51) 0.51 (0.38 to 0.68) Total rotationb 3 months 1.31 (1.01 to 1.70) 1.23 (0.99 to 1.52) 6 months 1.37 (0.97 to 1.95) 1.40 (1.11 to 1.77) 1 year 1.50 (1.10 to 2.05) 1.55 (1.24 to 1.94) 2 years 1.60 (1.23 to 2.09) 1.69 (1.42 to 2.01) a Statistically significant difference b 2-sample Mann–Whitney U-test.

between P and PBM.

A clinical evaluation at 2-year follow-up comprised 2 head/ liner replacements related to dislocation and instability (1 P and 1 PBM).

Discussion This study evaluates the migration of porous Exceed cups with or without BM coating, and we found that the PBM-coated cups had higher proximal migration at 6-month follow-up,

RSA Building on the experimental results of BM we expected better early bone ingrowth and consequently better fixation in the bone/implant interface in the PBM group (Schmidmaier et al. 2002, Daugaard et al. 2010). Clinically we found that PBM-coated cups had a higher proximal migration at 6-month follow-up, but no statistically significant difference in comparison with P-coated cups was found at 2-year follow-up. An earlier study on dogs showed that electrochemically applied HA coating was not visible after 4 weeks (Daugaard et al. 2010). This suggests that the coating has been resorbed leaving a space between the implant and bone. Such a gap may explain the increased migration of the PBM implant during the earliest months in the present study. To our knowledge, this is the first randomized clinical study of electrochemically applied HA coating on cups. Lazarinis et al. (2014) studied a cohort of hemispherical trabeculae-oriented-pattern cups with electrochemically applied HA. Similar to our results, they found an initial proximal migration that seemed to stabilize after 3 months. We also found statistically significant difference in the y-rotation (anteversion/retroversion) at 3-month follow-up. However, y-rotation varies over time and this finding is likely to be caused by variation. In accordance with studies on plasma-sprayed HA coatings we found little or no positive effect of electrochemically applied HA coating on migration of hemispherical cups after 2 years (Rohrl et al. 2004, Valancius et al. 2013). Our findings also indicate no improved long-term survival effect of electrochemically applied HA coating. This is in agreement with recent larger registry-based analysis and meta-analysis of HA coatings on cementless cups (Chen et al. 2015, Lazarinis et al. 2017). Both the P-coated cups and the PBM-coated cups stabilized after 6 months, and early RSA-measured cup stabilization is in agreement with a number of other studies of cementless hemispheric cups (Lazarinis et al. 2014, Salemyr et al. 2015, Hjorth et al. 2017, Nilsson et al. 2017). Only 1 other clinical study on BoneMaster coating exists in the literature, and it concerns findings of increased early retroversion of femoral stems coated with BM compared with plasma-sprayed HA (Flatoy et al. 2016). In agreement with our results, their femoral stems all stabilized after 3-month follow-up. BMD Low systemic bone quality (T-score < –1.0) has been shown to increase proximal cup migration at 3- and 6-month followup (Finnila et al. 2016). In order to avoid migration bias from patients with poor bone quality we excluded all patients with

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osteoporosis (T-score < –2.5) based on a preoperative DEXA scan of systemic BMD. In spite of randomization, there was a difference in distribution of BMD between the 2 groups. This may explain some of the early difference in proximal cup migration. Precision We included 4 patients with a CN between 150 and 200 on RSA analysis, and upgraded the RSA system during the study. However, the precision of proximal migration was comparable to similar studies on hemispheric cups (Hjorth et al. 2017, Shareghi et al. 2017). Patient-reported outcome In general, patients receiving P cups had a better self-perceived hip function at baseline compared with the PBM group. Although preoperative score does not affect the Patient Acceptable Symptom State (PASS) postoperatively it may explain why PBM cups had superior improvement from baseline to 2-year follow-up in HOOS Symptoms sub-score (Paulsen et al. 2014). Postoperatively, patients reached OHS exceeding 40 points, which is the threshold corresponding to PASS after THR, and also corresponding to the Danish background population-based value of OHS (Paulsen et al. 2012, Keurentjes et al. 2014). Strengths and weaknesses This study sample size calculation was originally based on group mean comparisons of cup migration in general after 5 years. After initiation of this study, Pijls et al. (2012) published a paper validating 2-year follow-up of proximal migration (Y-axis) as proxy measure for later revision. Therefore, we focused the primary endpoint of this study on proximal cup migration after 2 years, and reduced multiple testing of outcomes. The decision to change endpoint was made without knowledge of actual data as described by Evans (2007). The randomized blinded design and high precision of RSA are major strengths, along with a high degree of patient compliance with almost full follow-up. The generalizability is limited to patients within the study criteria, which were many, because we wanted to make groups as comparable as possible in order to limit variation and be able to find even small differences between coating groups. Longer-term effects of BoneMaster on polyethylene wear cannot be evaluated before 5 years’ follow-up because of the low wear in highly crosslinked UHMWPE liners. Summary We found a higher early proximal cup migration with porous and BoneMaster coating as compared with porous coating alone, which indicates no relevant positive effect of electrochemically applied HA (BoneMaster) on cup osseointegration. Based on this study and the current literature, we see no

advantage in additional BoneMaster coating on porous-coated acetabular cups. Supplementary data Table 2 is available as supplementary data in the online version of this article, http://dx.doi.org/10.1080/17453674.2019. 1687860

PBJ and MS wrote the manuscript and performed the statistical analyses. PBJ and KS performed image analyses. HD, SSJ, ML, KS, and MS contributed to planning, data interpretation, and manuscript revision. Acta thanks Stergios Lazarinis for help with peer review of this study.

Boe B, Heier T, Nordsletten L. Measurement of early bone loss around an uncemented femoral stem. Acta Orthop 2011; 82(3): 321-4. Charnley J. Long-term results of low-friction arthroplasty. Hip 1982:42-9. Chen Y L, Lin T, Liu A, Shi M M, Hu B, Shi Z L, Yan S G. Does hydroxyapatite coating have no advantage over porous coating in primary total hip arthroplasty? A meta-analysis. J Orthop Surg Res 2015; 10: 21. Daugaard H, Elmengaard B, Bechtold J E, Jensen T, Soballe K. The effect on bone growth enhancement of implant coatings with hydroxyapatite and collagen deposited electrochemically and by plasma spray. J Biomed Mater Res A 2010; 92(3): 913-21. DeLee J G, Charnley J. Radiological demarcation of cemented sockets in total hip replacement. Clin Orthop Relat Res 1976; (121): 20-32. DHR. National Report 2016. The Danish Hip Arthroplasty Registry; 2016. Evans S. When and how can endpoints be changed after initiation of a randomized clinical trial? PLoS Clin Trials 2007; 2(4): e18-e. Finnila S, Moritz N, Svedstro M E, Alm J J, Aro H T. Increased migration of uncemented acetabular cups in female total hip arthroplasty patients with low systemic bone mineral density: a 2-year RSA and 8-year radiographic follow-up study of 34 patients. Acta Orthop 2016; 87(1): 48-54. Flatoy B, Rohrl S M, Boe B, Nordsletten L. No medium-term advantage of electrochemical deposition of hydroxyapatite in cementless femoral stems: 5-year RSA and DXA results from a randomized controlled trial. Acta Orthop 2016; 87(1): 42-7. Hjorth M H, Lorenzen N D, Soballe K, Jakobsen S S, Stilling M. Equal primary fixation of resurfacing stem, but inferior cup fixation with anterolateral vs posterior surgical approach: a 2-year blinded randomized radiostereometric and dual-energy X-ray absorptiometry study of metal-on-metal hip resurfacing arthroplasty. J Arthroplasty 2017; 32(11): 3412-20. Keurentjes J C, Van Tol F R, Fiocco M, So-Osman C, Onstenk R, KoopmanVan Gemert A W, Poll R G, Nelissen R G. Patient acceptable symptom states after total hip or knee replacement at mid-term follow-up: thresholds of the Oxford hip and knee scores. Bone Joint Res 2014; 3(1): 7-13. Lazarinis S, Milbrink J, Mattsson P, Mallmin H, Hailer N P. Bone loss around a stable, partly threaded hydroxyapatite-coated cup: a prospective cohort study using RSA and DXA. Hip Int 2014; 24(2): 155-66. Lazarinis S, Makela K T, Eskelinen A, Havelin L, Hallan G, Overgaard S, Pedersen A B, Karrholm J, Hailer N P. Does hydroxyapatite coating of uncemented cups improve long-term survival? An analysis of 28,605 primary total hip arthroplasty procedures from the Nordic Arthroplasty Register Association (NARA). Osteoarthritis Cartilage 2017; 25(12): 1980-7. Lindgren V, Galea V P, Nebergall A, Greene M E, Rolfson O, Malchau H. Radiographic and clinical outcomes of porous titanium-coated and plasmasprayed acetabular shells: a five-year prospective multicenter study. J Bone Joint Surg Am 2018; 100(19): 1673-81.

Nelissen R G, Pijls B G, Karrholm J, Malchau H, Nieuwenhuijse M J, Valstar E R. RSA and registries: the quest for phased introduction of new implants. J Bone Joint Surg Am 2011; 93 (Suppl. 3): 62-5. Nilsson K G, Theodoulou A, Mercer G, Quinn S J, Krishnan J. Mid-term migration of a cementless, porous acetabular cup: a 5 year radiostereometric analysis. J Orthop 2017; 14(4): 454-60. Otten V T, Crnalic S, Rohrl S M, Nivbrant B, Nilsson K G. Stability of uncemented cups: long-term effect of screws, pegs and HA coating: a 14-Year RSA follow-up of total hip arthroplasty. J Arthroplasty 2016; 31(1): 156-61. Paulsen A, Odgaard A, Overgaard S. Translation, cross-cultural adaptation and validation of the Danish version of the Oxford hip score: assessed against generic and disease-specific questionnaires. Bone Joint Rese 2012; 1(9): 225-33. Paulsen A, Roos E M, Pedersen A B, Overgaard S. Minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) in total hip arthroplasty (THA) patients 1 year postoperatively. Acta Orthop 2014; 85(1): 39-48. Pijls B G, Nieuwenhuijse M J, Fiocco M, Plevier J W M, Middeldorp S, Nelissen R G H H, Valstar E R. Early proximal migration of cups is associated with late revision in THA: a systematic review and meta-analysis of 26 RSA studies and 49 survival studies. Acta Orthop 2012; 83(6): 583-91. Rohrl S M, Nivbrant B, Strom H, Nilsson K G. Effect of augmented cup fixation on stability, wear, and osteolysis: a 5-year follow-up of total hip arthroplasty with RSA. J Arthroplasty 2004; 19(8): 962-71.

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Salemyr M, Muren O, Eisler T, Boden H, Chammout G, Stark A, Skoldenberg O. Porous titanium construct cup compared to porous coated titanium cup in total hip arthroplasty: a randomised controlled trial. Int Orthop 2015; 39(5): 823-32. Schmidmaier G, Wildemann B, Schwabe P, Stange R, Hoffmann J, Sudkamp N P, Haas N P, Raschke M. A new electrochemically graded hydroxyapatite coating for osteosynthetic implants promotes implant osteointegration in a rat model. J Biomed Mater Res 2002; 63(2): 168-72. Shareghi B, Johanson P E, Karrholm J. Clinical evaluation of model-based radiostereometric analysis to measure femoral head penetration and cup migration in four different cup designs. J Orthop Res 2017; 35(4): 760-7. Soballe K, Hansen E S, H B R, Jorgensen P H, Bunger C. Tissue ingrowth into titanium and hydroxyapatite-coated implants during stable and unstable mechanical conditions. J Orthop Res 1992; 10(2): 285-99. Valancius K, Soballe K, Nielsen P T, Laursen M B. No superior performance of hydroxyapatite-coated acetabular cups over porous-coated cups. Acta Orthop 2013; 84(6): 544-8. Valstar E R, Gill R, Ryd L, Flivik G, Borlin N, Karrholm J. Guidelines for standardization of radiostereometry (RSA) of implants. Acta Orthop 2005; 76(4): 563-72. Wang H, Eliaz N, Xiang Z, Hsu H P, Spector M, Hobbs L W. Early bone apposition in vivo on plasma-sprayed and electrochemically deposited hydroxyapatite coatings on titanium alloy. Biomaterials 2006; 27(23): 4192-203.

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Fixation, sex, and age: highest risk of revision for uncemented stems in elderly women — data from 66,995 primary total hip arthroplasties in the Norwegian Arthroplasty Register Håvard DALE 1,2, Sjur BØRSHEIM 3, Torbjørn Berge KRISTENSEN 1, Anne Marie FENSTAD 1, Jan-Erik GJERTSEN 1,2, Geir HALLAN 1,2, Stein Atle LIE 1,4, and Ove FURNES 1,2 1 The

Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen; 2 Department of Clinical Medicine, University of Bergen, Bergen; 3 Department of Surgery, Voss Hospital, Voss; 4 Department of Clinical Dentistry, University of Bergen, Bergen, Norway Correspondence: havard.dale@helse-bergen.no Submitted 2019-04-17. Accepted 2019-09-30.

Background and purpose — There is no consensus on best method of fixation in hip arthroplasty. We investigated different modes of fixation in primary total hip arthroplasty (THA) and the influence of age and sex, to assess need for a differentiated approach. Patients and methods — The study was based on data from the Norwegian Arthroplasty Register in the period 2005–2017. Included were all-cemented, all-uncemented, reverse hybrid (uncemented stem and cemented cup), and hybrid (cemented stem and uncemented cup) THA designs that were commonly used, contemporary and well documented, using different causes of revision as endpoints. Results — From the included 66,995 primary THAs, 2,242 (3.3%) were revised. Compared with all-cemented THAs, all-uncemented had a higher risk of revision due to any cause (RR 1.4; CI 1.2–1.6), mainly due to an increased risk of periprosthetic fracture (RR 5.2; CI 3.2–8.5) and dislocation (RR 2.2; CI 1.5–3.0). Women had considerably higher risk of revision due to periprosthetic fracture after all-uncemented THA (RR 12; CI 6–25), compared with cemented. All-uncemented THAs in women of age 55–75 years (RR 1.3; CI 1.0–1.7) and over 75 years of age (RR 1.8; CI 1.2– 2.7), and reverse hybrid THAs in women over the age of 75 (RR 1.5; CI 1.1–1.9) had higher risk of revision compared with cemented. Hybrid THAs (RR 1.0; CI 0.9–1.2) and reverse hybrid THAs (RR 1.0; CI 0.7–1.3) had similar risk of revision due to any cause as cemented THAs. Interpretation — Uncemented stems (all-uncemented and reverse hybrid THAs) had increased risk of revision in women over 55 years of age, mainly due to periprosthetic fracture and dislocation, and should probably not be used in THA in these patients.

Cemented THAs have been reported to have better overall implant survival than uncemented THAs (Hailer et al. 2010, Mäkelä et al. 2014). Still, there has been a worldwide increase in the use of uncemented THAs, including in elderly patients (Troelsen et al. 2013, Mäkelä et al. 2014). Cemented THAs have been reported to be prone to aseptic loosening, mostly in younger patients, and in the long term, whereas THAs with uncemented components have been prone to revisions due to femoral fractures, dislocations, and infections, often early postoperatively (Pedersen et al. 2014). Differences in prosthesis survival between all-cemented and all-uncemented THAs seem to have evened out during the last decade, and reverse hybrid (uncemented stem and cemented cup) and hybrid fixation (cemented stem and uncemented cup) have shown good results in primary THA (Troelsen et al. 2013, Wyatt et al. 2014, Wangen et al. 2017). In most reports, the outcomes were stratified by age, with results in favor of cemented THAs in the oldest patients. Sex is considered less frequently. There may be need for a more differentiated approach to what mode of fixation would be beneficial for individual patients. One needs to look at all the different reasons for revision in the same cohort. In addition, to eliminate the impact of “poor prostheses” and make the assessment relevant, one should compare the findings in a “best-case” scenario, investigating only commonly used, contemporary, and well- documented prostheses. We compared prosthesis survival for primary all-cemented, all-uncemented, reverse hybrid (uncemented stem and cemented cup), and hybrid (cemented stem and uncemented cup) THAs relative to sex and age. We assessed the risk of revision for different causes, and assessed whether there were groups of patients in whom certain modes of THA fixation were superior or inferior.

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Table 1. Included commonly used, contemporary, and well-documented stems and cups employed in THA in Norway 2005-2017 THA fixation

Stem

Cemented Exeter1,

Cup

Elite4, IP/SP13, Spectron EF2, Contemporary1, Marathon4, Lubinus SP23, Exeter X3 Rimfit1, Charnley Modular4 Reflection (XLPE)2 Uncemented Corail4, Reflection uncemented2, Filler5, Trilogy7, Igloo5, Trident1, Hactiv6 Pinnacle4, R32 Reverse hybrid Corail4, Exeter1, Elite4, IP/SP13, Filler5, Contemporary1, Marathon4, Hactiv6 Exeter X3 Rimfit1, Reflection (XLPE)2 Hybrid Exeter1, Reflection uncemented2, Spectron EF2, Trilogy7, Trident1, Lubinus SP23, Pinnacle4, R32 Charnley Modular4 1 Stryker, 2 Smith & Nephew, 3 Waldemar 5 Biotechni, 6 Evolutis, 7 Zimmer Biomet.

Exeter1,

LINK, 4 DePuy,

Primary THAs in the NAR 2005–2017 n = 97,840 Excluded (n = 28,691): – THAs with uncommonly used components (<1,000), 11,645 – poor or dated THAs, 14,890 – THAs without 10-year documentation, 2,156 Commonly used, contemporary, well documented primary THAs n = 69,149 Excluded due to missing variables a (n = 2,154): – ASA class, 986 – indication for THA, 174 – surgical approach, 486 – articulation, 598 THAs included in the analysis (n = 66,995): – cemented, 25,687 – uncemented, 16,006 – reversed hybrid, 23,312 – hybrids, 1,999

Figure 1. Flowchart of inclusion and exclusion of THAs. a There may be more than 1 missing variable per THA.

Patients and methods Since its inception in 1987, the Norwegian Arthroplasty Register (NAR) has registered detailed information on primary THAs and THA revisions in Norway. Among the data collected is the patient’s identity, date of operation, indication for primary THA, type of implant, method of fixation, and other surgery-related factors. In addition, information on patientrelated factors like sex, age, and comorbidities is registered. The unique identification number of each Norwegian links the primary THA to any subsequent revisions, and the National Population Register, which provides information on death or emigration. The definition of revision is removal or exchange of the whole prosthesis or part(s) of the prosthesis. The surgeon fills in the register form immediately after surgery, and this is mailed and entered electronically at the NAR. The present study is based on validated data from the NAR, with 97% completeness of reporting of primary THAs, 88% reporting of revisions, and 100% coverage of Norwegian hospitals (Furnes et al. 2019). For this study, we assessed the fixation mode of commonly used, contemporary, and well-documented implants in cases with complete information on patient characteristics. A THA was considered commonly used when both the cup and stem had been used in more than 1,000 THAs, and contemporary when the cup and stem were still in use or used in at least 10 years of the study period. A THA was considered well documented if it had a documented 10-year survival of more than 90%. Whether the THAs were well documented were evaluated through: (1) Results in the NAR, (2) evaluation of the British Orthopaedic Device Evaluation Panel, and lastly (3) results in other arthroplasty registers with sufficient length of followup (i.e., Nordic, England and Wales, Australia). 10-year docu-

mentation was evaluated at the time of the analyses. Implants with documented poor performance were excluded. Comorbidity according to the ASA classification has been registered in the NAR since 2005. In addition, the use of highly cross-linked polyethylene (XLPE) was established at that time. Therefore, the period of inclusion and observation for the present study was from January 1, 2005 to December 31, 2017. From this time period, the NAR contained data on 97,840 primary THAs. 30,845 THAs were excluded due to infrequent use, poor performance, terminated use, lack of 10-year documentation, or due to missing information on essential variables. In the end, 66,995 primary THAs in 55,935 patients were eligible for analyses (Table 1 and Figure 1). Statistics We performed Kaplan–Meier (KM) survival analyses in addition to adjusted survival analyses by Cox regression models. Time of revision due to any cause or revision due to aseptic loosening, deep infection, periprosthetic fracture, dislocation, or other reasons were the endpoints in the analyses. All THAs were followed until their first revision, until the date of death or emigration of the patient, or until censoring at December 31, 2017. Patients were censored at time of death or emigration by linkage to the National Population Register. Adjusted hazard rate ratios, as a measure of relative risk (RR), were estimated for types of fixation, overall, for each sex, and in 3 age groups. In the Cox analyses, we adjusted for sex, age, ASA class, indication for primary THA, surgical approach, articulation, and head size of the prosthesis. Further, we adjusted for year of primary surgery to minimize the effect of time-dependent confounding.

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uncemented THAs were younger and slightly healthier than those with cemented THAs, with reverse THA Cemented Uncemented Reverse hybrid Hybrid hybrid and hybrid THA patients Included THAs 25,678 16,006 23,312 1,999 as intermediate groups (Tables 2 Included patients 22,537 13,706 20,259 1,689 and 3). 66% of the cemented stems Revised THAs at 10 years, n (%) 918 (3.6) 535 (3.3) 711 (3.0) 46 (2.3) Mean follow-up (range), years 5.8 (0–13) 3.9 (0–13) 4.4 (0–13) 3.1 (0–13) were polished taper slip (forced Median follow-up (IQR), years 5.8 (2.9–8.6) 3.7 (1.3–6.3) 4.2 (2.1–6.3) 2.3 (1.1–3.9) closed) stems. Mean age (range) 72 (25–97) 63 (12–95) 67 (16–97) 68 (21–96) Among the included 66,995 priMean ASA class 2.1 1.9 2.0 2.0 mary THAs, 2,210 (3.3%) were IQR: interquartile range revised. The 10-year KM survival and adjusted implant survival was 94–95% for all 4 modes of fixation The analyses were performed in accordance with the guide- (Figure 2, Table 4, see Supplementary data). However, comlines for statistical analyses of arthroplasty register data (Rans- pared with cemented THAs, uncemented THAs had a 40% tam et al. 2011). The proportional hazard assumptions of the higher risk of revision. Reverse hybrid and hybrid THA had Cox survival analyses were not completely fulfilled between the a similar risk of revision to cemented (Figure 2, Table 4, see 4 modes of fixation when tested by smoothed Schoenfeld residu- Supplementary data). als (Figures 3 and 5). This resulted in assessment of the risk of revision 0–1 year, 1–3 years, and 3–10 years postoperatively and Fixation and sex in the age groups less than 55, 55–75, and over 75 years. Men had a higher risk of revision (RR 1.6; CI 1.4–1.7) than In earlier register studies from the NAR we found that women (Figure 2). The risk of revision after uncemented THA potential overestimation of incidence of revision through the was higher in both men and women, whereas reverse hybrid effect of competing risks (death and revision) is negligible. and hybrid THAs had similar overall revision risks compared The competing risk analyses (Fine & Grey) will therefore give with cemented THAs within each sex (Figure 2, Table 4, see similar results to the Cox analyses (Ranstam and Robertsson Supplementary data). 2017). Based on this we chose to include results only from KM and Cox analyses. Bilateral THAs are dependent observa- Fixation, sex, and age tions, but the influence of bilaterality has been found to have In women the risk of revision after uncemented THA, comnegligible influence on outcome (Lie et al. 2004, Ranstam et pared with cemented, increased with age (Figure 3, Table 4, al. 2011). Hence, patients with bilateral THAs were included, see Supplementary data). In addition, the risk of revision after reverse hybrid THA, compared with cemented THA, was and considered independent. 95% confidence intervals (CI) were calculated for sur- increased in women older than 75 years (Figure 3, Table 4, see vival rates and RRs. We used the IBM SPSS 24.0 (IBM Corp, Supplementary data). In men, the risk of revision after uncemented THA was Armonk, NY, USA) and R statistical software (R Centre for Statistical Computing, Vienna, Austria) packages for analyses, increased compared with cemented THAs (Figures 2 and 3, and the study was performed in accordance with the STROBE Table 4, see Supplementary data). However, in contrast to women, the results for uncemented and reverse hybrid THAs and RECORD statements. were similar to cemented THAs in men over 55 years of age Ethics, data sharing plan, funding, and potential con(Figures 2 and 3, Table 4, see Supplementary data). Neverflicts of interests theless, there was a trend of increased risk of revision for The registration of data and the study was performed confi- uncemented, compared with cemented, THAs for men over dentially on patient consent and according to Norwegian and 75 years of age (Figures 2 and 3, Table 4, see Supplementary EU data protection rules. Data may be accessible upon appli- data). cation to the NAR. The study was fully financed by the NAR, Fixation, sex, and causes of revision and no conflict of interest is declared. Deep infection (1.2 %) was the most common cause of revision, followed by dislocation (0.7%), aseptic loosening (0.7%), periprosthetic fractures (0.4%), and other causes of revision Results (pain, wear, breakage of components, osteolysis, anisomelia, 65% of the THA patients were women, mean age was 68 years etc.) (0.4%). 93% of the periprosthetic fractures involved the (12–97), and mean ASA class was 2.0. Median follow-up was femur and 7% the acetabulum. 4.6 years (interquartile range: 2.1–7.2). The group of cemented In men, the risk of revision due to infection was slightly lower THAs had the longest follow-up. In general, patients with after reverse hybrid THA, compared with cemented (Table 5, Table 2. Main characteristics of the study population by modes of THA fixation

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Table 3. Distribution of patient and surgery related factors by mode of fixation

Number Number Cemented Uncemented Reverse of THAs revised (%) (%) hybrid (%) Hybrid (%) n = 66,995 n = 2,210 n = 25,678 n = 16,006 n = 23,312 n = 1,999

Risk factors

Sex Male 23,235 Female 43,760 Age < 45 2,055 45–54 5,455 55–64 15,707 65–74 24,484 75–84 16,462 ≥ 85 2,832 ASA class 1 12,501 2 41,924 3 12,339 4 231 Indication for primary THA Osteoarthritis 52,305 Inflammatory hip disease 1,495 Acute hip fracture 1,981 Complication after hip fracture 2,978 Complication after childhood hip disease 6,169 Osteonecrosis of the femoral head 1,683 Other diagnosis 384 Surgical approach Anterior 3,390 Anterolateral 6,906 Lateral 28,469 Posterolateral 28,230 Articulation Metal-poly 14,583 Metal-XLPE 29,827 Ceramic-poly 2,505 Ceramic-XLPE 16,920 Ceramic-ceramic 3,160 Head size, mm 28 31,559 32 31,557 36 3,879

989 1,221

30 70

39 61

36 64

0.3 2 14 39 40 7

8 16 31 33 12 1

3 9 29 37 19 3

2 10 27 29 27 6

368 1,336 495 11

13 62 24 0.5

25 62 13 0.3

20 63 17 0.2

16 68 16 0.3

1,698 49 73 143

80 2 4 6

72 2 2 3

80 2 3 4

71 1 1 3

169

93 17

2 0.6

3 0.8

3 0.4

3 0.3

98 240 1,028 844

0 5 54 41

9 3 22 66

8 23 46 23

0 1 8 92

626 857 87 544 96

51 44 1 4 0

0.2 31 2 48 19

6 51 9 34 0

1 85 2 10 2

1,219 875 116

65 33 2

14 71 15

53 46 1

18 52 30

75 196 505 784 548 102

Figure 4). The risk of revision due to dislocation, however, was 2.6-fold increased after uncemented THA, compared with cemented (Table 5, Figure 4). In women, the risk of revision due to periprosthetic fracture was grossly increased with an uncemented stem (uncemented or reverse hybrid THA) (Table 5, Figure 4). Even women with hybrid THAs had an increased risk of revision due to periprosthetic fracture, but the number of revisions (4) was very low in this group (Table 5). The risk of revision due to aseptic loosening, however, was decreased after uncemented THA in women, compared with cemented THAs. Fixation, sex, causes of revision, and time postoperatively Uncemented THAs had an increased risk of revision in the first year postoperatively compared with cemented THAs (Figure 5, Table 6, see Supplementary data). This was mainly due to increased risk of aseptic loosening (or lack of fixation), periprosthetic fracture, and dislocation in both

Adjusted implant survival (%) – all

Adjusted implant survival (%) – men

Adjusted implant survival (%) – women

100

Cemented Reverse hybrid Hybrid Uncemented

Years postoperatively

Figure 2. Adjusted implant survival curves with any revision as endpoint, for the 4 types of THA fixation in all THAs, THA in males, and THA in females, adjusted for age, sex (in all THAs only), ASA class, indication for primary THA, surgical approach, articulation, head size of the prosthesis, and year of primary surgery

Acta Orthopaedica 2020; 91 (1): 33–41

Log relative risk – women

–1

–2

–3

men and women (Table 6, see Supplementary data). During the first year postoperatively, compared with cemented THAs, reverse hybrid THAs also had a higher risk of aseptic loosening in both sexes (Table 6, see Supplementary data). In women, the risk of revision due to periprosthetic fracture after uncemented THA was increased 19-fold in the first year postoperatively, compared with cemented THAs (Table 6, see Supplementary data). In contrast to men, women had an 11 times increased risk of revision due to periprosthetic fracture after reverse hybrid THAs (Table 6, see Supplementary data) in the first year postoperatively. Between 1 and 3 years, the risk of revision was lower for uncemented, reverse hybrid, and hybrid THAs compared with cemented THAs, in both men and women, mainly due to increased risk of aseptic loosening after cemented THAs (Figure 5, Table 6, see Supplementary data). From 3 to 10 years postoperatively all 4 modes of fixations had similar overall risk of revision (Figure 5, Table 6, see Supplementary data). However, both men and women had a lower risk of revision due to aseptic loosening after uncemented THA (Table 6, see Supplementary data). Women, in contrast to men, had grossly increased risk of revision due to periprosthetic fracture 3 to 10 years after all THAs involving uncemented components, compared with cemented THAs (Table 6, see Supplementary data).

–3 20

100

Log relative risk – men

–1

–2

100

–3

–3 20

100

Age at primary THA

Figure 3. Graphical representation of the relationship between age at primary THA and the log relative risk (RR) for revision due to all causes for uncemented and reverse hybrid compared with cemented THAs, for women and men with 95% confidence intervals. The horizontal green line shows the reference hazard rate ratio (RR = 1) of cemented THAs. The vertical lines indicate 55 and 75 years of age. We adjusted for ASA class, indication for primary THA, surgical approach, articulation, head size of the prosthesis, and year of primary surgery in the analyses. Hybrid THAs are omitted due to low numbers. Adjusted implant survival (%) aseptic loosening – women

deep infection – women

periprosthetic fracture – women dislocation – women

other causes – women

100

Uncemented Reverse hybrid Cemented

97 0

aseptic loosening – men

deep infection – men

periprosthetic fracture – men

dislocation – men

other causes – men

100

97 0

Years postoperatively

Figure 4. Adjusted implant survival curves for different causes of revision for 3 types of THA fixation in women and men, adjusted for age, ASA class, indication for primary THA, surgical approach, articulation, head size of the prosthesis, and year of primary surgery. Hybrid THAs are omitted due to low numbers.

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hybrid THAs had similar overall results to cemented THAs, except for a reverse hybrid in women over the age of 75 THAs in men THAs in women years, where the risk of revision THAs Revisions Relative risk (CI) THAs Revisions Relative risk (CI) was higher. Aseptic loosening Traditionally, uncemented Cemented 7,756 83 1 17,922 118 1 THAs have been found, as in Uncemented 6,296 39 0.9 (0.5–1.6) 9,710 39 0.5 (0.3–0.8) our study, to have higher reviReverse hybrid 8,466 69 0.9 (0.6–1.5) 14,846 99 1.0 (0.7–1.4) Hybrid 717 2 0.5 (0.1–2.1) 1,282 1 0.2 (0.0–1.2) sion rates than cemented THAs Infection (Hailer et al. 2010, Mäkelä et Cemented 7,756 156 1 17,922 193 1 al. 2014, Kandala et al. 2015). Uncemented 6,296 106 1.1 (0.8–1.6) 9,710 66 1.3 (0.9–1.9) Reverse hybrid 8,466 126 0.7 (0.5–0.9) 14,846 119 0.9 (0.7–1.2) Despite this knowledge, there Hybrid 717 9 0.8 (0.4–1.6) 1,282 13 1.5 (0.8–2.8) has been a paradoxical increase Periprosthetic fracture in the use of uncemented THA Cemented 7,756 33 1 17,922 23 1 Uncemented 6,296 26 1.8 (0.9–3.6) 9,710 41 12.3 (6.2–24) (Troelsen et al. 2013, Mäkelä et Reverse hybrid 8,466 33 1.4 (0.7–2.6) 14,846 81 9.9 (5.6–18) al. 2014). Recent development Hybrid 717 0 1,282 4 7.4 (2.3–24) of wear-resistant articulating Dislocation Cemented 7,756 84 1 17,922 156 1 surfaces (i.e., XLPE), together Uncemented 6,296 71 2.6 (1.6–4.4) 9,710 65 1.8 (1.1–2.8) with manufacturers’ marketing Reverse hybrid 8,466 31 0.6 (0.4–1.0) 14,846 50 0.7 (0.4–1.0) skills, may have induced this Hybrid 717 5 1.1 (0.4–3.0) 1,282 6 1.2 (0.5–2.9) Other optimism in uncemented fixaCemented 7,756 24 1 17,922 48 1 tion among surgeons (Wechter Uncemented 6,296 39 1.4 (0.6–3.0) 9,710 43 1.2 (0.6–2.2) et al. 2013, Giebaly et al. 2016). Reverse hybrid 8,466 50 1.5 (0.8–2.9) 14,846 53 0.9 (0.6–1.6) Hybrid 717 3 1.6 (0.4–5.9) 1,282 3 1.0 (0.3–3.5) At least according to earlier findings from our register, the main problem with earlier generations of uncemented implants was wear and wear-related problems (osteolysis, loosening) (Havelin et al. 2000, 2002, Discussion Hallan et al. 2010). There is an increasing bulk of evidence We found good overall survival for common, contempo- that these issues are less of a problem with modern designs rary, well-documented primary THAs regardless of fixation (Broomfield et al. 2017, Devane et al. 2017). Yet another posmethod: cemented, uncemented, reverse hybrid, or hybrid sible reason for the increased usage of uncemented THAs may fixation. However, uncemented THAs had a slightly higher be inferior results of some commonly used cemented implants overall risk of revision compared with cemented THAs. This (Espehaug et al. 2009, Hallan et al. 2012). We assessed condifference was mainly caused by an increased risk of peri- temporary THAs, in a “best-case” scenario, comprising all prosthetic fracture and dislocation after uncemented THA, in patients in a national cohort. We still found inferior results particular when used in elderly women. Reverse hybrid and for uncemented THAs, compared with cemented and reverse Table 5. Risks of revision due to different causes, for men and women, for the 4 groups of fixation, adjusted for age, ASA class, indication for primary THA, surgical approach, articulation, head size of prosthesis, and year of primary surgery

Log relative risk

Log relative risk 2

Uncemented Cemented

Reverse hybrid Cemented

Hybrid Cemented

–1

–2

–2 0

Years postoperatively

Figure 5. Graphical representation of the relationship between year postoperatively and the log relative risk (RR) for revision due to all causes for uncemented, reverse hybrid, and hybrid THAs, compared with cemented THAs, with 95% confidence intervals. The horizontal green line shows the reference hazard rate ratio (RR = 1) of cemented THAs. The vertical lines indicate 1 and 3 years postoperatively. We adjusted for sex, age, ASA class, indication for primary THA, surgical approach, articulation, head size of the prosthesis, and year of primary surgery in the analyses

Acta Orthopaedica 2020; 91 (1): 33–41

hybrid THAs. The differences in implant survival were small, but sex and age influenced the results. Periprosthetic fractures was the revision cause with the most pronounced differences between the sexes. Thus, this is the strongest finding in our study, and has been found by others (Abdel et al. 2016, Wangen et al. 2017, Chatziagorou et al. 2019). Periprosthetic fractures were found to be strongly associated with uncemented and reverse hybrid THAs, and mostly so in women. The fractures were mainly located around the femoral stem. The risk of revision due to periprosthetic fracture was higher in women from the age of 55 and increasing with age. In addition, the risk of revision due to periprosthetic fractures associated with uncemented stems continued to be high up to 10 years postoperatively. This was in contrast to men, where there was only a trend of increased risk of revision due to periprosthetic fracture after 75 years of age, and only early postoperatively. The use of uncemented components in patients with deteriorating bone stock should probably be avoided, since impaction of components may result in fissures due to fragile cortical bone (Piarulli et al. 2013, Sidler-Maier and Waddell 2015, Abdel et al. 2016, Hasegawa et al. 2017, Dammerer et al. 2019). The poorer results after uncemented stems in elderly patients are supported by literature on both THA and hemiarthroplasty (Gjertsen et al. 2012, Mäkelä et al. 2014, Wangen et al. 2017). Womens’ grossly increased risk of periprosthetic fractures with uncemented stems, both early postoperatively and 3–10 years postoperatively, may be due to bone density loss (Alm et al. 2009, Sköldenberg et al. 2014). One of the cemented femoral stems included in our study was the polished taper slipped Exeter™ prosthesis. This implant has a long and successful record of accomplishment. However, polished taper slip (force closed) prostheses have been reported to have an increased risk of periprosthetic fracture (Thien et al. 2014, Palan et al. 2016, Kristensen et al. 2018, Chatziagorou et al. 2019). The Exeter stem (polished taper slip) was used in 66% of the THAs with cemented stems in the present study and inferior outcome with one stem design or brand could potentially affect the whole group. The increased risk of periprosthetic fractures after uncemented THA could therefore have been even more pronounced if other designs of cemented stems were used to a larger degree (Thien et al. 2014). Also on the acetabular side, uncemented components have been associated with periprosthetic fracture (Hasegawa et al. 2017, Dammerer et al. 2019). The 2nd most common cause of revision was dislocation. Both men and women had an increased risk of revision due to dislocation after uncemented THA, compared with cemented THA, in the first year postoperatively. This was despite the fact that a 28 mm prosthesis head was more common in cemented THAs. In addition, there was higher risk of early aseptic loosening for THAs involving uncemented stems. This may indicate problems with initial stability and orientation of components for uncemented THAs, and in particular stems. Bone stock quality and geometry of the implant may have influ-

enced these findings (Ogino et al. 2008, Finnila et al. 2016). The variation in the orientation of the components, especially the cup, may be larger with uncemented implants (Nishii et al. 2015, Suksathien et al. 2018). Wedge shaped femoral stems, commonly used in Norway, tend to dictate the version of the stem to a large degree (Al-Dirini et al. 2019). Thus, any malpositioning of the cup cannot always be sufficiently adjusted for with the stem. Also, the uncemented stem may subside in the femur more often than cemented ones (Selvaratnam et al. 2015). It may be that these factors lead to suboptimal position of the THA components, and thus to a higher risk of revision due to dislocation. The finding that hybrid and reverse hybrid THAs did not have increased risk of revision due to dislocation may indicate that there is an additive effect on the risk of dislocation when both components are uncemented. Infection was the most common cause of revision after primary THA. This may partly reflect an increased risk of revision due to infection as reported in other studies (Dale et al. 2012). Aseptic loosening was the 3rd most common cause of revision. This may confirm that our “best-case” selection included implants with good longevity regarding fixation, as intended. However, it also reflects the relatively short follow-up (median follow-up 4.6 years). A dilemma in evolution of arthroplasty is the conflict of interest between innovation and documentation of longevity. This is also illustrated by the contradiction in the inclusion criteria of the present study: contemporary and well documented. The differences between implants and fixation techniques may only be evident beyond 10–15 years postoperatively. In order to study contemporary THAs, we had a relatively short follow-up. Longer follow-up may change the results, particularly concerning revisions due to aseptic loosening, which is still the most common late cause of revision in studies with long term follow-up (Hailer et al. 2010). The follow-up was also slightly different for the 4 fixation groups as there had been a shift towards increased use of uncemented and reverse hybrid THAs with time. However, we had no indications on improved results for uncemented THAs, compared with cemented, at 10-year follow-up. Strengths and limitations We had the benefit of detailed information on patient- and surgery-related confounders. By way of example, the NAR uses catalogue numbers to identify implants and cements, securing near 100% coding accuracy. Accordingly, we were able to adjust for important differences between the patient groups. Because revisions are relatively rare, it may only be possible to study specific causes of revision in large databases such as national arthroplasty registers. We included a large number of common, contemporary, and well-documented THAs and detailed information on causes of revision and exact survival times. Because the results were based on data from a nationwide THA population, the results should also have good external validity.

Some selection bias and unknown confounding may, however, have affected our results. Patients who received uncemented THAs were in general younger and healthier than those who received cemented THAs. Hospitals with a preference for one type of fixation may have differences in case mix compared with hospitals choosing another fixation for the majority of their patients, differences that were not adjusted for in the analyses. We found that reverse hybrid THAs had a lower risk of revision due to infection, compared with cemented THAs, which could be the result of such bias. However, considering the number of cases, coverage of hospitals, completeness of the data, the strict inclusion criteria, and the fact that we adjusted for several clinically important risk factors in the analyses, we expect the selection bias and unknown confounding to be minor, and the study to be without major systematic errors. The NAR does not include radiographs nor information on bone stock quality. Assumptions on periprosthetic fractures and fixation relative to elderly women were therefore based on epidemiological and not individual data. In conclusion, longevity of primary THAs was good for cemented, uncemented, reverse hybrid, and hybrid THAs when common, contemporary, well-documented implants were used. However, uncemented THAs had a higher risk of revision, mainly due to more periprosthetic fractures and dislocations. Uncemented fixation should be considered as best avoided in women aged 55–75 years and avoided in women over the age of 75. The increased risk of revision due to periprosthetic fractures associated with uncemented components in elderly women, as found in our study, has resulted in a quality project in Norway where surgeons are advised to use only cemented stems in women over the age of 75. Supplementary data Tables 4 and 6 are available as supplementary data in the online version of this article, http://dx.doi.org/10.1080/17453674. 2019.1682851

The authors thank all Norwegian surgeons for conscientiously reporting THAs to the NAR, and the secretaries, IT analyst, and statisticians at the NAR for entering the data and preparing them for analyses. HD wrote the manuscript. HD, SAL, and AMF analyzed the data. All authors contributed to the design of the study, critical evaluation of the data and analyses, interpretation of the findings, and critical revision of the manuscript, through all stages of the study. Acta thanks Inari Laaksonen and Alma B. Pedersen for help with peer review of this study.

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Outpatient total hip or knee arthroplasty in ambulatory surgery center versus arthroplasty ward: a randomized controlled trial Christian HUSTED 1, Kirill GROMOV 1, Helle Krogshøj HANSEN 1, Anders TROELSEN 1, Billy B KRISTENSEN 2, and Henrik HUSTED 1 1 Department

of Orthopedic Surgery, Copenhagen University Hospital, Hvidovre; 2 Ambulatory Surgery Center, Copenhagen University Hospital, Hvidovre, Denmark Correspondence: christianhusted@live.dk Submitted 2019-08-17. Accepted 2019-10-08.

Background and purpose — Discharge on the day of surgery (DOS) in selected patients operated with total hip arthroplasty (THA) or total knee arthroplasty (TKA) has been shown to be feasible, but different factors may determine whether patients are discharged on the DOS or not and setting may be one of them. We investigated the importance of the setting in which the short stay following outpatient THA or TKA takes place: was there a difference between the proportion of patients being discharged on the DOS from an ambulatory surgery center (ASC) compared with patients staying on an arthroplasty ward? Patients and methods — 50 patients (30 TKA, 20 THA) were included in the study and postoperatively randomized to either staying in the ASC or the arthroplasty ward until discharge. All patients were operated under general anesthesia by the same experienced surgeon (HH) and were discharged upon fulfillment of standardized discharge criteria. Results — 24/25 of the patients who stayed in the ASC compared with 20/25 of the patients on the arthroplasty ward were discharged on the DOS following fulfillment of discharge criteria (p = 0.08). All THA patients were discharged on the DOS and significantly more TKA patients were discharged from the ASC (15/16) vs. from the ward (9/14) (p = 0.04). Interpretation — Despite fixed discharge criteria, the logistical setting may play a role for achieving discharge on DOS and the ASC may facilitate achieving discharge criteria earlier especially in TKA.

The successful implementation of fast-track hip and knee arthroplasty (THA and TKA) in many departments has resulted in a reduction in perioperative morbidity and mortality, with a concomitant reduction in length of stay (LOS) and a reduction in cost (Andreasen et al. 2017) as functional discharge criteria were achieved earlier. Therefore, standardized outpatient arthroplasty has gained interest in an increasingly competitive financial environment (Argenson et al. 2016, Vehmeijer et al. 2018). Fast-track is based on clinical and logistical optimization via identification of clinical and logistical barriers to overcome (Husted et al. 2011, Husted 2012). Accordingly, implementation of outpatient arthroplasty requires monitoring of safety, patient satisfaction, and economic impact. A various number of unselected THA and TKA patients are eligible for outpatient surgery depending on underlying demographics and comorbidities of the specific population. Though many patients undergo surgery in such a setting, the proportion of patients who are discharged on the day of surgery (DOS) as intended varies substantially from around 25% (Gromov et al. 2017) to 75–99% (Berger et al. 2009, Chen and Berger 2013, Hartog et al. 2015, Parcells et al. 2016, Goyal et al. 2017). Since no reports of consistent 100% discharge on DOS have been published, back-up allowing overnight stays for medical/surgical complications is considered mandatory by some (Crawford et al. 2019). While patient selection clearly plays a role in successful DOS discharge following THA and TKA, the logistical set-up may also influence the number of patients fulfilling the discharge criteria on DOS (DeCook 2019). This RCT examines whether outpatient surgery and subsequent postoperative stay at an ambulatory surgery center (ASC) improved discharge on DOS compared with a postoperative stay on an arthroplasty ward.

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Screened THA patients n = 64 Excluded (n = 44): – not meeting inclusion criteria, 41 – refused to participate, 3 Had surgery n = 20

Screened TKA patients n = 90 Excluded (n = 60): – not meeting inclusion criteria, 58 – refused to participate, 2 Had surgery n = 30

Outpatient surgery in daycare facility, 9 Discharge on day of surgery, 9

Outpatient surgery in daycare facility, 16 Discharge on day of surgery, 15

Staid at standard patient ward, 11 Discharge on day of surgery, 11

Staid at standard patient ward, 14 Discharge on day of surgery, 10

Figure 1. Flow chart of included THA patients. Table 1. Inclusion criteria • Patients with clinical and radiological osteoarthritis of the hip suitable for primary cementless THA and patients with clinical and radiological osteoarthritis of the knee suitable for primary CR TKA • Age 18–80 • ASA < 3 • Interested in and motivated for discharge on DOS • Family/relatives to be present for > 24 hours after discharge • Able to understand and give consent to the study

Patients and methods The CONSORT guidelines were followed. 154 patients (64 THA, 90 TKA) were screened for eligibility to have fast-track surgery with the intent of discharge on the DOS. Of those, 50 patients (33%) (20 THA, 30 TKA) were included in the study based on the inclusion criteria (Table 1, Figures 1 and 2). All 50 surgeries were done by the same experienced surgeon (HH) in the ASC between August 2016 and November 2018. Patients received information concerning the surgical procedure and intent of discharge on DOS provided there was fulfillment of the discharge criteria (Table 2). 1 week before surgery patients were informed and instructed on the upcoming procedure by the same experienced anesthesiologist (BBK) and physiotherapist. Patients received 400 mg of celecoxib and 1 g of paracetamol on the morning of surgery. A single intraoperative dose of 125 mg of methylprednisolone was administered IV. General anesthesia was achieved by 2–3 mg/kg of IV propofol and 0.5 µg/ kg/min remifentanil. A laryngeal mask was used for airway management and no oxygen was given during induction. Continuous infusion of propofol 10 mg/mL, 4–6 mg/kg/h and remifentanil 2 mg, 0.25–0.5 µg/kg/min was used to maintain anesthesia. Normothermia was maintained through forced air warming. Fluid loss during surgery was replaced with 0.9% saline, 15 mL/kg/h. All THAs were performed using a standard posterolateral approach with simple posterior soft-tissue repair. Infiltration anesthesia (LIA) was not used in THA’s. All

Figure 2. Flow chart of included TKA patients. Table 2. Discharge criteria • Activity level: Steady gait with crutches, no dizziness. Stairs if required • Nausea and/or vomiting: Minimal and efficiently treated with or without medications • Vital signs: Must be stable and consistent with age and preoperative baseline. Systolic blood pressure within 20 mmHg of preoperative levels. Saturation > 95%. Pulse < 100 while resting • Pain: The level of pain that the patient has should be acceptable to the patient. VAS < 3 at rest and VAS < 5 on mobilization • Surgical bleeding: Postsurgical bleeding should be consistent with expected blood loss for the procedure and not require repeated dressing change. Patients should be hemodynamically stable (no tachycardia (pulse >100 at rest) and hypotension sBP < 100) and show no clinical signs of anemia (paleness, dizziness during mobilization and fatigue).

TKAs were performed using a standard medial parapatellar approach without the use of tourniquet. Measured resection technique was used with cutting guides applied externally on the tibia and intramedullary on the femur and application of local infiltration analgesia (LIA, 150 mL Ropivacaine). No drains were used for any surgery. Postoperative radiographs were obtained in the operating room, approved by the surgeon and handed out to the patient. Until discharge and in case of VAS > 50 mm at rest patients were given rescue analgesics consisting of sufentanil 5–10 µg IV or 10 mg of oral morphine. Postoperatively, 200 mg/12 h of celecoxib and 1 g of paracetamol/6 h were administered up to and including postoperative day 6. Furthermore, 10 tablets of 10 mg opioid (morphine) were given to the patient to use at home if needed. Further pain management was handled by the patients’ general practitioners. Postoperative nausea and vomiting were treated with 4 mg of ondansetron. Oral thromboprophylaxis consisting of rivaroxaban was started 6–8 hours after surgery and continued for 2 days. No mechanical thromboprophylaxis or extended oral thromboprophylaxis was used. Physiotherapy was started as soon as possible after surgery and focused on achieving unassisted gait with crutches. Immediately after surgery in the ASC the patients were randomly selected (opaque numbered envelopes not discriminat-

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Table 3. Demographics, numbers, and statistical significance TKA patients

Ambulatory Arthroplasty surgery center ward p-value

Male, n (%) Female, n (%) BMI, mean (SD) Age (years), mean (SD) ASA score 1, n (%) ASA score 2, n (%) Surgery time (min), mean (SD) Blood loss (mL), mean (SD) OKS, mean (SD) pre-surgery) 3 months post-surgery ΔOKS

8 8 28 (4.2) 58 (7.7) 8 8 56 (11) 209 (78) 26 (6) 35 (5) 9 (9)

5 9 29 (4.5) 63 (10.1) 4 10 53 (9) 0.5 179 (77) 0.3 22 (7) 29 (9) 7 (9)

0.05 0.03 0.7

ing between THA or TKA) either to be taken to the arthroplasty ward or to stay in the ASC. Patients meeting discharge criteria before 8 pm were discharged to their own homes (Table 2). Patients staying in the ASC not meeting the discharge criteria prior to 8 pm were transferred to the arthroplasty ward for overnight stay. All patients were discharged to their own homes. Statistics Prior to the study, a pilot series of 20 patients were operated at the ASC with 95% discharged on the DOS. As 24–28% were discharged from the arthroplasty ward in a previous study (Gromov et al. 2017) and we estimated that number could double (60%) with the focus of the study, a power calculation using power 0.8, alpha 0.05, beta 0.2 found 2 x 21 patients to be needed to show a statistical difference. Thus, we included 25 patients in each arm to account for potential dropout. The Pearson chi-Square test and the independent samples t-test were used to compare data. Data was tested for normality using the Shapiro–Wilk test. A statistically significant difference between two sets of comparable data was defined as p < 0.05. All statistical analyses were performed in IBM SPSS Statistics 25 (IBM Corp, Armonk, NY, USA). Ethics, registration, funding, and potential conflicts of interest No approval from the National Ethics Committee was necessary (study protocol presented and waived), as this was a non-interventional observational study. The study was approved by the Danish Data Protection Agency (registration no. 2007-58-0015) and registered with ClinicalTrials.gov (Identifier: NCT03896282). There was no funding and no conflict of interest.

Results On the DOS 44 of the 50 patients were discharged, then 5 patients 1 day after surgery and 1 patient 2 days after surgery.

THA patients

Ambulatory Arthroplasty surgery center ward p-value

Male, n (%) Female, n (%) BMI, mean (SD) Age (years), mean SD ASA score 1, n (%) ASA score 2, n (%) Surgery time (min), mean (SD) Blood loss (mL), mean (SD) OHS, mean (SD) pre-surgery 3 months post-surgery ΔOHS

4 5 25 (5) 58 (8.8) 6 3 61 (12) 272 (218)

5 6 26 (5) 60 (7.2) 9 2 54 (8) 272 (154)

0.1 1.0

24 (4) 41 (3) 17 (5)

21 (3) 38 (7) 17 (6)

0.1 0.3 0.9

According to the randomization, 11/20 THA and 14/30 TKA patients were transferred to the arthroplasty ward after surgery and 9/20 THA and 16/30 TKA patients stayed at the ASC after surgery. All 20 THA patients were discharged on DOS and 24/30 of the TKA patients were discharged on the DOS. 9/14 of the TKA patients who were transferred to the arthroplasty ward after surgery were discharged on DOS compared with 15/16 of the TKA patients staying at the ASC. All patients who were not discharged directly from the ASC were transferred to the arthroplasty ward and discharged home on the next day. Between patients staying at the ASC and the patients at the arthroplasty ward, sex, age, ASA score, BMI, surgery time, blood loss, and Oxford Hip Score prior to surgery was similar (Table 3). A statistically significant difference between the 2 groups of patients was found regarding Oxford Knee Score pre-surgery indicating that patients at the ASC had less pain and better function prior to surgery. Oxford Knee and Hip Scores were also recorded 3 months after surgery and compared with the preoperative scores. No statistically significant difference was found in the progression of these scores between the two groups (Table 3). 24/25 of all the patients who stayed at the ASC were discharged on the DOS compared with 20/25 of the patients on the arthroplasty ward (p = 0.08). All THA patients were discharged, but significantly more TKA patients were discharged from the ASC (15/16) vs. from the ward (9/14) (p = 0.04). 3 weeks after surgery, TKA patients had their staples removed and pain VAS scores were assessed at rest and during activity with weight-bearing on the knee. Among TKA patients who stayed on the arthroplasty ward following surgery, a mean VAS score of 2.6 (SD 1.6) was recorded at rest whereas the average VAS score among TKA patients staying at the ASC was 1.4 (1.2) at rest (p = 0.06). During weight-bearing activity TKA patients from the arthroplasty ward had a mean VAS score of 3.4 (1.5) compared with a mean VAS score of 2.3 (1.6) among TKA patients from the ASC (p = 0.09).

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The THA patients had their staples removed 2 weeks after surgery and pain VAS scores at rest and activity were also recorded here. At rest, THA patients from the arthroplasty ward had a mean VAS score of 2.3 (1.8) whereas THA patients from the ASC had a mean VAS score of 1.4 (1.4) (p = 0.3). During activity, a mean VAS score of 3.3 (1.6) was recorded among THA patients from the arthroplasty ward compared with 2.6 (1.5) within the group of THA patients from the ASC (p = 0.4).

Discussion In this single-center randomized controlled trial, we found more patients being discharged on the DOS when staying in the ASC compared with patients staying on the arthroplasty ward following identical discharge criteria. Since all THA patients were discharged on the DOS, the difference in proportion of same-day discharge between the ASC and the ward is exclusively due to TKA patients. Logistical factors that could influence LOS—and hence specifically ability to discharge on the DOS—have been studied and include weekday of surgery and surgical start time on the DOS (Husted and Holm 2006, Keswani et al. 2016, Boylan et al. 2017) as well as bypassing the post-anesthesia care unit facilitating earlier functional rehabilitation (Lunn et al. 2012). Also, the specific setting, including the location immediately after surgery (single bed, multiple beds in same room, open area like ASC), type of bed (regular hospital bed or recovery bed) and the staffing, including immediate availability of anesthesiologic assistance, may be of importance. Hence, we studied the importance of a set-up in the ASC where patients are lying in recovery beds in an open space with full visibility, nurses around them and an anesthetist present. This was compared with a traditional arthroplasty ward set up for fast track during more than 15 years and familiar with outpatient arthroplasty (Gromov et al. 2017) where the patients are lying in beds confined to their room with other inpatients around them, nurses not within sight in the room (but on call immediately outside) and no anesthesiologist present. Several factors may explain the difference in same-day discharge ratio. A dissimilarity in motivation for discharge on the DOS between the 2 patient groups seems plausible. Patients staying on the arthroplasty ward following surgery shared the ward with inpatients who were not planning on same-day discharge as opposed to patients in the ASC who were surrounded by fellow outpatients from different specialties all intended to be discharged within a few hours. This difference may induce psychological priming to same-day discharge. On the arthroplasty ward, patients were staying in regular beds with pillows and duvets whereas recovery beds were used at the ASC. While the former may not encourage patients to get out of bed, the recovery beds, being less comfortable, were also tipped in anti-Trendelenburg very early, mimicking

sitting and standing positions and thereby improving hemodynamics and trying to overcome orthostatic intolerance. Differences between staff/patient ratio on the arthroplasty ward and the staff at the ASC could also be part of the explanation as the latter is more staff-intensive allowing more focus on each patient but at a higher cost (Husted et al. 2018). This could affect the efficiency of management of pain, nausea, and dizziness as the staff on the arthroplasty ward have more patients to look after and therefore cannot administer medicine as quickly to patients in need of it. Also, in the ASC, a dedicated anesthesiologist is monitoring the patients closely postoperatively resulting in faster and more efficient management of pain, nausea, and dizziness, which ultimately ensures earlier fulfilment of the fixed functional discharge criteria. The presence of the anesthetist was indeed a major difference, which reflects the nature of the set-up in the ASC. Where both groups were treated similarly re pain medication (paracetamol, celecoxib, methylprednisolone, LIA in TKA, general anesthesia) and had access to the same standard medication re pain reduction when needed (given by the nurses in both locations), the anesthetist could be consulted if needed in the ASC. He could intervene earlier regarding gaining sufficient pain control or treat dizziness believed to be due to orthostatic intolerance (ephedrine). However, no recording of the amount of consulting or the need for intervention by the anesthetist was performed as the study aim was simply to illuminate whether the different set-ups including the presence of a dedicated anesthetist in the ASC influenced the number of patients who could be discharged on the day of surgery. All the differences above in the setting probably contribute to the increased number of TKA patients able to be discharged on the DOS. As THA is an operation with less surgical stress response and less postoperative pain compared with TKA (Andersen et al. 2009), it seems that the specific setting has less importance for this group of patients, which may also at least partly explain the higher incidence of same-day discharge in THA patients (Hartog et al. 2015). As no other study has focused on the potential importance of different set-ups, future studies are necessary in order to define which factors are of specific importance, including an economic evaluation, as same-day surgery is associated with very low cost provided there is no increase in readmissions (Husted et al. 2018). There were no mortalities, no strokes, no myocardial infarctions, no pulmonary embolisms, and no deep venous thrombosis within 90 days after surgery among all patients. These findings are in line with the previous fast-track findings of very low mortality and morbidity, especially regarding thromboembolic complications (Husted et al. 2010, Jørgensen and Kehlet 2016, 2017) which contributed to the early mobilization perfected in outpatient arthroplasty (Gromov et al. 2019). It has previously been established that fast-track surgery leads to reduced pain compared with regular joint care proto-

cols (Fransen et al. 2018) but very limited literature is available on the differences in pain between inpatients and outpatients subsequent to total joint arthroplasty (Goyal et al. 2017). In this study patients had VAS scores recorded post-surgery. For the TKA patients, nearly statistically significantly less pain at rest and upon activity was found after 3 weeks in the ASC group. These differences in pain could be attributed to the fact that the TKA patients from the ASC also had better OKS prior to surgery although it could also be a result of better pain management in the early hours after surgery. Since pain scores were lower for THA patients from the ASC (not significantly though), further studies are needed to determine this and early recovery trajectories including pain scores are important measurements (Klapwijk et al. 2017, Porsius et al. 2018). A strength of this study arises from the standardized surgical, anesthetic, and analgesic regime for all patients. The study might be under-powered to demonstrate potential differences between the groups for secondary outcomes, and it was not powered regarding evaluation of safety aspects. This study has several limitations. The number of patients was sufficient according to the power calculation and the conservative estimation of twice as many patients being discharged from the arthroplasty ward, but it turned out that 3 times as many patients were discharged on the DOS. Hence, nearly statistically significant differences may have become significant if more patients had been included. Although operation, anesthesia, pain protocol, and physiotherapy were identical, the different settings include a multitude of differences and hence it is impossible to differentiate which specific parameter is paramount. The staff on the arthroplasty ward may have focused more on discharge on the DOS compared with earlier studies as a consequence of the competitive setting. Staff experience/expectation may indeed influence the likeliness of discharge, even though the universal use of strictly functional discharge criteria may overcome this. We tried to take that into account by ensuring experience with the sameday procedure in both locations by running a pilot series, also in the ASC, before starting and by doubling the expected number of patients able to be discharged from the ward on the day of surgery. Further studies should focus on evaluating all the potential differences between the set-ups in order to find the best cost–benefit set-up for both patients and hospital, which should also include measurement of patient satisfaction with the stays in the 2 different set-ups. Another limitation could be the pooling of THA and TKA patients as it seems that THA patients are less sensitive to the setting. However, we did not find such a difference in earlier studies (Gromov et al. 2017). Finally, the external validity may be questioned as the findings in this study may be unique for these specific settings. In summary, more TKA patients were discharged on the DOS when staying at the ASC compared to patients staying on the arthroplasty ward. Therefore, setting appears to play a role when it comes to successful discharges on the DOS

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among outpatients undergoing THA and TKA. The reasons for this may be manifold and include use of recovery beds, nurse/patient ratio, visibility of staff, and other patients being discharged, as well as the presence of an anesthetist to reduce pain, nausea, and dizziness immediately. Pain trajectories may be improved by this for the first few weeks. These findings require further investigation in order to establish reasons of clinical relevance. The multidisciplinary approach has always been emphasized in fast-track arthroplasty with overnight stay (Husted 2012). but may be even more pronounced in outpatient surgery where the role of the anesthetist becomes especially evident (Oosterholt et al. 2017).

CH, KG, BBK and HH planned the study. KG, HKH, AT, BBK and HH were responsible for the logistical set up and collected the data. CH, KG, BBK, AT and HH analyzed the data. CH wrote the first draft of the paper, all authors revised the paper. Acta thanks Michael Clarius and Stephan Vehmeijer for help with peer review of this study.

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Hartog Y M den, Mathijssen N M C, Vehmeijer S B W. Total hip arthroplasty in an outpatient setting in 27 selected patients. Acta Orthop 2015; 86(6): 667–70. Husted H. Fast-track hip and knee arthroplasty: clinical and organizational aspects. Acta Orthop Suppl 2012; 83(346): 1-39. Husted H, Holm G. Fast track in total hip and knee arthroplasty: experiences from Hvidovre University Hospital, Denmark. Injury 2006; 37 (Suppl. 5):S31-5. Husted H, Otte K S, Kristensen B B, Ørsnes T, Wong C, Kehlet H. Low risk of thromboembolic complications after fast-track hip and knee arthroplasty. Acta Orthop 2010; 81(5): 599-605. Husted H, Lunn T H, Troelsen A, Gaarn-Larsen L, Kristensen B B, Kehlet H. Why still in hospital after fast-track hip and knee arthroplasty? Acta Orthop 2011; 82(6): 679-84. Husted H, Kristensen B B, Andreasen S E, Skovgaard Nielsen C, Troelsen A, Gromov K. Time-driven activity-based cost of outpatient total hip and knee arthroplasty in different set-ups. Acta Orthop 2018; 89(5): 515-21. Jørgensen C C, Kehlet H; Lundbeck Foundation Centre for Fast-track Hip and Knee Replacement Collaborative group. Early thromboembolic events ≤ 1week after fast-track total hip and knee arthroplasty. Thromb Res 2016; 138: 37-42. Jørgensen C C, Kehlet H; Lundbeck Foundation Centre for Fast-track Hip and Knee Replacement Collaborative group. Time course and reasons for

90-day mortality in fast-track hip and knee arthroplasty. Acta Anaesthesiol Scand 2017; 61(4): 436-44. Keswani A, Beck C, Meier K M, Fields A, Bronson M J, Moucha C S. Day of surgery and surgical start time affect hospital length of stay after total hip arthroplasty. J Arthroplasty 2016; 31(11): 2426-31. Klapwijk L C, Mathijssen NM, Van Egmond J C, Verbeek B M, Vehmeijer S B. The first 6 weeks of recovery after primary total hip arthroplasty with fast track. Acta Orthop 2017; 88(2): 140-4. Lunn T H, Kristensen B B, Gaarn-Larsen L, Husted H, Kehlet H. Postanaesthesia care unit stay after total hip and knee arthroplasty under spinal anaesthesia. Acta Anaesthesiol Scand 2012; 56(9): 1139-45. Oosterholt R I, Simonse L W, Boess S U, Vehmeijer S B. Designing a care pathway model: a case study of the outpatient total hip arthroplasty care pathway. Int J Integr Care 2017; 17(1): 2. Parcells B W, Giacobbe D, Macknet D, Smith A, Schottenfeld M, Harwood D A, et al. Total joint arthroplasty in a stand-alone ambulatory surgical center: short-term outcomes. Orthopedics 2016; 39(4): 223–8. Porsius J T, Mathijssen N M C, Klapwijk-Van Heijningen L C M, Van Egmond J C, Melles M, Vehmeijer S B W. Early recovery trajectories after fast-track primary total hip arthroplasty: the role of patient characteristics. Acta Orthop 2018; 89(6): 597-602. Vehmeijer S B W, Husted H, Kehlet H. Outpatient total hip and knee arthroplasty. Acta Orthop 2018; 89(2): 141-4.

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Changes in health-related quality of life are associated with patient satisfaction following total hip replacement: an analysis of 69,083 patients in the Swedish Hip Arthroplasty Register Gabrielle S RAY 1, Philip EKELUND 2,3, Szilard NEMES3,4, Ola ROLFSON 2–4, and Maziar MOHADDES 2–4 1 Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, USA; 2 Sahlgrenska University Hospital, Department of Orthopaedics, Gothenburg, Sweden; 3 Swedish Hip Arthroplasty Register, Gothenburg, Sweden; 4 Department of Orthopaedics, Institute of Clinical Sciences, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Correspondence: gabriellesdonahue@gmail.com Submitted 2018-10-16. Accepted 2019-10-09.

Background and purpose — Total hip replacement (THR) aims mainly to improve quality of life via restoration of hip function and provision of pain relief. This study sought to assess whether improvements in quality of life between the preoperative and 1-year postoperative period were associated with patient satisfaction Patients and methods — Data were extracted for 69,083 THR operations with complete data reported to the Swedish Hip Arthroplasty Register (SHAR) between 2008 and 2015. Health-related quality of life and patient satisfaction were captured using the Euro-Qol-5D (EQ-5D) and visual analogue scale (VAS), respectively. Multivariable analysis was performed to assess associations between the changes in preand postoperative EQ5D and patient satisfaction. Results — In patients reporting severe or moderate problems with mobility preoperatively, improvement to no problems was associated with numerically higher patient satisfaction (coefficient –18 [95% CI –22 to –14] and –18 [–18 to –17]). Improvement in the self-care dimension from severe or moderate problems to no problems was associated with numerically higher patient satisfaction (–15 [–16 to –14] and –13 [–15 to –11]). Improvement from severe problems with the ability to perform usual activities to no problems was associated with numerically higher patient satisfaction (–18 [–19 to –17]). This association was also found for improvement in pain/discomfort and anxiety/depression (–16 [–17 to –15] and –15 [–16 to –14]). Interpretation — Our results indicate that satisfaction with the operated hip is a valid patient-reported outcome reflecting the changes in different EQ-5D dimensions and should be included in the follow-up of patients after THR surgery.

The 2 main goals of total hip replacement (THR) are pain relief and restoration of hip function (Pivec et al. 2012). The success of total joint replacement has largely been measured through implant survivals and the 10-year success rate of THR has been reported to be as high as 95% (Pivec et al. 2012). Yet, 10–15% of patients undergoing THR report persistent pain and functional limitation postoperatively (Nikolajsen et al. 2006). It could be argued that using only implant survival analysis fails to identify patients who achieve the 2 primary goals of surgical intervention. These shortcomings of implant survival analysis have been identified (Wylde and Blolm 2011) and patient-reported outcome measures (PROMs) have been used as a more adequate indicator of surgical success from the patient’s perspective. PROMs and patient satisfaction measures are increasingly being utilized by surgeons, hospitals, insurance companies, and health policy-makers to monitor quality of services (Baumann et al. 2009). Patient satisfaction is known to be a combination of subjective and social-cultural feelings with various cognitive, behavioral, and psychological influences (Brokelman et al. 2012). Thus, it is critical to understand what this metric truly captures in patients following THR surgery with respect to hip function and pain relief (Baumann et al. 2009). Since 2002, the Swedish Hip Arthroplasty Register (SHAR) has instituted a standardized PROMs program in the follow-up of all THR patients. A visual analogue scale (VAS) addressing patient satisfaction with the outcome of the surgical intervention is obtained in the postoperative PROMs questionnaire. The VAS satisfaction is a simple instrument that has demonstrated good validity and reliability (Brokelman et al. 2012). It is unknown how accurately this measure reflects the outcome of the surgery with respect to pain relief and restoration of hip function.

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Table 1. Demographics of patient population included in the study

Total hip replacements reported to SHAR 2008–2015 n = 127,660

Variable Excluded (n = 58,577): – second hip replacement, 28,215 – missing data, 30,362 Included in the study n = 69,083

Figure 1. Flowchart of patients receiving THR enrolled in the Swedish Hip Arthroplasty Register between 2008 and 2015 meeting inclusion criteria for the present study.

The SHAR captures health-related quality of life using the Euro-Qol-5D (EQ-5D), which assesses the patient’s current health in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Patients grade their current level of function in each dimension into 1 of 3 levels of disability (none, moderate, or severe) (EuroQolGroup 1990). This study sought to assess if changes observed in the 5 dimensions of the EQ-5D between the preoperative and postoperative period were associated with patient satisfaction 1 year following THR.

Patients and methods The Swedish Hip Arthroplasty Register collects data on all patients undergoing THR in Sweden including date of birth and sex, diagnoses, type of implant and fixation method used, ASA classification, height, and weight. Additionally, since 2002 PROMs are administered to all patients preoperatively and, unless revised, at 1, 6, and 10 years postoperatively. These PROMs consist of a 10-item questionnaire including Charnley’s functional categories (A, B, and C) (Callaghan et al. 1990), VAS for pain, and the EQ-5D instrument. In the postoperative intervals, a VAS for satisfaction is also collected, which ranges from 0 (satisfied) to 100 (dissatisfied). The vertical line is supplemented by subscale indicators for ordered response levels (0 to 20, very satisfied; 20–40, satisfied; 40–60, uncertain; 60–80, not satisfied; and 80–100, dissatisfied) (Rolfson et al. 2011). Data were extracted for all 127,660 THR surgeries reported to SHAR between 2008 and 2015 (Figure 1). In patients having both hips operated during the study period only the first operated hip was included. 69,083 cases were included in the present study (Table 1). Statistics For each EQ-5D dimension, data were recorded for the 3 levels of disability (1= none, 2 = moderate, and 3 = severe). Changes between the preoperative and postoperative EQ-5D were then calculated. For each patient, responses to each EQ-5D component were directly compared between preoperative and postoperative questionnaires and improvement; stagnation or decline were presented as proportions. Multi-

Age, mean (SD) Women n (%) Men, n (%) Height (cm), mean (SD) Weight (kg), mean (SD)

68 (10) 38,994 (56) 30,089 (44) 170 (10) 79 (16)

variable regression models were used to examine relationships between the satisfaction VAS obtained 1 year postoperatively and the categorical changes in each EQ-5D dimension. 5 different models were thus built, one for each EQ-5D dimension. Satisfaction VAS was used as a continuous outcome variable. Age and sex were controlled for in all 5 regression analyses. Patients reporting moderate problems both preoperatively and 1 year postoperatively (i.e., 2 to 2) were used as the reference group. Unstandardized regression coefficients were obtained for each categorical change in EQ-5D components (e.g., moderate problems to no problems). This means these coefficients are measured in the same units as the outcome. Thus, the regression coefficients should be interpreted as the adjusted deviation from the reference value. The reference value was always the VAS satisfaction of patients who reported moderate problems in that respective EQ-5D domain both prior and after the surgery. The VAS Satisfaction ranges between 0 and 100, with 0 representing the best possible outcome and 100 the worst possible outcome. Statistical analyses were conducted using R version 3.4.2 (R Foundation for Statistical Computing, Vienna, Austria). Ethics, funding, and potential conflicts of interest As this was a prospective observational register study, no additional intervention was necessary. Each patient voluntarily participated in the questionnaire and all personal data are aggregated to ensure patient de-identification. Patients also have the right to leave the PROM-program at any time. The study is part of a large research project, which has been approved by the Regional Ethical Review Board in Gothenburg (entry number 271-14). There was no funding for this project and no conflicts of interest.

Results EQ-5D differences The majority of patients reported moderate or severe problems preoperatively in the mobility, usual activities, and pain/discomfort dimensions of the EQ-5D. Problems with self-care or anxiety/depression preoperatively were less common (Table 2). The greatest improvement 1 year postoperatively was seen in the pain/discomfort dimension as 66% of patients reported

Acta Orthopaedica 2020; 91 (1): 48â&#x20AC;&#x201C;52

Table 2. Distribution of reported problems with respect to all 5 EQ-5D dimensions preoperatively and 1-year following THR Factor No problem Mobility Self-care Usual activity Pain/discomfort Anxiety/depression

5,250 (8) 52,874 (77) 26,335 (38) 1,042 (1.5) 39,604 (57)

Preoperative EQ-5D 1-year Postoperative EQ-5D Moderate problems Severe problems No problems Moderate problems Severe problems 63,557 (92) 15,562 (23) 35,414 (51) 39,205 (57) 27,032 (39)

276 (0.4) 647 (0.9) 7,334 (11) 28,836 (42) 2,447 (3.5)

41,863 (61) 63,811 (92) 53,480 (77) 30,357 (44 53,978 (78)

27,116 (39) 4,865 (7.0) 14,145 (21) 35,440 (51) 14,020 (20)

104 (0.2) 407 (0.6) 1,458 (2.1) 3,286 (4.8) 1,085 (1.6)

Figure 2. Forest plot of the multivariable analysis of the association between patient satisfaction and changes in the pre- and postoperative EQ-5D: (A) mobility dimension; (B) self-care dimension; (C) usual activities dimension; (D) pain/discomfort dimension; and (E) anxiety/depression dimension. Coefficient values are given on the right-hand side of the figure.

improvement, 32% reported no change, and 2% reported worse problems with pain/discomfort. 55% of patients reported improvements in mobility, 19% reported improvements with respect to self-care, 47% reported improvements in the ability to perform usual activities, and 28% reported improvements in the anxiety/depression dimension. Associations between changes in EQ-5D and VAS satisfaction In patients reporting problems with mobility preoperatively, improvement to no problems with mobility at 1 year postoperatively was associated with higher patient satisfaction (Table 3, see Supplementary data). Patients who reported severe problems with mobility pre- and postoperatively had greater dissatisfaction with their THR procedure and patients reporting deterioration from no problems to severe problems with mobility had the greatest dissatisfaction with their THR procedure (Figure 2A).

Improvement in the self-care dimension from moderate or severe problems preoperatively to no problems 1 year following THR was associated with higher patient satisfaction (Table 4, see Supplementary data). Patients who worsened between the preoperative period and 1 year following their THR from no problems to moderate problems or moderate problems to severe problems with self-care had greater dissatisfaction with their THR procedure (Figure 2B). Patients reporting any improvement in their ability to perform usual activities 1-year following THR had greater patient satisfaction with their procedure, with the highest patient satisfaction found amongst those who reported severe problems in this domain preoperatively and improved to no problems postoperatively (Table 5, see Supplementary data). Conversely, any patient reporting worsening difficulty with their ability to perform usual activities had greater dissatisfaction with their THR procedure, particularly in patients worsening from no problems to severe problems postoperatively (Figure 2C).

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Patients reporting moderate or severe pain/discomfort preoperatively with improvement to no pain postoperatively had greater satisfaction with their THR procedure (Table 6, see Supplementary data). Patients reporting worsening pain/discomfort from no problems to severe problems, or moderate problems to severe problems postoperatively had greater dissatisfaction following their THR procedure (Figure 2D). In patients reporting moderate or severe anxiety/depression preoperatively, improvement to no problems 1 year postoperatively was associated with higher patient satisfaction (Table 7, see Supplementary data). Patients reporting any worsening of anxiety/depression had greater dissatisfaction following their THR procedure, particularly patients who reported no problems preoperatively and severe problems postoperatively (Figure 2E).

Discussion Patient satisfaction is an important metric now collected in the follow-up of arthroplasty procedures to assess subjective outcomes. The satisfaction VAS is a simple instrument used to quantify patient satisfaction after THR. This score has demonstrated good validity and reliability (Brokelman et al. 2012). In the Swedish Hip Arthroplasty Register, the satisfaction VAS, as well as the EQ-5D, is collected postoperatively to measure surgical success from the patient’s perspective (Rolfson et al. 2011). It is currently unknown how well patient satisfaction mirrors changes reported in the EQ-5D. Our study sought to investigate the relationship between the satisfaction VAS obtained 1 year postoperatively and the changes between the pre- and postoperative scores in the different EQ-5D dimensions. We hypothesized that there would be high correlations between the satisfaction VAS and the degree of improvement in health-related quality of life. Our study indicated strong relationships between the satisfaction VAS and changes in each dimension of the EQ-5D. For all 5 dimensions, patient satisfaction was associated with improvement from severe problems preoperatively to no problems 1 year postoperatively. Conversely, patient dissatisfaction was associated with deterioration from no problems to severe problems in 4 of the 5 dimensions: usual activity, pain/discomfort, mobility, and anxiety/depression. For all 5 dimensions, patients reporting no problems postoperatively reported high satisfaction with the most recent treatment of their hip. Regardless of preoperative scores, patients reporting severe problems in usual activities, pain/discomfort, mobility, and the anxiety/depression dimensions 1 year after THR more frequently reported dissatisfaction with their surgical intervention. The SHAR appropriately measures the quality of surgical intervention by assessing restoration of hip function and pain relief through the EQ-5D instrument, a VAS for pain, and a VAS for satisfaction. Patient satisfaction has proven to be a multi-faceted expression of affective, cognitive, and subjec-

tive feelings (Brokelman et al. 2012). Previous literature has demonstrated that the patient’s mental well-being and preoperative expectations contribute to their satisfaction with their surgical intervention (Bourne et al. 2010). Preoperative anxiety has been associated with lower rates of patient satisfaction following THR (Rolfson 2010). Our study similarly identified that patients with persistent or increased anxiety between the pre- and postoperative periods have less satisfaction following THR. However, patients with preoperative anxiety, either moderate or severe, who report no anxiety 1 year postoperatively have increased patient satisfaction. A high proportion of patients reported moderate or severe problems with anxiety/depression preoperatively (n = 29,479, 43%). This could be due to the fact that 99% of patients were reporting moderate or severe pain and 92% reported limited mobility, signifying that there was substantial impairment in quality of life, or indicative of the high degree of anxiety that could accompany the natural stress all patients endure prior to having a surgical procedure. This may also be due to the inherent limitation of the EQ-5D 3-level questionnaire. The response options for patients are “I am not anxious or depressed,” “I am moderately anxious or depressed,” or “I am extremely anxious or depressed.” These 3 options fail to distinguish between moderate anxiety prior to a surgical intervention and persistent moderate anxiety and depression. To our knowledge, no studies have previously assessed how the satisfaction VAS reflects the changes in the EQ-5D between the preoperative and postoperative time periods in patients undergoing THR. In a study of patients undergoing total knee replacement surgery, patient dissatisfaction was found to be related to lack of improvement in preoperative status in pain scores and functional scores; however, patient satisfaction was assessed using a questionnaire allowing patients to only respond “Yes”, “No,” or “I’m not sure” (Jacobs and Christensen 2014). This limits its extension to the present study. Prior literature has identified age and sex as predictive variables for patient satisfaction following THR (Palazzo et al. 2014, Schaal et al. 2016). Thus, we included age and sex in all regression analyses to account for their confounding nature. Additional studies have demonstrated that symptomatic arthritis in another large joint is predictive of dissatisfaction with THR at 1 year postoperatively (Anakwe et al. 2011). Unfortunately, we could not account for that as the data were extracted from the SHAR, which does not have this detailed clinical information for all patients. This, and identification of other variables associated with patient satisfaction after THR, should be the focus of future research. Additionally, future research should investigate whether other regularly utilized PROMs, such as the Harris Hip Score, are associated with quality of life. Our study has some limitations. First, the EQ-5D 3 level questionnaire might not be an optimal instrument to discern minor disabilities. For example, with respect to the pain dimension, if a patient has only minor pain occasionally,

neither the option of “no pain” nor that of “moderate pain” truly captures the patient’s experience. A questionnaire with more alternatives for each dimension might be more effective for capturing all levels of disability; however, the time and effort required to fill in such a form may lower response rates. Second, as the EQ-5D is a generic instrument designed to capture health-related quality of life, it is difficult to determine patient responses that are strictly attributable to their hip disease. For instance, in our study some patients reported increased pain following THR surgery and it is possible that the increased pain reported is related to another diseased joint. Additionally, like most registry studies, our study suffers from some loss to follow-up. Of the 99,445 eligible patients with unilateral hip replacement, only 69,083 patients had complete PROMs for analysis. The 30,362 patients excluded with missing PROMs may have had higher or lower baseline QoL characteristics than the studied population, therefore this may bias the results. Finally, as the patients we included had hip replacements between 2008 and 2015, it is possible that patient expectations changed during that time period affecting quality of life and satisfaction; however, we believe that the robust sample size generated from this study period strengthens the study and arthroplasty practices did not change drastically in this time period. Our study draws on a large, nationwide register that is a reliable method for data capture and is the largest study conducted on this topic to date. As modern medicine relies increasingly on patient-reported outcomes as a tool to gauge success and quality of care, it remains paramount to better understand factors predictive of patient satisfaction. We were able to demonstrate clear associations between satisfaction VAS and changes in the different dimensions of the EQ-5D. Our results indicate that satisfaction with the operated hip is a valid patient-reported outcome reflecting the changes in different EQ-5D dimensions and should be included in the follow-up of patients following THR surgery. Supplementary data Tables 3–7 are available as supplementary data in the online version of this article, http://dx.doi.org/10.1080/17453674.2019. 1685284.

MM, OR, and PE conceived and designed the study. SN performed statistical analyses. GD and PE drafted the manuscript. All authors contributed to the interpretation of results, and reviewed and edited the manuscript. Acta thanks Richard Bohm and Per Kjærsgaard-Andersen for help with peer review of this study.

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Anakwe R E, Jenkins P J, Moran M. Predicting dissatisfaction after total hip arthroplasty: a study of 850 patients. J Arthroplasty 2011; 26(2): 209-13. doi: 10.1016/j.arth.2010.03.013. Baumann C, Rat A C, Osnowycz G, Mainard D, Cuny C, Guillemin F. Satisfaction with care after total hip or knee replacement predicts self-perceived health status after surgery. BMC Musculoskelet Disord 2009; 10: 150. doi: 10.1186/1471-2474-10-150. Bourne R B, Chesworth B M, Davis A M, Mahomed N N, Charron K D. Patient satisfaction after total knee arthroplasty: who is satisfied and who is not? Clin Orthop Relat Res 2010; 468(1): 57-63. doi: 10.1007/s11999-009-1119-9. Brokelman R B, Haverkamp D, van Loon C, Hol A, van Kampen A, Veth R. The validation of the visual analogue scale for patient satisfaction after total hip arthroplasty. Europ Orthop Traumatol 2012; 3(2): 101-5. doi: 10.1007/s12570-012-0100-3. Callaghan J J, Dysart S H, Savory C F, Hopkinson WJ. Assessing the results of hip replacement: a comparison of five different rating systems. J Bone Joint Surg Br 1990; 72(6): 1008-9. EuroQolGroup. EuroQol—a new facility for the measurement of healthrelated quality of life. Health Policy 1990; 16(3): 199-208. Jacobs C A, Christensen C P. Factors influencing patient satisfaction two to five years after primary total knee arthroplasty. J Arthroplasty 2014; 29(6): 1189-91. doi: 10.1016/j.arth.2014.01.008. Nikolajsen L, Brandsborg B, Lucht U, Jensen T S, Kehlet H. Chronic pain following total hip arthroplasty: a nationwide questionnaire study. Acta Anaesth Scand 2006; 50(4): 495-500. doi: 10.1111/j.1399-6576.2006.00976.x. Palazzo C, Jourdan C, Descamps S, Nizard R, Hamadouche M, Anract P, Boisgard S, Galvin M, Ravaud P, Poiraudeau S. Determinants of satisfaction 1 year after total hip arthroplasty: the role of expectations fulfilment. BMC Musculoskelet Disord 2014; 15: 53. doi: 10.1186/1471-2474-15-53. Pivec R, Johnson A J, Mears S C, Mont M A. Hip arthroplasty. Lancet 2012; 380(9855): 1768-77. doi: 10.1016/S0140-6736(12)60607-2. Rolfson O. Patient-reported outcome measure and health-economic aspects of total hip arthroplasty: a study of the Swedish Hip Arthroplasty Register. Institute of Clinical Sciences, Department of Orthopaedics, University of Gothenburg, Sahlgrenska Academy; 2010. Rolfson O, Karrholm J, Dahlberg L E, Garellick G. Patient-reported outcomes in the Swedish Hip Arthroplasty Register: results of a nationwide prospective observational study. J Bone Joint Surg Br 2011; 93(7): 867-75. doi: 10.1302/0301-620X.93B7.25737. Schaal T, Schoenfelder T, Klewer J, Kugler J. Determinants of patient satisfaction and their willingness to return after primary total hip replacement: a cross-sectional study. BMC Musculoskelet Disord 2016; 17: 330. doi: 10.1186/s12891-016-1196-3. Wylde V, Blom A W. The failure of survivorship. J Bone Joint Surg Br 2011; 93(5): 569-70. doi: 10.1302/0301-620X.93B5.26687.

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The neck–shaft angle: an update on reference values and associated factors Cornelius S FISCHER 1, Jens-Peter KÜHN 2,6, Henry VÖLZKE 3, Till ITTERMANN 3, Denis GÜMBEL 1, Richard KASCH 4, Lyubomir HARALAMBIEV 1, René LAQUA 5, Peter HINZ 1, and Jörn LANGE 1 1 Clinic

of Trauma, Reconstructive Surgery and Rehabilitation Medicine, University Medicine Greifswald, Greifswald; 2 Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald; 3 Institute for Community Medicine, Ernst-Moritz-Arndt University of Greifswald, Greifswald; 4 Center for Orthopedics, Trauma Surgery and Rehabilitation Medicine; Clinic and Outpatient Clinic for Orthopedics and Orthopedic Surgery, University Medicine Greifswald, Greifswald; 5 Department of Radiology, Städtisches Krankenhaus Kiel, Kiel; 6 Clinic and Policlinic of Radiology, University Hospital Dresden, Carl-Gustav-Carus University, Dresden, Germany Correspondence: joern.lange@uni-greifswald.de Submitted 2019-08-17. Accepted 2019-10-18.

Background and purpose — The neck–shaft angle (NSA) is valuable for diagnostics and therapy of the hip, but current reference values derive mostly from studies on anatomic specimens, small cohorts, or are hospital-based. Moreover, associated factors such as age, sex, or anthropometric data have rarely been considered. Therefore, we determined associated factors for NSA and reassessed the historical reference values in a general adult population. Methods — NSAs on both sides of 3,226 volunteers from the population-based Study of Health in Pomerania (SHIP) were measured with MRI. SHIP drew a representative sample of the population of Pomerania (northeastern Germany). NSAs were compared with sex, age, and anthropometric data by bivariable linear regression models. Reference values were assessed by quantile regressions for 2.5th and 97.5th percentiles. Results — The mean NSA was 127° (SD 7), while men had a lower NSA than women (95% confidence interval [CI] 0.4°–1.4°). The reference range was 114°–140°. Age was inversely associated with NSA (CI –0.2 to –0.1). Body height was positively associated with the NSA, while BMI and waist circumference showed a negative association. There was no association between body weight and NSA. Interpretation — The historical lower limit of 120° might be too high, so the radiological prevalence of hip pathology might have been overestimated. The previously reported influence of age, sex, and body height on the NSA has been confirmed.

The femoral neck–shaft angle (NSA) or centrum-collumdiaphyseal angle has long served as an important measure to quantify the inclination between the femoral neck and the femoral shaft. Due to its importance in diagnostics for many pathologies of the proximal femur and resultant therapy, e.g., corrective osteotomy (Srisaarn et al. 2019), the NSA is still frequently used by surgeons. However, the currently published reference ranges were mostly based on anatomic specimens, small cohorts (Boese et al. 2016), or originated from hospitalbased studies. Varying ranges have been described as reference ranges, between 120° and 140° in CT images and radiographs. Thresholds for Coxa vara range between < 120° (Beall et al. 2008, Dolan et al. 2011, Boese et al. 2015) and < 130° (Morvan et al. 2013), and for Coxa valga from ≥ 135° (Beall et al. 2008, Coskun Benlidayi et al. 2015) to > 140° (Dolan et al. 2011, Morvan et al. 2013). Those thresholds were mostly used in older studies on hip pathology (Tönnis and Heinecke 1999, Lequesne et al. 1964). Because of changing lifestyles, people are older, heavier, and taller now than they were several decades ago. Therefore, a reevaluation of the above-mentioned thresholds is motivated. Possible sex-based differences in the NSA have been investigated, with divergent results. Some documented higher NSA for men (Elbuken et al. 2012, Nissen et al. 2005, Mitra et al. 2014), others for women (Boissonneault et al. 2014), or no sex difference at all was found (Doherty et al. 2008, Gilligan et al. 2013). The decrease of NSA from childhood to adulthood is generally accepted (Anderson and Trinkaus 1998, Beall et al. 2008, Boese et al. 2016). Reduction in NSA with increasing age has been described (Beall et al. 2008, Boese et al. 2015), but the opposite results have also been published (Anderson

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and Trinkaus 1998, Nissen et al. 2005, Doherty et al. 2008, Elbuken et al. 2012, Gilligan et al. 2013). Given the variety of physiological factors influencing NSA, adjusted reference values might be advantageous for more precise interpretation. Therefore, we determined up-to-date NSA reference ranges and assessed associations between the NSA, sex, age and anthropometric data (weight, height, BMI, and waist circumference). Moreover, reference values adjusted to the already described associations with sex and age were calculated.

Methods Design and sample The Study of Health in Pomerania (SHIP) (Völzke et al. 2011) is an ongoing population-based project. It consists of 2 independent cohorts, SHIP and SHIP-Trend. To ensure a representative cohort, participants were recruited randomly from official resident registry office files as a sample of the population from a defined region in northeastern Germany (northern and eastern Pomerania) and stratified by sex, age, and city of residence. In 1997, 6,265 eligible adults were chosen for the baseline assessment (SHIP-0) in which 4,308 (2,192 women) volunteers participated (response 68.8%). Between 1997 and 2001, the SHIP-0 examinations were performed. 2 follow-up examinations took place between 2002 and 2006 (SHIP-1; n = 3,300) and between 2008 and 2012 (SHIP-2; n = 2,333). For the second cohort (SHIP-Trend), a stratified sample (n = 8,016) was drawn in 2008 with the same stratification variables used. 4,420 (2,275 women) participants were then examined (response 50%) (Völzke et al. 2011). The invitation procedure consisted of 3 written invitations, phone calls, and 1 personal contact. As an associated project of SHIP, all participants with a complete hip protocol were included in the MRI examination from SHIP-2 and SHIP-Trend. Overall 3,317 out of 6,753 volunteers (SHIP-2 and SHIP-Trend) participated in the MRI examination. Dropouts were for instance caused by claustrophobia, metal implants, or personal reasons. Of 3,317 potential participants, 34 interrupted their examination due to acute problems. Furthermore, 57 of 3,283 completed pelvic MRIs had to be excluded because of missing data (36), total hip arthroplasty (18), extreme deformity (2), or suboptimal quality (1) (Fischer et al. 2018). MRIs of 3,226 volunteers with a mean age of 53 years (SD 14) with no difference between sexes were adequate for the current study. Further information on recruitment and selection has been published previously (Völzke et al. 2011, Fischer et al. 2018). MRI protocol As a part of the standardized whole-body MRI, pelvic MRI was performed in a 1.5-Tesla MR scanner (Magnetom Avanto; Siemens Medical Systems, Erlangen, Germany). All MRI

Figure 1. The neck–shaft angle (x) is composed of a and b; a = femoral neck axis, b = femoral shaft axis.

examinations were performed in a supine position by 4 trained technicians in a standardized manner. The NSA was assessed by using a coronal turbo inversion recovery magnitude sequence (repetition time 4,891 msec; echo time 67 msec; flip angle 180°; voxel size 2.1 × 1.6 × 5.0 mm; scan time 2:25 minutes) and an axial pelvic proton density-turbo spin echo-fat saturation sequence (repetition time 3,230 msec; echo time 34 msec; flip angle 180 degrees; voxel size 1.6 × 1.6 × 3.0 mm; scan time 2:43 minutes). Image analysis All measurements were performed by a trained observer, blinded to all information about the volunteers, using OsiriX version 5.8.5 (PIXMEO; Bernex, Switzerland). The NSA was measured on a coronal planar image through the center of the femoral head, which was identified by using axial slices simultaneously. It is defined by the femoral neck axis and the femoral shaft axis (Figure 1). The femoral neck axis was formed by connecting the center of the femoral head and the center of the femoral neck. Both center points were assessed through the center of a best-fitting circle. The femoral shaft axis was detected by two midpoints in the diaphysis of the femur. The midpoints were determined by the center of a bestfitting circle as well (Beall et al. 2008). Statistics For reliability assessment, 25 cases were measured twice by one examiner (CF). These cases were measured again by another examiner (JL). Intrareader and interreader variability (Bland and Altman plots) were between –0.31% (SD1.37) and 0.31% (SD 1.69) (mean difference), implying good reliability. Descriptive statistics such as mean values, standard deviations (SD), ranges, and percentiles were used to describe the cohort. For numerical variables, categorical variables were tested with the chi-square test. All reported p-values were 2-tailed. P-values less than 0.05 were considered statistically significant. The correlation between sides (left and right) was calculated with Spearman’s correlation coefficient.

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Table 1. Study cohort characteristics. Data are presented as mean (SD) [range] Total Men Women Factor (n = 3,226) (n = 1,587) (n = 1,639) Age Weight, kg Height, cm BMI Waist, cm a a Waist

53 (14) [21–90] 80 (15) [44–143] 170 (9) [146–202] 28 (4) [17–48] 90 (13) [55–145]

53 (14) [21–90] 88 (13) [53–143] 177 (7) [156–202] 28 (4) [18–42] 96 (11) [66–145]

52 (13) [21–88] 73 (13) [44–126] 164 (6) [146–189] 27 (5) [17–48] 84 (12) [54–122]

circumference (2 women and 1 man missing).

Table 2. Descriptive results neck-shaft angle. Data are presented as mean (SD) [range] Neck-shaft Total a Men Women angle (n = 6,452) (n = 3,174) (n = 3,278) Right 127.7 (7.1) [96–153] 127.7 (7.1) [96–153] 127.9 (7.1) [99–152] Left b 126.0 (7.4) [101–153] 125.3 (7.7) [101–151] 126.8 (7.1) [103–153] Mean b,c 126.9 (6.7) [102–151] 126.5 (6.8) [102–151] 127.4 (6.6) [102–149] a Paired t-test (total right vs. total b Sign test (men vs. women): p < c Mean of left and right side.

left): p < 0.001. 0.001.

Ethics, funding, and potential conflicts of interests Each participant gave written informed consent and the local ethics commission approved the SHIP study (BB 39/08, 19.06.2008). This study was performed as a SHIP-associated project (SHIP/2015/145/D) at University Medicine Greifswald, Germany. The SHIP study is part of the Community Medicine Research Net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grant No. 03ZIK012), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MR imaging was supported by the Federal State of Mecklenburg-Vorpommern, the Federal Ministry of Education and Research, and a joint grant from Siemens Healthcare, Erlangen, Germany. Each author certifies that no competing interests exist.

Results

1,639 of the 3,226 participants were female. The mean age was 53 (SD 14) years and no differences in age were observed between the sexes (Table 1). The mean values of body height, body weight, BMI, and Neck-shaft angle (°) Neck-shaft angle (°) 130 130 waist circumference were higher in men. The mean NSA for all 6,452 measured hips (left 129 129 and right side) was 127° (SD 7, range 102°–151°). Right hip joints had a higher NSA than left hip joints. 128 128 Additionally, women showed higher NSA than men on the left and the mean of both sides (Table 2). 127 127 A correlation between left and right NSA values was documented (r = 0.7, p = 0.001). Additionally, 126 a 0.9° (95% CI 0.4°–1.4°) higher NSA in women 126 was detected. Furthermore, age was inversely associ125 ated with NSA (β –0.1; CI –0.2 to –0.1). The NSA 125 150 160 170 180 190 200 18 20 25 30 35 decreases by 1.4° per decade. The reference range Body height (cm) BMI for the whole population was 114°–140°. Stratified Figure 2. The negative association Figure 3. The positive association by sex, the female reference range was 115°–140°, between neck–shaft angle and body between neck–shaft angle and body mass index is shown. height is shown. while the male range was 113°–140°. Age- and sexadjusted reference values for women can be calcuAssociations with demographic and anamnestic data, lated by NSA = 125.78 – 0.195 × age for the lower limit and including possible interactions between the parameters, were NSA = 147.82 – 0.158 × age for the upper limit. For men, the assessed by linear regression analysis. Fractional polynomials lower limit can be calculated by NSA = 120.18 – 0.128 × age (FP) were tested for potential non-linear associations between and the upper limit by NSA = 145.34 – 0.124 × age. age and NSA. Interactions between age and sex were tested, BMI was inversely associated with the NSA in a non-linwith p < 0.1 considered statistically significant. Stratified by ear fashion (Figure 2, p < 0.001). The decrease in NSA was sex, age-specific upper and lower reference limits were calcu- greater for lower BMI. While body weight was not statistically lated by quantile regressions for the 2.5th and 97.5th percen- significant (p = 0.2), body height was (Figure 3, p = 0.004). tile. Moreover, reference values were calculated by the 95% Per 10 cm of body height, the NSA increased 0.4°. Like BMI, reference interval (mean ± 1.96 × SD). All statistical analyses waist circumference was inversely associated with the NSA were performed using Stata 14.1 (StataCorp, College Station, in a non-linear fashion (p < 0.001). The decrease was more TX, USA). pronounced for smaller than for larger waist circumferences.

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Various results for the association with age have been described (Nissen et al. 2005, Elbuken et al. Author, year Method Population Age (range) n Mean (SD) 2012). Our study showed a decrease Alonso et al. 2000 DXA Spain 70 235 M 126.3 (4.4) of NSA with age in both sexes, 70 310 F 124.6 (4.2) which confirms this association in Doherty et al. 2008 AP radiograph England 64 1,103 R 128.3 (7.1) L 128.3 (7.1) a general population and supports Kaptoge et al. 2008 DXA US 74 6,839 F 127.2 (6.0) results of previous studies (Beall Elbuken et al., 2012 DXA Turkey (20–108) 18,943 M 129.6 et al. 2008, Boese et al. 2015). An F 129.1 Bagaria et al. 2012 AP radiograph India (20–80) 141 M 127.7 (3.9) explanation for this association 70 F 126.6 (4.8) might be decreasing bone mineral Gilligan et al. 2013 Femora – – 8,271 126.4 (5.6) density and physiological changes. Mitra et al. 2014 AP radiograph Iran 35 (24–42) 100 M R 127.5 (5.3) L 127.6 (5.6) We detected a difference between 44 (28–57) 100 F R 125.4 (6.0) sides with higher NSA for the L 126.6 (6.3) right hip. This could be explained Boese et al. 2015 CT, coronal Germany 53 (18–89) 200 M 129.6 (5.9) reconstruction 54 (18–100) 200 F 131.9 (6.8) by the fact that most people have (femoral neck plane) R 130.8 (6.7) a dominant right side, but since L 130.8 (6.3) various results on side differences Dimitriou et al. 2016 3D CT US 47 (31–58) 61 R 126.7 (4.8) L 126.6 (4.5) have been reported (Doherty et al. Present study MRI coronal plane Germany 53 (21–90) 1,587 M 126.5 (6.8) 2008, Gilligan et al. 2013, Boese 52 (21–88) 1,639 F 127.4 (6.6) et al. 2015, Dimitriou et al. 2016), DXA = Dual-energy X-ray absorptiometry, M = male, F = female, R = right hip, L = left hip it could also support the thesis of individual side asymmetry (Anderson and Trinkaus 1998). Regarding the widely discussed differences in sex (Nissen et al. 2005, Elbuken et al. 2012, Gilligan et al. 2013, Mitra et al. 2014), we Discussion assessed higher NSA in females confirming previous results The neck–shaft angle is frequently used for diagnostics, pre- (Boissonneault et al. 2014, Boese et al. 2015). Moreover, we operative planning, and therapy (Srisaarn et al. 2019), but no found a positive association with body height on the NSA, as consensus on thresholds or reference ranges exists to date. In did Nissen et al. (2005). Body weight was not associated with addition, various associations with sex and age are described, NSA, but a negative association with BMI and waist circumwhile other possible associations have rarely been investigated. ference was detected. Therefore, previous results regarding Our study may have been limited by the use of non-rota- the BMI (Elbuken et al. 2012, Mitra et al. 2014) were contion-corrected coronal MRI images. However, the review firmed. Interestingly, the decrease in NSA was stronger for by Boese et al. (2016) documented a difference of only 1° lower BMI. Regarding normal values, Boese et al. (2015) described between rotation-corrected and non-corrected NSA. Therefore, we suggest that our measurements in coronal MR images mean NSA on rotation-corrected CT images of 130.8° (SD are reliable. Nevertheless, due to the 3-D morphology of the 6.49) for the femoral neck plane and 133.6° (SD 6.81) for the femur, it is possible that the NSA has been underestimated. anterior pelvic plane. Nevertheless, several studies with large However, previous studies showed similar values for the NSA sample sizes report values similar to ours (Alonso et al. 2000, (Table 3). A second limitation may be the cross-sectional Kaptoge et al. 2008, Bagaria et al. 2012, Boissonneault et al. study design, which limits conclusions on cause-and-effect 2014, Mitra et al. 2014). Furthermore, a review of 21 studrelationships. Thus, further longitudinal studies are necessary. ies showed a mean NSA of 128.8° (Boese et al. 2016). HowThe final limitation may be the possible inclusion of partici- ever, varying reference values between 120° and 140° have pants with hip pathology. Nonetheless, severe pathology can been described (Beall et al. 2008, Dolan et al. 2011, Boese reasonably be ruled out, because it is mostly treated surgically et al. 2015). Given that these thresholds were mostly adopted with metal implants, which should be seen on MRI. Moreover, by older studies (Lequesne et al. 1964, Tönnis and Heinecke our sample was a general population, so it could be expected 1999), and considering changed lifestyles since then, our that the majority are healthy. Due to the large sample of the study provides up-to-date reference values. Our results supgeneral population, the standardized data acquisition, and the port the historical upper limit of 140° as the physiological randomized selection process, we assume that reliable pop- benchmark for general populations. Our lower limit is about ulation-based data were provided. We found mean NSAs of 6° lower than the previously used limit of 120°, so the radio126.5° (SD 6.75) for men and 127.4° (SD 6.55) for women. logical prevalence of hip pathology might have been overestimated. Since associations with sex and age are frequently The reference range was 113.9° to 140.0°. Table 3. Neck-shaft angle in other studies

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described, sex- and age-adjusted reference values for the NSA may be more accurate for diagnostics, preoperative planning, and orthopedic surgery. In conclusion, we support the historical threshold of the NSA regarding the upper limit of 140° but propose a lower limit of 114° based on a general population of adults.

CF performed all measurements. CF, JL, JPK, DG, and PH were responsible for the study design and conception. RL programmed the plugin for all measurements. TI and HV performed the statistical analyses. RK and LH provided advice on study design. All authors revised and approved the manuscript. The authors would like to thank their four trained technicians Angela Doss, Petra Bartel, Brigitte Olbrich, and Vera Radons, who performed all MRI examinations, all members of the Insitute of Community Medicine, and all participants. Acta thanks Sebastian Gehmert and Per Kjærsgaard-Andersen for help with peer review of this study.

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Dimitriou D, Tsai T, Yue B, Rubash H E, Kwon Y, Li G. Side-to-side variation in normal femoral morphology: 3D CT analysis of 122 femurs. Orthop Traumatol Surg Res 2016; 102(1): 91–7. Doherty M, Courtney P, Doherty S, Jenkins W, Maciewicz R A, Muir K, Zhang W. Nonspherical femoral head shape (pistol grip deformity), neck shaft angle, and risk of hip osteoarthritis: a case-control study. Arthritis Rheum 2008; 58(10): 3172–82. Dolan M M, Heyworth B E, Bedi A, Duke G, Kelly B T. CT reveals a high incidence of osseous abnormalities in hips with labral tears. Clin Orthop Relat Res 2011; 469(3): 831–8. Elbuken F, Baykara M, Ozturk C. Standardisation of the neck–shaft angle and measurement of age-, gender- and BMI-related changes in the femoral neck using DXA. Singapore Med J 2012; 53(9): 587–90. Fischer C S, Kuhn J, Ittermann T, Schmidt C, Gumbel D, Kasch R, Frank M, Laqua R, Hinz P, Lange J. What are the reference values and associated factors for center–edge angle and alpha angle? A population-based study. Clin Orthop Relat Res 2018; 476(11): 2249–59. Gilligan I, Chandraphak S, Mahakkanukrauh P. Femoral neck–shaft angle in humans: variation relating to climate, clothing, lifestyle, sex, age and side. J Anat 2013; 223(2): 133–51. Kaptoge S, Beck T J, Reeve J, Stone K L, Hillier T A, Cauley J A, Cummings S R. Prediction of incident hip fracture risk by femur geometry variables measured by hip structural analysis in the study of osteoporotic fractures. J Bone Miner Res 2008; 23(12): 1892–1904. Lequesne M, Lemoine A, Massare C. Le “complet” radiographique coxofémoral: Dépistage et bilan préopératoire des vices architecturaux de la hanche. J Radiol Electrol Med Nucl 1964; 45:27–44. Mitra A, Khadijeh B, Vida A P, Ali R N, Farzaneh M, Maryam V F, Vahid Y. Sexing based on measurements of the femoral head parameters on pelvic radiographs. J Forensic Leg Med 2014; 23: 70–5. Morvan J, Bouttier R, Mazieres B, Verrouil E, Pouchot J, Rat A, Guellec D, Guillemin F, Coste J, Saraux A. Relationship between hip dysplasia, pain, and osteoarthritis in a cohort of patients with hip symptoms. J Rheumatol 2013; 40(9): 1583–9. Nissen N, Hauge E M, Abrahamsen B, Jensen, J E B, Mosekilde L, Brixen K. Geometry of the proximal femur in relation to age and sex: a crosssectional study in healthy adult Danes. Acta Radiol 2005; 46(5): 514–18. Srisaarn T, Salang K, Klawson B, Vipulakorn K, Chalayon O, Eamsobhana P. Surgical correction of coxa vara: evaluation of neck shaft angle, Hilgenreiner-epiphyseal angle for indication of recurrence. J Clin Orthop Trauma 2019; 10(3): 593–8. Tönnis D, Heinecke A. Acetabular and femoral anteversion: relationship with osteoarthritis of the hip. J Bone Joint Surg Am 1999; 81(12): 1747–70. Völzke H, Alte D, Schmidt C O, Radke D, Lorbeer R, Friedrich N, Aumann N, Lau K, Piontek M, Born G, Havemann C, Ittermann T, Schipf S, Haring R, Baumeister S E, Wallaschofski H, Nauck M, Frick S, Arnold A, Jünger M, Mayerle J, Kraft M, Lerch M M, Dörr M, Reffelmann T, Empen K, Felix S B, Obst A, Koch B, Gläser S, Ewert R, Fietze I, Penzel T, Dören M, Rathmann W, Haerting J, Hannemann M, Röpcke J, Schminke U, Jürgens C, Tost F, Rettig R, Kors J A, Ungerer S, Hegenscheid K, Kühn J, Kühn J, Hosten N, Puls R, Henke J, Gloger O, Teumer A, Homuth G, Völker U, Schwahn C, Holtfreter B, Polzer I, Kohlmann T, Grabe H J, Rosskopf D, Kroemer H K, Kocher T, Biffar R, John U, Hoffmann W. Cohort profile: the study of health in Pomerania. Int J Epidemiol 2011; 40(2): 294–307.

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Postoperative mortality after a hip fracture over a 15-year period in Denmark: a national register study Ossian GUNDEL 1, Lau Caspar THYGESEN 2, Ismail GÖGENUR 1, and Sarah EKELOEF 1 1 Center

for Surgical Science, Department of Surgery, Zealand University Hospital, Koege, Denmark; 2 National Institute of Public Health, University of Southern Denmark, Copenhagen K, Denmark Correspondence: OG: qrb124@alumni.ku.dk Submitted 2019-04-25. Accepted 2019-09-23.

Background and purpose — In Denmark, 44 per 10,000 persons over the age of 50 years suffered a hip fracture (HF) in 2011. We characterized the patients and identified risk factors associated with 30-day, 90-day, and 1-year postoperative mortality in Denmark from 2000 to 2014. Patients and methods — The study builds upon data from the Danish National Patients Register and the National Causes of Death Register including all acute hospitalized HF patients aged 18 years and above. Outcomes were 30-day, 90-day, and 1-year postoperative mortality. Mortality risk was analyzed with a univariable and multivariable Cox regression including predefined variables. Results — 113,721 acute hospitalized HF patients were admitted to Danish hospitals between 2000 and 2014. The 30-day mortality risk was 9.6%, 16% at 90 days, and 27% at 1 year after HF surgery. Mortality risk was similar from 2000 to 2014 while the median lengths of stay declined from 14 (IQR 8–25) to 8 (IQR 5–11) days. Male sex, increasing age, higher Charlson Comorbidity Index, per- and subtrochanteric fracture, and operation type other than total hip arthroplasty were independently associated with postoperative mortality. Interpretation — Short- and long-term mortality was high after hip fracture surgery and did not decline in Denmark from 2000 to 2014.

In the Danish population, 44 per 10,000 persons over the age of 50 years suffered a hip fracture (HF) in 2011 (Driessen et al. 2016). The majority of patients with HF are elderly women with multiple comorbidities including cardiovascular, pulmonary, and genitourinary diseases, diabetes, and dementia. Compared with the general population, patients with HF have an up to 3-fold increased mortality risk (Goldacre et al. 2002). Previous studies have found a 30-day mortality risk between 5.6% and 11% (Roberts and Goldacre 2003, Roche et al. 2005), and 1-year mortality risk between 22% and 33% (Goldacre et al. 2002, Brauer et al. 2009). Age and preoperative comorbidities are known to correlate with both postoperative complications and mortality (Roche et al. 2005, Sathiyakumar et al. 2016). A study from Canada showed a high and increased incidence of HF until the beginning of the 21st century (Cheng et al. 2011). Thereafter, the prevalence of HFs has increased but the incidence rate has dropped (Rosengren et al. 2017). It is uncertain whether this drop has been accompanied by a concomitant decrease in postoperative mortality. Combined with the high economic impact of HF patients (Leal et al. 2016), the incidence rate and postoperative mortality have a large impact on the national healthcare system. We estimated the 30-day, 90-day, and 1-year postoperative mortality, identified risk factors for mortality after hip fracture, and describe the time trend in mortality risk after HF surgery in Denmark from 2000 to 2014.

Patients and methods Data sources This cohort study used data from the Danish National Patients Register (DNPR) and the National Causes of Death Register (NCDR). In Denmark, all contacts between a citizen and the © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of the Nordic Orthopedic Federation. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI 10.1080/17453674.2019.1680485

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healthcare system are recorded by a unique civil registration number and stored in the national registers. In the DNPR all hospital data are registered: admission, discharge, treatment, and operation date and time, as well as diagnoses and types of examination, treatment, and operation. Since 1994, all contacts have been registered and coded using International Classification of Diseases and Related Health Problems (ICD-10) from the World Health Organization; before that ICD-8 was used (Lamberts et al. 2014). Procedures and operations are classified using the Nordic Classification of Surgical Procedures, which is developed and maintained by the Nordic Medico-Statistical Committee (NOMESCO) (Schmidt et al. 2015). In the NCDR, time of death and primary and secondary causes of death are registered. The reporting of the study follows the STROBE statement. Population and definitions The population consisted of patients aged 18 or above admitted acutely with an HF to a Danish hospital between 2000 and 2014. HF was defined by the ICD-10 codes: S72.0 (collum femoris fracture), S72.1 (pertrochanteric femur fracture), S72.1A (intertrochanteric femur fracture), S72.1B (trochanteric femur fracture), S72.2 (subtrochanteric femur fracture), and S72.8A (femoral head fracture). Patients were only included in the study if they had undergone a surgical procedure for their HF with a NOMESCO operation code: KNFB (primary inserting of hip joint prosthesis), KNFC (secondary inserting of hip joint prosthesis), KNFE (operation on hip joint capsula and ligaments), KNFF (operation on hip joint synovia and joint surface), KNFG (hip joint resection, arthroplasty, and arthrodesis), KNFJ (hip fracture operation, including internal and external fixation), KNFK (bone operation on thighbone, including resection and osteosynthesis), KNFT (operation on hip joint and thighbone, including pseudarthrosis, and bone deformity), and KNFQ (amputation of hip and thighbone). Only patients undergoing HF surgery for the first time were included in the study. Diagnoses registered within 5 years of admission were used to create an individual comorbidity score using the Charlson Comorbidity Index (CCI). The ICD-10 codes in DNPR used to construct CCI in this study have previously been found to have a high positive predictive value (Thygesen et al. 2011). The comorbidity hazard ratio was found by comparing with non-comorbid patients. Outcome The outcomes were all-cause 30-day, 90-day, and 1-year mortality after surgery for an HF. As a descriptive measure, cause-specific mortality was also reported. Length of stay was recorded. Statistics Descriptive statistics of continuous variables were expressed as mean (SD) or median (interquartile range [IQR]), while

categorical data were expressed as numbers and percentages. Univariable and multivariable Cox regressions were performed. We adjusted for the predefined variables: sex, age, fracture type, operation type, CCI score, and comorbidities (previous acute myocardial infarct [AMI], heart failure, cerebrovascular disease, peripheral vascular disease, chronic obstructive pulmonary disease [COPD], kidney disease, liver disease, diabetes, rheumatic disease, cancer, cancer metastases, and dementia). The proportional hazards assumption was checked graphically with the empirical score process (Lin et al. 1993). Interactions between sex and age, as well as operation type and fracture type, were analyzed. Only the interaction between sex and age was statistically significant and therefore included in the analysis. All variables were included simultaneously in the multivariable analyses. Results were expressed as hazard ratios (HR) (95% CI). Trends over time in mortality were analyzed with logistic regression and number of HF and length of hospital stay were analyzed with ANOVA models. The assumptions of Gaussian distributed residuals were evaluated graphically; length of stay had to be log-transformed to fulfil assumptions. Statistical analyses were performed with SAS version 9.4 (SAS Institute, Cary, NC, USA). A 2-sided p-value < 0.05 was considered statistically significant. Ethics, funding, and potential conflicts of interest The study was approved by the Danish Data Protection Agency (Approval number: REG-161-2015. Case number 15-000241). In Denmark—by law—register studies without the use of biological material do not require ethics committee approval. The study has not received any funding. None of the authors has any conflicts of interest to declare.

Results Baseline data After excluding non-acute admissions, non-hip fracture diagnosis and operation codes, we ended up with 113,957 unique HF patients in the period 2000–2014 (Figure 1). Baseline characteristics are shown in Table 1 stratified on 30-day, 90-day, and 1-year mortality. The mean age was 79 years, and 70% were female. The median length of stay was 10 days and declined from 14 to 8 days from 2000 to 2014 (Figure 2). The number of HF decreased from 8,219 in 2000 to 6,556 in 2014 (Figure 3). Mortality The postoperative mortality risk was 9.6% for 30-day, 16% for 90-day, and 27% for 1-year. From 2000 to 2013, the postoperative 30-day, 90-day, and 1-year mortality risks showed no clear trend towards an increase or decrease (Figure 4). Cardiovascular death was the most common; at 1 year 27% of patients had died of cardiovascular disease and ischemic

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Median days of stay with IQR

Contacts with hip fracture from the DNPR a 2000–2014 n = 8,119,464

Non-hospitalized patient contacts n = 5,604,373 Admission contacts with hip fracture n = 8,119,464

Acute patient contacts n = 1,720,150

Patient contacts with diagnosis codes: DS720, DS721, DS721A, DS721B, DS722, and DS728A n = 158,485

Patient contacts with operation codes: KNFB, KNFC, KNFE, KNFF, KNFG, KNFJ, KNFK, KNFT, and KNFQ n = 134,406

Patient with first admission n = 119,285

Patient included with correct diagnosis and operation code n = 113,721

Excluded: Elective patient contacts n = 794,941 Excluded: Admission codes other than hip fracture n = 1,561,664

Excluded: Incorrect operations code n = 24,080

Excluded: Patients with secondary admission n = 15,121 Excluded: Operation before January 1, 2000 or after December 31, 2014 n = 5,567

Figure 1. Inclusion flowchart. a Danish National Patient Register

heart disease accounted for 17% of the total deaths (Table 2, see Supplementary data). Subtrochanteric and pertrochanteric fractures were associated with an increased risk of mortality, and patients undergoing a total hip arthroplasty seemed to have a reduced risk of mortality in the uni- and multivariable Cox regression analysis (Tables 3 and 4, see Supplementary data). In both the uni- and multivariable Cox regression male sex, increasing age, and CCI were statistically significantly associated with mortality. We found a statistically significant interaction between sex and age in all analyses. Moreover, the majority of the individual organ-specific comorbidities were statistically significantly associated with an increased risk of postoperative mortality (Table 4). Both existing cerebrovascular and rheumatic disease were associated with a reduced risk of postoperative mortality.

2000 2002 2004 2006 2008 2010 2012 2014

Figure 2. Median length of stay in days with interquartile range (IQR) after hip fracture surgery. ANOVA test of periodic effect, p < 0.01

Annual number of hip fracture surgeries 9,000

6,000

3,000

2000 2002 2004 2006 2008 2010 2012 2014

Figure 3. Trend in number of hip fracture surgeries from 2000 to 2014. ANOVA test of periodic effect, p < 0.001.

Mortality (%) 30

1-year mortality 90-day mortality 30-day mortality

Discussion This study found a 30-day postoperative mortality risk of 9.6%, 90-day of 16%, and 1-year of 27%. Over a 15-year period (2000–2014), the mortality risk varied but with no overall increase or decrease over time. Male sex, increasing age, higher CCI score, type of fracture, and operation

2000

2002

2004

2006

2008

2010

2012

Figure 4. Trends in hip fracture mortality from 2000 to 2013. The year 2014 is missing since follow-up ended in 2014. Logistic regression of periodic effect, 1-year mortality trend, p < 0.001; 90-day mortality trend, p = 0.9; and 30-day mortality trend, p = 0.1.

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Table 1. Baseline characteristics of Danish hip fracture patients in the period 2000–2014. Values are frequency (%) and [95% confidence interval] unless otherwise specified Characteristic Age, mean (SD) Women Length of stay (IQR), days Fracture type a Collum femoris fracture Pertrochanteric fracture Subtrochanteric fracture Type of operation Open/closed reposition External fixation Internal fixation Hemiarthroplasty Arthroplasty Other Comorbidities Acute myocardial infarction Heart failure Cerebrovascular disease Peripheral vascular disease Chronic obstructive pulmonary disease Kidney disease Liver disease Diabetes Rheumatic disease Cancer Metastasis Dementia Charlson Comorbidity Index 0 1–2 3–4 ≥ 5

All patients n = 113,721

30-day mortality n = 10,913 (9.6%)

90-day mortality n = 18,412 (16.2%)

1-year mortality n = 30,429 (26.8%)

78.9 (11.7) 84.6 (8.9) 79,161 (69.6) [69.3–69.9] 6,315 (57.9) [56.9–58.8] 10 (6–17) 7 (4–12)

84.2 (9.1) 83.3 (9.5) 11,367 (61.7) [61.0–62.4] 19,352 (63.6) [63.1–64.1] 8 (4–16) 10 (5–18)

60,891 (53.5) [53.3–53.9] 5,309 (8.7) [8.5–8.9] 44,541 (39.2) [38.9–39.5] 4,700 (10.6) [10.3–10.8] 8,289 (7.3) [7.1–7.4] 904 (10.9) [10.2–11.6]

9,128 (15.0) [14.7–15.3] 15,441 (25.4) [25.0–25.7] 7,808 (17.5) [17.2–17.9] 12,627 (28.4) [27.9–28.8] 1,476 (17.8) [17.0–18.6] 2,361 (28.5) [27.5–29.5]

1,251 (1.1) [1.0–1.2] 112 (9.0) [7.4–10.5] 98 (0.1) [0.1–0.1] 7 (7.1) [2.0–12.2] 82,549 (72.6) [72.2–72.8] 7,677 (9.3) [9.1–9.5] 24,896 (21.9) [21.7–22.1] 2,686 (10.8) [10.4–11.2] 4,331 (3.8) [3.7–3.9] 252 (5.8) [5.1–6.5] 596 (0.5) [0.5–0.6] 179 (30.0) [26.4–33.7]

193 (15.4) [13.4–17.4] 331(26.5) [24.0–28.9] 16 (16.3) [9.0–23.6] 23 (23.5) [15.1–31.9] 13,015 (15.8) [15.5–16.0] 21,865 (26.5) [26.2–26.8] 4,494 (18.1) [17.6–18.5] 7,121 (28.6) [28.0–29.6] 439 (10.1) [9.2–11.0] 765 (17.7) [16.5–18.8] 255 (42.8) [38.8–46.8] 324 (54.4) [504–58.4]

4,749 (4.2) [4.1–4.3] 905 (19.1) [17.9–20.2] 7,904 (7.0) [6.8–7.1] 1,799 (22.8) [21.8–23.7] 13,099 (11.5) [11.3–11.7] 1,800 (13.7) [13.2–14.3] 5,208 (4.6) [4.5–4.7] 734 (14.1) [13.2–15.0] 8,734 (7.7) 2,051 (1.8) 1,540 (1.4) 7,916 (7.0) 2,789 (2.5) 7,052 (6.2) 1,459 (1.3) 9,616 (8.5)

[7.5–7.8] [1.7–1.9] [1.3–1.4] [6.8–7.1] [2.4–2.5] [6.1–6.3] [1.2–1.3] [8.3–8.6]

66,097 (58.1) [57.8–58.4] 30,113 (26.5) [26.2–26.7] 11,163 (9.8) [9.5–10.0] 6,348 (5.6) [5.5–5.7]

1,357 (28.6) [27.3–29.9] 2,634 (33.3) [32.3–34.4] 2,915 (22.3) [21.5–23.0] 1,192 (22.9) [21.8–24.0]

1,977 (41.6) [40.2–43.0] 3,843 (48.6) [47.5–49.7] 4,644 (35.5) [34.6–36.3] 1,930 (37.1) [35.8–38.4]

1,566 (17.9) [17.1–18.7] 519 (25.3) [23.4–27.2] 186 (12.1) [10.5–13.7] 1,097 (13.9) [13.1–14.6] 256 (9.2) [8.1–10.3] 1,106 (15.7) [14.8–16.5] 370 (25.4) [23.1–27.6] 1,927 (20.0) [19.2–20.8]

2,449 (28.0) [27.1–29.0] 725 (35.4) [33.3–37.4] 295 (19.2) [17.2–21.1] 1,729 (21.8) [20.9–22.8] 478 (17.1) [15.7–18.5] 1,933 (27.4) [26.4–28.5] 669 (45.9) [43.3–48.4] 3,166 (32.9) [32.0–33.9]

3,791 (43.4) [42.4–44.4] 1,096 (53.4) [51.3–55.6] 524 (34.0) [31.7–36.4] 2,795 (35.3) [34.3–36.4] 802 (28.8) [27.1–30.4] 3,060 (43.4) [42.2–44.6] 1,040 (71.3) [69.0–73.6] 4,702 (49.0) [47.9–49.9]

3,855 (5.8) [5.7–6.0] 3,641 (12.1) [11.7–12.5] 1,948 (17.5) [16.8–18.2] 1,469 (23.1) [22.1–24.2]

6,878 (10.4) [10.2–10.6] 12,200 (18.5) [18.2–18.8] 6,075 (20.2) [19.7–20.6] 9,888 (32.8) [32.3–33.4] 3,111 (27.9) [27.0–28.7] 4,773 (42.8) [41.8–43.7] 2,348 (37.0) [35.8–38.2] 3,568 (56.2) [55.0–57.4]

Abbreviations: 95% CI = 95% confidence interval; IQR = interquartile range; SD = standard deviation a From here down, the percentages in 30-day, 90-day, and 1-year mortality are calculated by rows.

were independently associated with postoperative mortality. Comorbidities such as kidney and liver disease, COPD, heart failure, dementia, and cancer with metastases had a strong association with short- and long-term postoperative mortality while the presence of a cerebrovascular or rheumatic disease decreased the mortality risk. Length of stay decreased from 2000 to 2014, from a median of 14 to 8 days. The number of surgical interventions for first-time HF was also found to have decreased in the period 2000 to 2014. Surprisingly, we found that patients with a known cerebrovascular disease had a decreased risk of postoperative mortality. These patients are treated with preventive anticoagulant drugs, thus the finding might reflect the preventive effect of anticoagulant medication on postoperative cardiovascular events and mortality. Regarding the decreased risk of postoperative mortality in patients with known rheumatoid arthritis, the improvements in the treatment of rheumatoid arthritis in the past decades could potentially explain the study result. No conclusion can be drawn on these matters, which should be further investigated.

In the uni- and multivariate Cox regression, we found an association between type of fracture, type of operation, and the risk of postoperative mortality. There exists no international consensus on whether the type of fracture influences postoperative mortality following HF surgery. One study with 41,000 patients found that patients with a collum femoris fracture had a longer mean survival time compared with patients with a trochanteric fracture (Kannegaard et al. 2010) whereas a smaller study with 428 patients found no association (Panula et al. 2011). A study from the American College of Surgeons’ National Surgical Quality Improvement database including around 9,500 patients with hip fractures found no difference in mortality comparing different types of operations (Sathiyakumar et al. 2015). However, a retrospective register study with 11,253 Swedish patients found that total hip arthroplasty had a lower mortality rate compared with hemiarthroplasty (Hansson et al. 2017). Further studies are needed to shed light on whether the type of operative procedure influences the postoperative mortality following HF surgery and whether the prognosis of specific comorbid elderly patients can be modulated

by choosing procedures with less trauma and thus less surgical stress. Even though the multivariable analysis was adjusted for age and background comorbidities, these results may reflect confounding by indication and should be interpreted with caution. Patients may have been pre-selected for certain surgical interventions based on their pre-surgical characteristics. In recent years, there has been a high awareness of fasttrack surgery. The goal is to operate on the patient within 24 hours of admission, achieve fast postoperative mobilization, adequate nutrition, and minimize the use of analgesic drugs (Kehlet and Dahl 2003). The time from admission with an HF to surgery correlates to increased mortality (Liu et al. 2017), and with fast-track surgery a decrease in the postoperatively mortality has been reported (Pedersen et al. 2008). We found a decline in median length of stay from 14 in 2000 to 8 days in 2014, but on a national level we found postoperative mortality to be relatively unchanged. National implementation of fasttrack HF surgery could potentially improve the postoperative course (Egerod et al. 2010). This study has limitations as it is an observational study and unmeasured confounding is present. The patients were selected by diagnosis and operation codes in the DNPR. Therefore, patients with incorrect coding may not be included; however, the DNPR is validated (Lynge et al. 2011). We did not have data on patients’ daily medicine consumption, smoking, and alcohol intake as well as the patient’s physiological status including BMI, disease severity, frailty, and sociodemographic status. Furthermore, the mortality of patients with HF was not compared with a normal population, and it is therefore not clear whether the mortality is higher in this group. Postoperative complication is not part of this study design but could be relevant in future studies. In summary, in this national Danish cohort study, patients undergoing surgery for a hip fracture had postoperative mortality of 9.6% at 30 days, 16% at 90 days and 27% at 1 year. The postoperative mortality varied between years but did not decline from 2000 to 2013. But the length of stay declined from a median of 14 days in 2000 to 8 days in 2014. Further interventional studies must be undertaken in order to improve survival after HF surgery, and potentially study whether a national fast-track program could improve postoperative survival, as seen in regional studies. Supplementary data Tables 2–4 are available as supplementary data in the online version of this article, http://dx.doi.org/10.1080/17453674. 2019.1680485 OG, LT, IG, and SE conceived and designed the analysis of the study. OG collected the data through the National Patients Register. OG, LT and SE performed the analysis. All authors contributed to the writing of the manuscript. Acta thanks Håvard Dale and Mikk Jürisson for help with peer review of this study.

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Brauer C A, Coca-Perraillon M, Cutler D M, Rosen A B. Incidence and mortality of hip fractures in the United States. JAMA 2009; 302(14): 1573-9. Cheng S Y, Levy A R, Lefaivre K A, Guy P, Kuramoto L, Sobolev B. Geographic trends in incidence of hip fractures: a comprehensive literature review. Osteoporos Int 2011; 22(10): 2575-86. Driessen J H M, Hansen L, Eriksen S A, van Onzenoort H A W, Henry R M A, van den Bergh J, Abrahamsen B, Vestergaard P, de Vries F. The epidemiology of fractures in Denmark in 2011. Osteoporos Int 2016; 27(6): 2017-25. Egerod I, Rud K, Specht K, Jensen P S, Trangbaek A, Rønfelt I, Kristensen B, Kehlet H. Room for improvement in the treatment of hip fractures in Denmark. Dan Med Bull 2010; 57(12): A4199. Goldacre M J, Roberts S E, Yeates D. Mortality after admission to hospital with fractured neck of femur: database study. BMJ 2002; 325(7369): 868-9. Hansson S, Nemes S, Kärrholm J, Rogmark C. Reduced risk of reoperation after treatment of femoral neck fractures with total hip arthroplasty. Acta Orthop 2017; 1-5. Kannegaard P N, van der Mark S, Eiken P, Abrahamsen B. Excess mortality in men compared with women following a hip fracture: national analysis of comedications, comorbidity and survival. Age Ageing 2010; 39(2): 203-9. Kehlet H, Dahl J B. Anaesthesia, surgery, and challenges in postoperative recovery. Lancet 2003; 362(9399): 1921-8. Lamberts M, Gislason G H, Lip G Y H, Lasse n JF, Olesen J B, Mikkelsen A P, Sørensen R, Køber L, Torp-Pedersen C, Hansen M L. Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study. Circulation 2014; 129(15): 1577-85. Leal J, Gray A M, Prieto-Alhambra D, Arden N K, Cooper C, Javaid M K, Judge A. Impact of hip fracture on hospital care costs: a population-based study. Osteoporos Int 2016; 27(2): 549-58. Lin D Y, Wei L J, Ying Z. Checking the Cox model with cumulative sums of martingale-based residuals. Biometrika 1993; 80(3): 557. Liu S K, Ho A W, Wong S. Early surgery for Hong Kong Chinese elderly patients with hip fracture reduces short-term and long-term mortality. Hong Kong Med J 2017; 23(4): 374-80. Lynge E, Sandegaard J L, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011; 39(7 Suppl.): 30-3. Panula J, Pihlajamäki H, Mattila V M, Jaatinen P, Vahlberg T, Aarnio P, Kivelä S-L. Mortality and cause of death in hip fracture patients aged 65 or older: a population-based study. BMC Musculoskelet Disord 2011; 12(1): 105. Pedersen S J, Borgbjerg F M, Schousboe B, Pedersen B D, Jørgensen H L, Duus B R, Lauritzen J B. A comprehensive hip fracture program reduces complication rates and mortality. J Am Geriatr Soc 2008; 56(10): 1831-8. Roberts S E, Goldacre M J. Time trends and demography of mortality after fractured neck of femur in an English population, 1968–98: database study. BMJ 2003; 327(7418): 771-5. Roche J J W, Wenn R T, Sahota O, Moran C G. Effect of comorbidities and postoperative complications on mortality after hip fracture in elderly people: prospective observational cohort study. BMJ 2005; 331(7529): 1374. Rosengren B E, Björk J, Cooper C, Abrahamsen B. Recent hip fracture trends in Sweden and Denmark with age-period-cohort effects. Osteoporos Int 2017; 28(1): 139-49. Sathiyakumar V, Greenberg S E, Molina C S, Thakore R V, Obremskey W T, Sethi M K. Hip fractures are risky business: an analysis of the NSQIP data. Injury 2015; 46(4): 703-8. Sathiyakumar V, Avilucea F R, Whiting P S, Jahangir A A, Mir H R, Obremskey W T, Sethi M K. Risk factors for adverse cardiac events in hip fracture patients: an analysis of NSQIP data. Int Orthop 2016; 40(3): 439-45 Schmidt M, Schmidt S A J, Sandegaard J L, Ehrenstein V, Pedersen L, Sørensen H T. The Danish National patient registry: a review of content, data quality, and research potential. Clin Epidemiol 2015; 7: 449-90. Thygesen S K, Christiansen C F, Christensen S, Lash T L, Sørensen H T. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients. BMC Med Res Methodol 2011; 11(1): 83.

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Is there a weekend effect after hip fracture surgery? A study of 74,410 hip fractures reported to the Norwegian Hip Fracture Register Andrea BOUTERA 1,2, Eva DYBVIK 2, Geir HALLAN 2,3, and Jan-Erik GJERTSEN 2,3 1 Faculty of Medicine, University of Bergen, Bergen; 2 The Norwegian Hip Fracture Register, Department of Orthopedic Surgery, Haukeland University Hospital, Bergen; 3 Department of Clinical Medicine (K1), University of Bergen, Bergen, Norway Correspondence: jan-erik.gjertsen@helse-bergen.no Submitted 2019-08-23. Accepted 2019-10-07.

Background and purpose — The term “weekend effect” describes differences in outcomes between patients treated at weekends compared with weekdays. We investigated whether there is a weekend effect for the risk of reoperation and mortality after hip fracture surgery at Norwegian hospitals. Patients and methods — We included data from 76,410 hip fractures in patients 60 years and older reported to the Norwegian Hip Fracture Register (NHFR) between 2005 and 2017. Cox survival analyses with adjustments for age, sex, ASA class, type of fracture, operating method, and waiting time from fracture to surgery were used to calculate the risk of reoperation and death after surgeries performed at weekends compared with surgeries performed on weekdays. Results — The mean age for all patients was 82 years, and 71% were female. 73% of fractures occurred on weekdays (Monday to Friday) and 27% during weekends (Saturday and Sunday). 71% of fractures were operated on a weekday and 29% at a weekend. Slightly increased mortality was observed during the 2 first months after weekend admission with hip fracture (HR 1.08; 95% CI 1.03–1.14). This did not continue in subsequent months, but the initial effect of weekend presentation was still apparent at 1-year follow-up. Further, there was no difference in mortality between patients who were operated at a weekend and patients operated on a weekday. Neither were there any differences in the risk of reoperation between weekday and weekend when comparing day of fracture or day of surgery. Interpretation — Patients who suffered a hip fracture during a weekend had slightly increased mortality in the first 2 months postoperatively. Whether the surgery was done on weekdays or at weekends did not affect mortality or the risk of reoperation.

The “weekend effect” describes the difference between patients admitted or treated at weekends compared with weekdays (Party et al. 1977). In an effort to understand and prevent adverse outcomes after hospital admission, several studies have studied the “weekend effect” in hip fractures (Smith et al. 2014, Thomas et al. 2014, Kristiansen et al. 2016, Nijland et al. 2017). Early surgery for hip fracture patients has been shown to be associated with better outcome, but at weekends there may be less staffing, lower efficiency at the hospitals, longer waiting time, and surgeons with less experience (Daugaard et al. 2012, Mathews et al. 2016, Authen et al. 2018). Another aspect is that medical staff at weekends often may be less familiar with the patients under their care (Kent et al. 2016). Weekend admission and weekend surgery may therefore be a risk factor for increased mortality for hip fracture patients. To ensure that hip fractures are treated within the time limits given in several recommendations, there is a need to operate these fractures also during weekends (Ranhoff et al. 2019). Several studies have reported higher mortality for hip fracture patients operated during weekends (Thomas et al. 2014, Kent et al. 2016, Kristiansen et al. 2016). Other studies have not found any weekend effect for hip fracture patients (Foss and Kehlet 2006, Boylan et al. 2015, Nandra et al. 2017, Sayers et al. 2017, Asheim et al. 2018). Therefore, we investigated whether there is a weekend effect for risks of reoperation and mortality after hip fractures, by using data from the Norwegian Hip Fracture Register (NHFR). Our hypothesis was that the mortality and risk of reoperation was greater for patients suffering a hip fracture or operated due to a hip fracture at a weekend compared with weekdays.

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Hip fractures in NHFR 2005–2017 n = 104,980 Excluded (n = 28,570): – date of fracture missing, 19,711 – age < 60 years, 5,624 – pathologic fractures, 1,356 – other missing information, 1,879 (i.e. time from fracture to surgery, ASA score, type of fracture, operation method) Included in the studey n = 76,410 Day of fracture: – weekday, 55,406 – weekend, 21,004

Day of surgery: – weekday, 54,558 – weekend, 21,852

Figure 1. Patient selection.

Patients and methods This retrospective observational study was performed using routinely collected data in the Norwegian Hip Fracture Register (NHFR). Since 2005 the NHFR has aimed to improve and assure the quality of hip fracture treatment in Norway (Gjertsen et al. 2008). The NHFR has provided a detailed picture of trends in care, particularly in respect of change in surgical techniques (Gjertsen et al. 2017, Johansen et al. 2017). After each hip fracture surgery, the surgeon fills in a standardized paper form that is sent to the register. The form gives information on the patient’s age, sex, ASA class, cognitive function, and unique personal identification number assigned to each inhabitant in Norway. Day of operation and fracture, delay to surgery, classification of the fracture, type of operation, cause and type of reoperation, information on implants, duration of surgery, and surgeon’s experience is also registered. In this way, the NHFR can monitor the outcome of primary operations, any subsequent reoperations, and mortality for hip fracture patients treated in Norwegian hospitals. Compared with the Norwegian Patient Registry the completeness of primary operations in the NHFR is 95% for hemiarthroplasties and 88% for osteosyntheses (Furnes et al. 2019). The patients were categorized according to the ASA score system. Further, we divided patients into the following age categories: 60–74 years, 75–79, 80–84, 85–89, and over 90 years. Cognitive impairment was classified as: yes, no, or uncertain. Less than half of the cases in the NHFR had information on the exact time of fracture, but almost all cases had the date of fracture and operation registered. Therefore, we chose to define each day of the week as full days from 00–24 hours. “Weekdays” were defined as Monday through Friday and “Weekends” as Saturday and Sunday. One could argue that the weekend starts on Friday afternoon/evening, but at most Norwegian hospitals the staffing on Friday afternoon/evening is exactly the same as on any other “Weekday” afternoon/evening. This simple definition of “Weekdays” and “Weekends” can therefore be justified.

Surgeon’s experience has been registered in the NHFR since 2011. Surgeon’s experience was divided into 3 groups: less than 3 years’ experience, more than 3 years’ experience, and missing information on surgeons’ experience. Waiting time from fracture to surgery was identified by 5 groups: 0–6 hours, > 6–12 hours, > 12–24 hours, > 24–48 hours, and > 48 hours. As of December 31, 2017, the NHFR had information on 104,980 hip fractures treated between 2005 and 2017 (Figure 1). We excluded operations with missing data on day of fracture, ASA class, type of fracture, operation method, and time interval from fractures to surgery. Further, operations in patients under 60 years and operations of pathological fractures were excluded to get a more homogeneous patient group. After exclusion, 76,410 hip fractures remained for analyses. Of these, 55,406 (73%) hip fractures occurred on weekdays and 21,004 (27%) occurred during weekends. 54,558 (71%) hip fractures were operated on weekdays and 21,852 (29%) at weekends. Statistics A chi-square test was used to compare means for categorical variables. Survival analyses were performed using Kaplan– Meier and Cox regression methods. Follow-up time was calculated from the index operation until the first reoperation, emigration, death, or December 31, 2018 (end of study), whichever came first. Cox multiple regression models were used to compare hazard ratios (HRs) for reoperation and death among patient groups (weekdays/weekends). Adjustments were done for age groups, sex, ASA class, type of fracture, operation method, and time from fracture to surgery. These adjustments were done as earlier studies on similar patient populations in the NHFR have shown that these specific variables may influence mortality and risk for reoperation. Adjustments for patients operated on both sides were not done, since an earlier study has shown that this will not alter the conclusion for the entered covariates (Lie et al. 2004). Reoperation and mortality were studied within 30, 60, 180, and 365 days after surgery. Further, sub-analyses using a more common definition of “Weekend” (Friday 4 pm–Monday 8 am) were done for patients with information on exact time of fracture. P-values < 0.05 were considered statistically significant. Proportionality assumptions were checked using log minus log plots and these were fulfilled. The statistical analyses were performed using IMB-SPSS Statistics, version 24.0 for Windows (IBM Corp, Armonk, NY, USA) and the statistical package R, version 3.4.0 (http://www.R-project.org). The study was performed in accordance with the RECORD statement. Ethics, funding, and potential conflicts of interest The NHFR has permission from the Norwegian Data Protection Authority to collect and store data on hip fracture patients (permission issued January 3, 2005; reference number 2004/1658-2 SVE/-). The patients have signed a written,

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Table 1. Baseline characteristics for all patients with separate numbers for day of fracture and day of surgery. Values are frequency (%) Characteristics

Day of fracture Day of surgery Weekday Weekend p-value a Weekday Weekend p-value a

Total (76,410) 55,406 21,004 54,558 21,852 Age category 0.003 < 0.001 60–74 9,603 (17) 3,873 (19) 9,464 (17) 4,012 (18) 75–79 7,873 (14) 2,950 (14) 7,717 (14) 3,106 (14) 80–84 12,536 (23) 4,569 (22) 12,247 (23) 4,858 (22) 85–89 14,272 (26) 5,399 (26) 14,087 (26) 5,584 (26) ≥ 90 11,122 (20) 4,213 (20) 11,043 (20) 5,584 (20) Female sex 39,452 (71) 14,978 (71) 0.3 38,817 (71) 15,513 (71) 0.3 ASA classification 0.1 0.001 1 2,300 (4.2) 941 (4.5) 2,251 (4.1) 990 (4.5) 2 18,839 (34) 7,195 (34) 18,518 (34) 7,516 (34) 3 30,367 (55) 11,472 (55) 29,901 (55) 11,938 (55) 4 3,818 (6.9) 1,369 (6.5) 3,804 (7.0) 1,383 (6.3) 5 82 (0.1) 27 (0.1) 84 (0.2) 25 (0.1) Cognitive impairment 0.2 0.01 No 35,472 (64) 13,398 (64) 34,698 (64) 14,172 (65) Yes 13,687 (25) 5,313 (25) 13,704 (25) 5,296 (24) Uncertain 5,252 (9.5) 1,938 (9.2) 5,189 (9.5) 2,001 (9.2) Missing 995 (1.8) 355 (1.7) 967 (1.8) 383 (1.8) Type of fracture 0.7 0.6 Undisplaced FNF 8,168 (15) 3,063 (15) 8,104 (15) 3,127 (14) Displaced FNF 22,679 (41) 8,752 (42) 22,396 (41) 9,035 (41) Basocervical FNF 2,004 (3.6) 718 (3.4) 1,952 (3.6) 770 (3.5) Trochanteric AO/OTA A1 9,414 (17) 3,552 (17) 9,250 (17) 3,716 (17) AO/OTA A2 8,829 (16) 3,309 (16) 8,651 (16) 3,487 (16) AO/OTA A3 940 (1.7) 349 (1.7) 923 (1.7) 366 (1.7) Subtrochanteric 2,906 (5.2) 1,079 (5.1) 2,833 (5.2) 1,152 (5.3) Other 466 (0.8) 182 (0.9) 449 (0.8) 199 (0.9) a Pearson’s

chi-square test. FNF = femoral neck fracture.

Table 2. Operative data with separate numbers for day of fracture and day of surgery. Values are frequency (%) Characteristics

Day of fracture Weekday Weekend p a

Day of surgery Weekday Weekend

Total (76,410) 55,406 21,004 54,558 21,852 Surgeon’s experience level b 0.5 1.0 < 3 years 4,680 (16) 1,789 (16) 4,612 (16) 1,857 (16) ≥ 3 years 22,375 (79) 8,591 (79) 22,085 (79) 8,881 (79) Missing 1,450 (5.1) 522 (4.8) 1,407 (5.0) 565 (5.0) Time from fracture to operation < 0.001 < 0.001 0–6 hours 2,579 (4.7) 1,197 (5.7) 2,614 (4.8) 1,162 (5.3) > 6–12 hours 9,266 (17) 3,441 (16) 9,200 (17) 3,507 (16) > 12–24 hours 20,190 (36) 7,807 (37) 19,414 (36) 8,583 (39) > 24–48 hours 15,970 (29) 5,675 (27) 15,628 (29) 6,017 (28) > 48 hours 7,401 (13) 2,884 (14) 7,702 (14) 2,583 (12) Type of primary operation 0.7 0.2 Screw osteosynthesis 10,968 (20) 4,246 (20) 10,862 (20) 4,352 (20) Hemiprosthesis 19,734 (36) 7,524 (36) 19,452 (36) 7,776 (36) Sliding hip screw 11,712 (21) 4,408 (21) 11,493 (21) 4,627 (21) Sliding hip screw + TSP 5,021 (9.1) 1,863 (8.9) 4,855 (8.9) 2,029 (9.3) Short IM nail 4,604 (8.3) 1,710 (8.1) 4,535 (8.3) 1,779 (8.1) Long IM nail 2,371 (4.3) 896 (4.3) 2,383 (4.4) 884 (4.0) Other 996( 1.8) 357 (1.7) 948 (1.7) 405 (1.9) a Pearson’s chi-square test. b Registered since 2011.

TSP = trochanteric support plate; IM = intramedullary.

informed consent, and in case they were not able to understand or sign, their next of kin could sign the consent form on their behalf. The Norwegian Hip Fracture Register is financed by the Western Norway Regional Health Authority. No competing interests were declared.

Results Patients The mean age of all patients was 82 years, and 71% were female. About 25% of the study population had cognitive impairment, and 62% of all patients were ASA class 3 or higher. There were small differences in baseline characteristics between the treatment groups (Table 1). Operation data for day of fracture and day of surgery showed only small statistically significant differences in type of primary operation and waiting time (Table 2). Mortality and reoperations Patients sustaining a hip fracture during weekends had 0.3–0.7% higher mortality than patients sustaining a hip fracture during weekdays (Figure 2, Table 3, see Supplementary data). Increased mortality was observed during the 2 first months after weekend admission with hip fracture (HR 1.03). This did not continue in subsequent months, but this initial effect of weekend presentation was still apparent at 1-year follow-up. Mortality was, however, independent of the day of surgery (Figure 3, Table 3, see Supplementary data). The risk of reoperation was independent of the day of injury and the day of surgery (Table 4, see Supplementary data). Analyses including only patients with information on exact time of fracture, and using a more common definition of “Weekend” (Friday 4 pm–Monday 8 am), gave similar results regarding both mortality and reoperations. Subanalyses also showed that risks of reoperation and mortality after 1 year for technically demanding fractures

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Adjusted 30-day mortality (%)

Adjusted 365-day mortality (%)

Adjusted 30-day mortality (%)

Time of fracture Weekend Weekday

Adjusted 365-day mortality (%) 30

Time of surgery Weekend Weekday

20 6

6 15

15 4

4 10

10 2

Time of surgery Weekend Weekday

0 0

Days postoperatively

Weeks postoperatively

0 0

Days postoperatively

Weeks postoperatively

Figure 2. 30-day (left panel) and 1-year (right panel) mortality, grouped after time of fracture. Cox survival curves adjusted for differences in age, sex, ASA class, type of fracture, operation method and time from fracture to surgery.

Figure 3. 30-day (left panel) and 1-year (right panel) mortality, grouped on after time of surgery. Cox survival curves adjusted for differences in age, sex, ASA class, type of fracture, operation method and time from fracture to surgery.

(displaced femoral neck fractures and intertrochanteric/subtrochanteric fractures) and technically demanding surgeries (hemiarthroplasties and long IM nails) were independent of day of fracture as well as day of surgery (Table 5, see Supplementary data). Further, analyses showed that both healthy (ASA 1–2) patients (HR 1.08, 95% CI 1.00–1.16) and comorbid (ASA 3–5) patients (HR 1.04, 95% CI 1.00–1.08) with hip fracture occurring during the weekend had a small, but statistically significant increased mortality, but no increased risk of reoperations. Further, patients aged 80–89 years had increased risk of death when sustaining a fracture during weekends (HR 1.09, CI 1.04–1.14), but no increased risk of reoperations compared with fracture on weekdays. For the patients aged 60–79 years and ≥ 90 years there were no differences in mortality or reoperation risk when investigating either day of fracture or day of surgery.

outcomes, including length of stay, delay to surgery, longerterm mortality, and reoperation rates, did not differ between weekdays and weekend admission or surgery (Sheikh et al. 2018). Our results, and results from the UK, did not show a weekend effect; this implies that guidelines can be helpful. Other factors than weekend surgery probably influence the mortality in hip fracture patients more. Some studies have suggested that surgical delay is one of the most important factors affecting the mortality for hip fracture patients (Daugaard et al. 2012, Sayers et al. 2017). We found a small difference in delay to surgery in baseline characteristics of patients. We identified a slightly increased mortality in the first 2 months postoperatively for fractures during weekends, which may suggest that the quality of medical treatment during weekends is poorer compared with weekdays. Lower levels of nursing have been shown to be associated with increased mortality (Cram et al. 2004, Pauls et al. 2017). Thus, a decreased quality of perioperative treatment of hip fracture patients during weekends can explain the differences found in our study. One of the key factors in a well-run hip fracture unit is the multidisciplinary team input, particularly from the orthogeriatric service (Thomas et al. 2014). Patients sustaining a fracture during the weekend may have delayed orthogeriatric assessment. In addition, delays in community service like home care, at a nursing home, and in emergency rooms could affect time from fracture to admission to hospital during weekends. In addition to reduced staff quantity at weekends, the weekend medical staff can be less experienced and less familiar with the patients on the ward (Kent et al. 2016). Less experienced staffing could cause a delay in preparation of hip fracture patients for the theatre as well. Reduced staffing at weekends also lowers the surgical capacity. The overall increase in difficulties in accessing subspecialty opinions, access to past medical records, less staffing, delay to surgery, and less experienced medical staff can probably all contribute to the increase in mortality for weekend fractures (Thomas et al. 2014).

Discussion Overall, our results demonstrate that hip fracture patients at Norwegian hospitals had the same outcomes after surgery regardless of whether surgery was performed on a weekday or at a weekend. This is in line with several studies reporting on various outcomes (Foss and Kehlet 2006, Boylan et al. 2015, Mathews et al. 2016, Nandra et al. 2017, Nijland et al. 2017, Sayers et al. 2017, Asheim et al. 2018). National guidelines for treatment of hip fracture patients are currently used at most hospitals in Norway (Ranhoff et al. 2019). The NICE guidelines recommend surgery on the same day or the day after the fracture (National Institute for Health and Clinical Excellence 2011). These guidelines contribute to standardized treatment of hip fracture patients on weekdays and at weekends. Thomas et al. (2014) found no differences in 30-day mortality rates between weekdays and weekends in a retrospective review of 2,989 patients with hip fractures. Another study with 1,326 patients demonstrated that specific

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A recently published study on the weekend effect for hip fracture treatment in Norway based on data from the Norwegian Patient Register (NPR) found slightly increased mortality for patients admitted on Sundays and during holidays, but the most remarkable result was that early morning admission and weekend discharge increased the mortality rate (Asheim et al. 2018). Other studies have also reported increased mortality for patients admitted during holidays, but not during weekdays and weekends (Foss and Kehlet 2006, Asheim et al. 2018). The strength of our study is the large number of patients included in a national register with high completeness and relatively long patient follow-up. The fact that the study presents national results increases the external validity of this study. Register-based studies do, however, have limitations including selection bias, information bias, and confounding (Varnum et al. 2019). We adjusted for possible confounding variables. The experience level of the surgeon was classified according to years of experience. However, it is likely that this classification does not necessarily reflect the volume of hip fracture operations that a surgeon has performed. In our study 27% of cases were excluded for different reasons, of which missing data constituted 21%. Incomplete reporting of reoperations may occur, but there is no reason to suspect a difference in reporting between surgeries or fractures on weekdays compared with weekends. With the large number of patients in our study small differences between groups may reach statistical significance without being of clinical importance. Therefore, the clinical importance needs to be considered for all results presented. In conclusion, patients who sustained a hip fracture during a weekend demonstrated a somewhat higher mortality in the first two months postoperatively compared with weekdays in our study. Other authors have proposed that the overall quality of treatment is somewhat poorer during weekends. This emphasizes the importance of optimal perioperative treatment of hip fracture patients during weekends too. Operating hip fractures during weekends did not increase mortality or risk of reoperations. Accordingly, no clear weekend effect could be found at Norwegian hospitals in this study. Supplementary data Tables 3–5 are available as supplementary data in the online version of this article, http://dx.doi.org/10.1080/17453674.2019. 1683945 AB, ED, and JEG planned the study. AB wrote the initial draft. AB and ED performed the statistical analyses. All authors contributed in the interpretation of the results, and improvement of the manuscript. The authors thank all the Norwegian orthopedic surgeons who have loyally reported to the register. Acta thanks Antony Johansen and Arkan S Sayed-Noor for help with peer review of this study.

Asheim A, Nilsen S M, Toch-Marquardt M, Anthun K S, Johnsen L G, Bjårngaard J H. Time of admission and mortality after hip fracture: a detailed look at the weekend effect in a nationwide study of 55,211 hip fracture patients in Norway. Acta Orthop 2018; 89(6): 610-14. Authen A L, Dybvik E, Furnes O, Gjertsen J E. Surgeon’s experience level and risk of reoperation after hip fracture surgery: an observational study on 30,945 patients in the Norwegian Hip Fracture Register 2011–2015. Acta Orthop 2018; 89(5): 486-502. Boylan M R, Rosenbaum J, Adler A, Naziri Q, Paulino C B. Hip fracture and the weekend effect: does weekend admission affect patient outcomes? Am J Orthop 2015; (10): 458-64. Cram P, Hillis S L, Barnett M, Rosenthal G E. Effects of weekend admission and hospital teaching status on in-hospital mortality. Am J Med 2004; 117(3): 151-7. Daugaard C L, Jorgensen H L, Riis T, Lauritzen J B, Duus B R, van der Mark S. Is mortality after hip fracture associated with surgical delay or admission during weekends and public holidays? A retrospective study of 38,020 patients. Acta Orthop 2012; 83(6): 609-13. Foss N B, Kehlet H. Short-term mortality in hip fracture patients admitted during weekends and holidays. Br J Anaesth 2006; 96(4): 450-4. Furnes O, Gjertsen J-E, Hallan G, Visnes H, Gundersen T, Fenstad A M, Kvinnesland I A, Dybvik E, Kroken G C. Norwegian National Advisory Unit on Arthroplasty and Hip Fractures. Annual report 2019. ISBN: 97882-91847-24-5 ISSN: 1893-8914. Gjertsen J E, Engesaeter L B, Furnes O, Havelin L I, Steindal K, Vinje T, Fevang J M. The Norwegian Hip Fracture Register: experiences after the first 2 years and 15,576 reported operations. Acta Orthop 2008; 79(5): 583-93. Gjertsen J, Dybvik E, Furnes O, Fevang J M, Havelin L I, Matre K, Engesæter L B. Improved outcome after hip fracture surgery in Norway: 10-year results from the Norwegian Hip Fracture Register. Acta Orthop 2017; 88(5): 505-11. Johansen A, Golding D, Brent L, Close J, Gjertsen J, Holt G, Hommel A, Pedersen A B, Dieter N. Using national hip fracture registries and audit databases to develop an international perspective. Injury 2017; 48(10): 2174-9. Kent S J, Adie S, Stackpool G. Letters to the Editor: Morbidity and in-hospital mortality after hip fracture surgery on weekends versus weekdays. J Orthop Surg (Hong Kong) 2016; 24(1): 41-4. Kristiansen N S, Kristensen P K, Nørgård B M, Mainz J, Johnsen S P. Offhours admission and quality of hip fracture care: a nationwide cohort study of performance measures and 30-day mortality. Int J Qual Health Care 2016; 28(3): 324-31. Lie SA, Engesaeter L B, Havelin L I, Gjessing H K, Vollset S E. Dependency issues in survival analyses of 55,782 primary hip replacements from 47,355 patients. Stat Med 2004; 23(20): 3227-40. Mathews J A, Vindlacheruvu M, Khanduja V. Is there a weekend effect in hip fracture patients presenting to a United Kingdom teaching hospital? World J Orthop 2016; 7(10): 678-686. Nandra R, Pullan J, Bishop J, Baloch K, Grover L, Porter K. Comparing mortality risk of patients with acute hip fractures admitted to a major trauma centre on a weekday or weekend. Sci Rep 2017; 7(1): 1233. National Institute for Health and Clinical Excellence. The management of hip fractures in adults (Clinical guideline CG 124); 2011. Available from https://www.nice.org.uk/Guidance/GC124 Nijland L M G, Karres J, Simons A E, Ultee J M, Kerkhoffs G M M J, Vrouenraets B C. The weekend effect for hip fracture surgery. Injury 2017; 48(7): 1536-41. Party W, Early F O R, Deathsnewcastle C. Newcastle survey of deaths in early childhood 1974/76, with special reference to sudden unexpected deaths. Working party for early childhood deaths in Newcastle. Arch Dis Child 1977; 52(11): 828-35. Pauls L A, Johnson-Paben R, McGready J, Murphy J, Pronovost P, Wu C. the weekend effect in hospitalized patients: a meta-analysis. J Hosp Med 2017; 12(9): 760-6. Ranhoff A H, Saltvedt I, Frihagen F, Raeder J, Maini S, Sletvold O. Interdisciplinary care of hip fractures: orthogeriatric models, alternative models, interdisciplinary teamwork. Best Pract Res Clin Rheumatol 2019; 33(2): 205-26.

Sayers A, Whitehouse M R, Berstock J R, Harding K A, Kelly M B, Chesser T J. The association between the day of the week of milestones in the care pathway of patients with hip fracture and 30-day mortality: findings from a prospective national registryâ&#x20AC;&#x201D;The National Hip Fracture Database of England and Wales. BMC Med 2017; 15(1): 62. Sheikh H Q, Aqil A, Hossain F S, Kapoor H. There is no weekend effect in hip fracture surgery: a comprehensive analysis of outcomes. Surgeon 2018; 16(5): 259-264. Smith T, Pelpola K, Ball M, Ong A, Myint P K. Pre-operative indicators for

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Risk of reoperation within 12 months following osteosynthesis of a displaced femoral neck fracture is linked mainly to initial fracture displacement while risk of death may be linked to bone quality: a cohort study from Danish Fracture Database Anne M NYHOLM 1,2, Henrik PALM 3, Håkon SANDHOLDT 4, Anders TROELSEN 1, Kirill GROMOV 1, and DFDB COLLABORATORS 4 1 Clinical

Orthopaedic Researc Hvidovre (CORH), Department of Orthopaedics, Copenhagen University Hospital Hvidovre, Copenhagen; 2 Department of Orthopaedics, Holbaek Sygehus, Holbaek; 3 Department of Orthopaedics, Copenhagen University Hospital Bispebjerg, Copenhagen; 4 Clinical Research Centre, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark 5 DFDB collaborators: Bjarke Viberg, Department of Orthopaedics, Kolding Hospital, Kolding; Jakob V Fristed, Department of Orthopaedics, Vejle Sygehus, Vejle; John K Petersen, Department of Orthopaedics, SUH Koege, Koege; Karl T Haak, Department of Orthopaedics, Holbaek Sygehus, Holbaek; Klaus Sander, Department of Orthopaedics, Aabenraa Hospital; Lasse Bayer, Department of Orthopaedics, North Zealand Hospital, Hilleroed; Mathias B Ho, Department of Orthopaedics, Regional Hospital in Horsens, Horsens; Michael Brix, Department of Orthopaedic Surgery, Odense University Hospital, Odense; Peter T Tengberg, Department of Orthopaedic Surgery, Copenhagen University Hospital Hvidovre, Copenhagen; Michael Krasheninnikoff, Department of Orthopaedics, Nykoebing Falster Hospital, Nykoebing Falster; Thomas Bloch, Department of Orthopaedics, Slagelse Hospital, Slagelse; Peter Rasmussen, Department of Orthopaedics, Copenhagen University Hospital Bispebjerg Hospital, Copenhagen, Denmark Correspondence: rienyholm@gmail.com Submitted 2019-08-14. Accepted 2019-11-07.

Background and purpose — Most guidelines use patient age as a primary decision factor when choosing between osteosynthesis or arthroplasty in displaced femoral neck fractures. We evaluate reoperation and death risk within 1 year after osteosynthesis, and estimate the influence of age, sex, degree of displacement, and bone quality. Patients and methods — All surgeries for femoral neck fractures with parallel implants (2 or 3 screws or pins) performed between December 2011 and November 2015 were collected from the Danish Fracture Database. Radiographs were analyzed for initial displacement, quality of reduction, protrusion, and angulation of implants. The bone quality was estimated using the cortical thickness index (CTI). Garden I and II type fractures with posterior tilt < 20° were excluded. Results — 654 patients with a mean age of 69 years were included. 59% were female. 54% were Garden II with posterior tilt > 20° or Garden III, and 46% were Garden IV. Only 38% were adequately reduced. 19% underwent reoperation and 18% died within 12 months. Female sex, surgical delay between 12 and 24 hours vs. < 12 hours, Garden IV type fracture, inadequate reduction, and protrusion of an implant were associated with statistically significant increased reoperation risk. No significant association between reoperation and age, CTI, or the initial angulation of implants was found. Notably, CTI was linked inversely with death risk. Interpretation — Reoperation risk is linked mainly to primary displacement and reduction of the fracture, with no apparent effect of age or bone quality. Bone quality may be linked with risk of death.

The existing guidelines for treatment of displaced femoral neck fractures differ in their recommendations: most rely primarily or solely on the age of the patient, with osteosynthesis for patients younger than 65–75 years of age and arthroplasty for patients above this age, while a few simply advise arthroplasty for all displaced femoral neck fractures (Palm and Teixidor 2015). However, in addition to patient age, several other patient-related factors are known at the time of the surgery and may be useful to guide the treatment—but the influence of these factors on risk of reoperation is not well investigated. We evaluated the risk of reoperation and death within 1 year following osteosynthesis of displaced femoral neck fractures, and estimated the influence of the age and sex of the patient, the degree of fracture displacement, and bone quality, in order to provide further evidence for nuancing the decision process and to improve outcome after a displaced femoral neck fracture.

Patients and methods From December 2011 to November 2015, 5,774 surgeries for a primary femoral neck fracture (AO/OTA classification, 31B) were prospectively registered in the Danish Fracture Database (DFDB, www.dfdb.dk) (Gromov et al. 2014). Cases were selected for inclusion as described in a previous study of the same cohort (Nyholm et al. 2018), leaving 1,558 surgeries with use of screws or pins (parallel implants) (Figure 1). Data included age, sex, surgical delay, OTA/AO fracture classification, and ASA score. Time to surgery was defined as the

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Primary femoral neck fracture surgeries recorded December 2011 to November 2015 in the Danish Fracture Database (DFDB) n = 5,774 Cases excluded on procedures performed (n = 4,216): – hemiarthroplasty, 3,110 – total hip arthroplasty, 346 – sliding hip screw, 585 – plate, 39 – cephalomedullary nail, 35 – procedures classified as ”other”, 86 – obvious erroneus entries, 15 Neck fracture surgeries performed with parallel implants n = 1,558 Cases excluded (n = 306): – duplicate records in DFDB, 25 – foreign citizens, 3 – < 8 surgeries performed in the department during inclusion time, 15 – incorrect date of surgery in DFDB, 18 – trochanteric fracture pattern, 4 – alternative surgical technique, 17 – dead prior to postoperative radiography, 10 – new fracture of the hip before postoperative radiography, 5 – quality of radiographs did not allow evaluation, 2 – radiographs not available, 193 – postoperative radiographs taken > 5 days after surgery, 8 – previous fracture of the hip, 4 – bilateral fractures of the hip at time of surgery, 1 – maldeveloped caput, 1 Relevant cases with available measurements n = 1,252 Non-displaced fractures excluded (n = 598) Displaced fractures included in the study n = 654

Figure 1. Case selection for inclusion in this study.

time from fracture diagnosis (preoperative radiograph) until the onset of surgery. Pre- and postoperative radiographs (standard trauma AP and lateral view) of cases were collected from treating depart-

Figure 3. Cortical thickness index (CTI) is thickness of the cortices (white line minus black line) in relation to the diameter of the bone (white line) 10 cm below the tip of trochanter minor (grey vertical line). CTI = (white line – black line)/white line.

ments and analyzed for fracture displacement in accordance with the Garden classification (Figure 2), posterior tilt as measured by Palm et al. (2009), result of reduction (displacement and posterior tilt), implant protrusion into the joint (evaluated by eye), angle of implants to the lateral cortex of the femoral shaft measured as described by Nyholm et al. (2018) and cortical thickness index (CTI) measured as the part of the diameter of the femoral shaft that consisted of cortex measured 10 cm below the tip of the trochanter minor (Figure 3) as described by Sah et al. (2007). In this process 306 cases were excluded for various reasons (Figure 1), leaving 1,252 cases with available radiographs. Of these, 598 cases with initially non-displaced fractures with a posterior tilt of < 20° were excluded, leaving 654 cases with fracture types that according to guidelines are eligible for arthroplasty in patients ≥ 70 years of age (initially displaced fractures or non-displaced fractures with a posterior tilt ≥ 20°) for analysis (Figure 1) (Palm et al. 2012). As described previously, intra- and inter-reader analyses were performed by 2 authors (HP and AMN), where measure-

Figure 2. Degree of fracture displacement. The fractures were divided into 2 groups: “Mildly displaced” fractures: Garden type II fractures (A) with ≥ 20° posterior tilt measured on the axial view (B), Garden type III fractures (C), and “Severely displaced” fractures: Garden type IV fractures (D).

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ments of 50 cases were performed twice with at least a 3-week interval between each read. This demonstrated a “Good” or Excellent” correlation for all included measures (Nyholm et al. 2018 and Table 1, see Supplementary data). Based on the radiographic measurements, the fractures were divided into 2 groups: “Mildly displaced” (Garden II type fractures with > 20° posterior tilt and Garden III type fractures) and “Severely displaced” (Garden IV type fracture) (see Figure 2). For the quality of the reduction, the fractures were divided into 3 groups: “Fully reduced” (non-displaced in AP view, < 10° posterior tilt), “Partly reduced” (non-displaced in AP view, > = 10° posterior tilt) and “Not reduced” (displaced in AP view). After finishing radiographic analysis, data on any further surgery of the hip (ICD-10 KNF*) were collected from the National Patient Register (Landspatientregisteret, NPR) and analyzed to identify relevant reoperations as previously described (Nyholm et al. 2018). A relevant reoperation was defined as either a re-osteosynthesis of the primary fracture, an implant and femoral head removal, or an arthroplasty. Simple removal of the implants was not considered a relevant reoperation. Relevant reoperations were side-matched to the fracture surgery to ensure that the reoperation was not conducted in a contralateral hip. Data on vital status were collected from the NPR as well. Follow-up for all cases was 12 months. Statistics The variables of interest were patient age, sex, initial fracture displacement, and bone quality (CTI). As surgical delay, result of reduction, protrusion of an implant into the joint, and angulation of the implants to the femoral shaft have previously been shown to influence risk of reoperation, these factors were all included as co-variables in an effort to optimize the models. The apparent effect of the included variables on the risk of reoperation was evaluated using Cox regression analysis. Time at risk was defined as time from the surgery until either reoperation, death, another non-relevant reoperation or surgery of the hip (reoperation for infection, a new fracture, femoral amputation), or end of follow-up. Because death is a frequent occurrence in this population and influences the risk of reoperation in a patient, to support the interpretation of the analysis of risk of reoperation a separate Cox regression with death as outcome was performed. Time at risk was defined as time from surgery to death or end of follow-up. For variables with several levels the overall effect in the model was evaluated using a likelihood ratio test. The fit of both models was evaluated using a proportional hazards test based on weighted residuals and was found to be acceptable. To evaluate the possibility of over-fitting, the variance of estimates in the model was compared with smaller models and found to be consistent, which suggest the models were not over-fitted. To illustrate the magnitude of the risk of death and reoperation in different patient groups, several estimates of the probability of reoperation and death were made based on the Cox

regression models for reoperation and death. 95% confidence intervals (CI) were used. All data handling and analysis was performed using R software (version 3.4.3; 11/30/2017; R Foundation for Statistical Computing, Vienna, Austria) (R 2017). Ethics, registration, data sharing plan, funding, and potential conflicts of interests This is a retrospective study, with all data collected from databases or radiographic analyses. No intervention was made, and the patients and families have not been contacted. There were therefore no ethical issues in relation to this study. A protocol with specified methods and outcomes was written prior to onset of the study. Permission to obtain and process data was obtained from the Danish Data Protection Agency (Datatilsynet, j.nr.: 2012-58-0004, local j.nr.: AHH-2015-032, I-Suite nr.: 03738) prior to the onset of the study. Study protocol and data managing/analysis files from R-studio will be available upon reasonable request; please contact corresponding author. Permissions to access data will have to be obtained from the relevant authorities, registries, and departments. All costs were financed by the Department of Orthopaedics, Copenhagen University Hospital Hvidovre, Denmark. There were no conflicts of interest for any authors in relation to this study.

Results 654 cases were included. Mean age was 69 years (21–102) and 385 (59%) were female. In 356 (54%) of the cases the fracture was mildly displaced (Garden II with posterior tilt > 20° or Garden III) and in 298 (46%) it was severely displaced (Garden IV) (Table 2). 28% had surgery within 12 hours, 78% within 24 hours, and 89% within 36 hours. 245 (38%) were adequately reduced, while the fracture was still ad latus displaced in the neck region on AP view or with > 10° posterior tilt in 409 (62%). In 18 (3%) cases an implant protruded into the joint. In 124 (19%) cases, the patient underwent a relevant reoperation, and in 117 (18%) cases the patient died. A larger proportion of the patients with a mildly displaced fracture died, but the patients in this group tended to be older (60% of patients with mild displacement were older than 70 years vs. 19% of patients with severely displaced fractures) (Table 2). Female sex (HR 1.8; CI 1.2–2.6), surgical delay between 12 and 24 hours vs. < 12 hours (HR 1.7; CI 1.1–2.6), severe displacement (Garden IV type fracture, HR 3.1; CI 2.0–4.7), insufficient reduction (HR 1.7; CI 1.1–2.5), and protrusion of an implant HR 2.4 (CI 1.0–5.5) were associated with statistically significant increased risk of reoperation. No statistically significant association between reoperation and age, CTI, or the angulation of implants was found (Table 3). In the death risk analysis increasing age of the patient, male sex, and high ASA score were associated with increasing risk

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Table 2. Demographics and measurements of included cases. Values are frequency (%) Reoperated a Dead a Total b Factor n = 124 (19) b n = 117 (18) b n = 654 Sex Male 40 (15) 53 (20) 269 (41) Female 84 (22) 64 (17) 385 (59) Age ≤ 50 5 (9) 1 (2) 54 (8) 51–60 17 (16) 10 (9) 109 (17) 61–70 65 (29) 25 (11) 227 (35) 71–80 13 (13) 15 (15) 97 (15) 81–90 18 (17) 30 (29) 104 (16) > 90 6 (10) 36 (58) 63 (10) Cortical thickness index < 0.3 2 (13) 7 (46) 15 (2) 0.3–0.4 15 (19) 22 (28) 78 (12) 0.4–0.5 45 (19) 53 (22) 238 (36) 0.5–0.6 45 (17) 28 (11) 263 (40) 0.6–0.7 11 (25) 4 (9) 44 (7) > 0.7 0 0 0 (0) Hours to surgery < 12 27 (15) 25 (14) 182 (28) 12–24 75 (23) 61 (19) 325 (50) 24–36 12 (16) 13 (17) 77 (12) 36–48 5 (16) 7 (23) 31 (5) > 48 2 (10) 7 (35) 20 (3) Fracture displacement c Mildly displaced 43 (12) 67 (19) 356 (54) Severely displaced d 81 (27) 50 (17) 298 (46) Quality of reduction Fully reduced e 33 (13) 38 (16) 245 (37) Partly reduced f 18 (21) 16 (19) 85 (13) Not reduced g 73 (23) 62 (19) 322 (49) Angle of implants h > 125° 112 (18) 111 (18) 621 (95) ≤ 125° 10 (33) 5 (17) 30 (5) Protrusion of implant into the joint No protrusion 118 (19) 113 (18) 636 (97) Protusion 6 (33) 4 (22) 18 (3) a Percentage of the number of cases in each subgroup. b Percentage of the total number of patients. c Garden II with > 20° posterior tilt or Garden III type fracture. d Garden IV type fracture. e Non-displaced in AP view, < 10° posterior tilt (PT). f Non-displaced in AP view, ≥ 10° PT. g Displaced in AP view. h Angle of implants to the lateral cortex of the femoral shaft in

AP.

of death. An inverse correlation between increasing CTI and risk of death was found (thinner cortex was associated with increased risk of death). Severely displaced fractures had a higher risk of death, but no statistically significant association with the quality of the reduction was found (Table 4). Estimation of likelihood of death and reoperation for predefined patients with optimal surgical result (surgical delay < 12 hours, good reposition with implants angled > 125° to the lateral cortex of the femoral shaft, and no protrusion into the joint) demonstrated that risk of death depended in great part on the age, the sex, and the ASA score of the patient, while the risk of reoperation was primarily determined by the initial fracture displacement. A decrease in the CTI from 0.5 (average of the

Table 3. Cox regression analysis of risk of reoperation Factor

Univarible Multivariable analyses analysis HR (CI) HR (CI)

Age Per 1 year increase 1.0 (0.99–1.01) 1.0 (0.99–1.02) Sex Female 1 1 Male 0.64 (0.44–0.93) 0.57 (0.38–0.87) ASA score 1–2 1 1 3–4 1.3 (0.88–1.9) 1.5 (0.96–2.2) Hours to surgery < 12 1 1 12–24 1.7 (1.1–2.6) 1.7 (1.1–2.6) 24–36 1.1 (0.53–2.1) 0.94 (0.44–2.0) > 36 0.95 (0.42–2.2) 0.95 (0.40–2.3) Test for overall effect p = 0.05 p = 0.06 Cortical thickness index Per 0.1 increase 0.95 (0.76–1.2) 1.0 (0.80–1.4) Fracture type Mildly displaced 1 1 Severely displaced 2.5 (1.8–3.7) 3.1 (2.0–4.7) Reduction a Fully reduced 1 1 Partly reduced 1.6 (0.92–2.9) 2.0 (1.1–3.8) Not reduced 1.8 (1.2–2.7) 1.6 (1.1–2.5) Test for overall effect p < 0.01 p = 0.03 Angle of implants to the lateral cortex of the femoral shaft in AP > 125° 1 1 ≤ 125° 2.0 (1.0–3.8) 1.7 (0.90–3.4) Protrusion of implant No protrusion 1 1 Protrusion 2.1 (0.94–4.9) 2.4 (1.0–5.5) a See

footnotes Table 2.

included group) to 0.4 (below the cut-off by Sah et al. (2007) for BMD-T score of –2.5) did not affect the risk of reoperation but did increase the risk of death for all estimates (Table 5). For an 80-year-old female with a severely displaced fracture, the estimated risk of reoperation within 1 year is > 20% (Table 5). If, however, the fracture is only mildly displaced, the risk of reoperation for all patient types is < 10%, indicating that if no severely displaced fractures are treated with osteosynthesis with parallel implants, the risk of reoperation following osteosynthesis should be 3–10% (Table 5) (providing they are sufficiently reduced prior to fixation). In our cohort, 12% of the cases with mildly displaced fractures underwent a relevant reoperation (Table 2). If only cases with sufficiently reduced fractures were considered, the reoperation rate dropped to 8% (11 reoperations in 137 patients with only mildly displaced fractures that were sufficiently reduced).

Discussion In this registry-based study of risk factors for reoperation and death following displaced femoral neck fractures treated with osteosynthesis no significant association between patient age

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Table 4. Cox regression analysis of risk of death Factor

Univarible Multivariable analysis analysis HR (CI) HR (CI)

Age Per 1 year increase 1.07 (1.05–1.08) 1.05 (1.03–1.07) Sex Female 1 1 Male 1.1 (0.83–1.7) 1.6 (1.1–2.4) ASA score 1–2 1 1 3–4 5.7 (3.8–8.4) 3.7 (2.4–5.7) Hours to surgery < 12 1 1 12–24 1.4 (0.88–2.4) 1.4 (0.85–2.2) 24–36 1.3 (0.64–2.5) 1.1 (0.58–2.3) > 36 2.2 (1.1–4.1) 1.3 (0.65–2.6) Test for overall effect p = 0.2 p = 0.6 Cortical thickness index Per 0.1 increase 0.58 (0.48–0.71) 0.72 (0.58–0.89) Fracture type Mildly displaced 1 1 Severely displaced 0.89 (0.62–1.3) 1.6 (1.1–2.5) Reduction a Fully reduced 1 1 Partly reduced 1.2 (0.68–2.2) 0.91 (0.48–1.7) Not reduced 1.3 (0.84–1.9) 1.1 (0.69–1.7) Test for overall effect p = 0.5 p = 0.9 Angle of implants to the lateral cortex of the femoral shaft in AP > 125° 1 1 ≤ 125° 0.94 (0.38–2.3) 0.85 (0.34–2.1) Protrusion of implant No protrusion 1 1 Protrusion 1.3 (0.47–3.5) 2.0 (0.72–5.5) a See

footnotes Table 2.

or cortical thickness index (CTI) and risk of reoperation was found. The main risk factors for reoperation were the amount of initial displacement, insufficient reduction, implant protrusion, increasing surgical delay, and female sex. In our secondary death risk analysis, an association between increased risk of death and increasing age, increasing ASA score, male sex, decreasing CTI, and severely displaced fracture type was found. Although this study is based on consecutive patients with data collected prospectively in a nationwide database, the general limitations of observational studies still apply. The number of observations is limited and the fact that no statistically significant associations were found for several covariates may be due to lack of power in our sample and should be interpreted with care. A concern is that the patients in this study have been selected for osteosynthesis, as older patients with severely displaced fractures should primarily receive arthroplasty in accordance with Danish guidelines (Palm et al. 2012). The fact that we do not find any effect of age on risk of reoperation should therefore be interpreted with caution. The increase in risk of death with increasing age may well impact negatively on the risk of reoperation (patients who have died are not at risk of reoperation, and morbid patients may not receive a relevant

Table 5. Estimates of risk of reoperation and death for predefined cases 1 year postoperatively. Values are percentages Sex, ASA score CTI 0.5 CTI 0.4 Displacement Estimated risk of Estimated risk of Age death reoperation death reoperation Male, 1–2 Mild 50 2 4 3 3 60 4 4 5 4 70 6 4 8 4 80 10 4 14 4 Severe 50 3 10 5 10 60 6 11 8 11 70 10 12 13 12 80 16 13 22 12 Male, 3–4 Mild 50 8 5 11 5 60 13 5 17 5 70 21 6 28 6 80 33 6 42 6 Severe 50 12 15 17 15 60 20 16 27 16 70 32 17 41 16 80 48 18 59 17 Female, 1–2 Mild 50 1 6 2 6 60 2 6 3 6 70 4 7 5 7 80 7 7 9 7 Severe 50 2 17 3 17 60 4 19 5 18 70 6 20 9 19 80 10 21 14 20 Female, 3–4 Mild 50 5 9 7 9 60 8 9 11 9 70 14 10 18 10 80 22 11 29 10 Severe 50 8 25 11 24 60 13 26 18 26 70 21 27 28 27 80 33 29 43 28 All estimates are made with the surgical parameters as for an optimal surgery: surgical delay < 12 hours, reduction to non-displaced with < 10° posterior tilt, with implant-angle > 125° and without implant protrusion into the joint. CTI = Cortical thickness index

reoperation due to poor health). The intra- and inter-reader measurements demonstrated a “good” or “excellent” correlation between the readers for all included measurements, indicating a reproducible reading of the radiographs, but the uncertainty between the 2D view seen on the radiographs and the 3D “reality” has not been validated and introduces an unknown uncertainty to the results. It is not our custom to follow these patients until healing and it was therefore not possible to evaluate the actual risk of non-union, avascular necrosis, or fracture displacement. Therefore, reoperation with secondary arthroplasty, revision of primary osteosynthesis, or femoral head removal was chosen as primary endpoint under the assumption that in our all-access, free-of-charge healthcare system all patients with clinically relevant complications such as pain and/or restriction of mobility would receive reoperation. It

is, however, possible that some patients may not have undergone reoperation owing to patient-related causes. A follow-up of 12 months was chosen since previous studies with longer follow-up have demonstrated that 80–90% of all reoperations fall within this timeframe (Murphy et al. 2013), and the high mortality in this patient population is likely to introduce unnecessary confounding with a longer follow-up. The risk factors for reoperation following femoral neck fractures have been evaluated in previous studies; however, most of those cohorts were quite small with less than 150 patients included. Our study, with 654 included cases, underlines the previous findings that for displaced femoral neck fractures a smaller initial displacement of the fracture in AP and/or lateral view (posterior tilt), as well as good reduction and avoiding protrusion of the implants into the hip joint, is associated with a reduced risk of subsequent reoperation (Bjørgul and Reikerås 2007, Hoelsbrekken et al. 2012, Yang et al. 2013). In contrast to the initial fracture displacement the latter 2 factors are both influenced by the surgeon and therefore possible to optimize. Several studies have demonstrated a better outcome with lower mortality as well as fewer healing complications and reoperations when the surgery is performed by a surgeon with experience in the specific procedure and performs it with some regularity (Strömqvist et al. 1992, Palm et al. 2007, Nyholm et al. 2015). Even though the procedure is generally viewed as less demanding, these findings underline the need for proper skill training and supervision of inexperienced surgeons as well as a potential benefit of concentrating the surgeries/supervision on fewer, but more experienced surgeons. It has previously been suggested that poor bone quality is a major risk factor for failure following internal fixation of femoral neck fractures due to the association between poor bone quality and increased risk of primary fractures (Estrada et al. 2002). In our evaluation of the bone quality we chose to measure the bone quality by use of the CTI, which correlates well with BMD regardless of observer experience level (Nguyen et al. 2018) and is more easily accessible for the surgeon preoperatively than performing an acute gold standard DEXA scan (Sah et al. 2007, Nguyen et al. 2018). In contrast to this theory our study aligns with other newer studies in not finding such an association (Viberg et al. 2014). We did, however, find a quite strong inverse association between a low CTI and increased risk of death. Previous studies have demonstrated an association between poor bone quality and poor muscle quality (Papageorgiou et al. 2019) and it could thus be that the CTI is a surrogate measurement of the fitness and nutritional status of the patient. We have no information on the nutritional status of the included patients and therefore this is a theory to investigate in future studies. Based on the findings of our study, the CTI could be used as a marker to identify high-risk patients for postoperative mortality. In line with our findings, risk of death has previously been associated with patient-related factors (age, sex, ASA score) and postoperative medical complications (Bjørgul and Reik-

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erås 2007). Increasing surgical delay has previously been associated with an increasing risk of mortality following hip fracture (Khan et al. 2009, Nyholm et al. 2015), but the association with risk of reoperation has not been evaluated to the same extent. It has been suggested that expeditious treatment of displaced fractures is necessary to reduce the disturbance in blood supply for the femoral head and thus reduce the risk of avascular necrosis. In accordance with a previous study by Hoelsbrekken et al. (2012) we found that for initially displaced fractures increasing delay is associated with increased risk of later failure. Whether to perform internal fixation or arthroplasty in displaced femoral neck fractures has been investigated quite extensively, primarily in patients older than 60–75 years of age (Parker and Gurusamy 2006, Rogmark and Johnell 2006) and, here, literature in general recommends a primary arthroplasty. The main argument is that studies with 12 months’ follow-up indicate lower risk of reoperation, less pain, faster re-convalescence, and better function, with no increased risk of mortality with arthroplasty (Gjertsen et al. 2010). Another often used argument for a primary arthroplasty in the elderly is the theory that risk of reoperation is increased with increasing age. As our study, in agreement with previous studies (Gregersen et al. 2015), did not support this theory, we feel this argument is weak. As a consequence, the argument for internal fixation in younger patient also weakens, which merits a lower age limit for when to insert an arthroplasty for a displaced femoral neck fracture. Although long term follow-up of primary arthroplasty in younger fracture patients is missing, arthroplasties for osteoarthrosis have in recent years achieved a 5-year and 20-year implant survival rate of 95% and 80% respectively (DHR 2016), and even among patients < 50 years it is 60–75% (DHR 2016). Furthermore, a larger number of younger hip fracture patients have been shown to be comorbid with either chronic diseases or disabilities and/or with an unhealthy lifestyle (tobacco and alcohol) (Rogmark et al. 2018) and these may therefore in many cases be regarded as fragility fractures in a population with a shorter life expectancy than a background population of the same age. We therefore recommend re-thinking the indication for primary arthroplasty for displaced femoral neck fractures and basing the decision on whether patients are at risk of outliving an arthroplasty, thus needing reoperation later on. This would demand a broader evaluation of the patient’s risk factors for not only reoperation, but also of death, such as high ASA score, specific comorbidities, and perhaps also low CTI for optimizing the treatment of the individual patient. This merits routinely considering a primary prosthesis for fracture patients still of working age as a viable option, depending on the general medical fitness and activity level. The very youngest and fittest hip fracture patients have not been sufficiently evaluated in radiographic studies and, beyond theoretically superior fracture healing, these patients are at high risk of outliving their prosthesis due to both age and physical demands.

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In such patients much is to be gained from preserving their natural anatomy if at all possible, and in case of later fracture collapse and reoperation they are well suited for an elective secondary arthroplasty. Supplementary data Table 1 is available as supplementary data in the online version of this article, http://dx.doi.org/10.1080/17453674.2019. 1698503

AMN: Planned the study, wrote the protocol, collected and analyzed the data, performed the intra- and inter-reader analysis, wrote and revised the paper. HP: Planned the study, revised the protocol, supervised the data collection and analysis, performed the intra- and inter-reader analysis, and revised the paper. HS: Planned the study, supervised the statistical analyses, and revised the paper. AT: Planned the study and revised the paper. KG: Planned the study, revised the protocol, supervised the data collection and analysis, and revised the paper. The DFDB collaborators (BV, JVF, JKP, KTH, KS, LB, MBH, MB, PTT, MK, TB, and PR) are responsible for the everyday collection of data and maintenance of the Danish fracture database, and have provided the data for this study. They have all revised and approved of the initial design of the study, they have made a large contribution to the data collection (both by their local efforts to ensure proper data collection for the Danish Fracture Database, and by facilitating access to the radiographs for analysis), they have revised and approved the manuscript, and they hold a shared responsibility for the accuracy of the data presented. This study could not have been conducted without the continuous meticulous registration effort of the orthopedic surgeons nationwide. Furthermore, great help has been given from the radiological departments at Copenhagen University Hospital Bispebjerg, North Zealand Hospital, SUH Koege, Holbaek Hospital, Nykoebing Falster Hospital, Odense University Hospital, Kolding Hospital, Aabenraa Hospital, Vejle Hospital, Regional Hospital in Horsens, Slagelse Hospital, and especially Henning Thygesen, Copenhagen University Hospital Hvidovre, with retrieving the radiographs. Thomas Kallemose is acknowledged for statistical and technical support and Bjarke Viberg for technical support for the radiographs retrieved from Region South. Acta thanks Jan-Erik Gjertsen and Torsten Johansson for help with peer review of this study.

Bjørgul K, Reikerås O. Outcome of undisplaced and moderately displaced femoral neck fractures. Acta Orthop 2007; 78(4): 498-504. DHR. Danish Hip Arthroplasty Registry, Annual report, 2016; 2016. p. 1-117. Estrada L S, Volgas D A, Stannard J P, Alonso J E. Fixation failure in femoral neck fractures. Clin Orthop Relat Res 2002; (399): 110-18. Gjertsen J-E, Vinje T, Engesaeter L B, Lie S A, Havelin L I, Furnes O, Fevang J M. Internal screw fixation compared with bipolar hemiarthroplasty for treatment of displaced femoral neck fractures in elderly patients. J Bone Joint Surg Am 2010; 92(3): 619-28. Gregersen M, Krogshede A, Brink O, Damsgaard E M. Prediction of reoperation of femoral neck fractures treated with cannulated screws in elderly

patients. Geriatr Orthop Surg Rehabil 2015; 6(4): 322-7. Gromov K, Brix M, Kallemose T, Troelsen A. Early results and future challenges of the Danish Fracture Database. Dan Med J 2014; 61(6): A4851. Hoelsbrekken S E, Opsahl J-H, Stiris M, Paulsrud O, Stromsoe K. Failed internal fixation of femoral neck fractures. Tidsskr Nor Laegeforen 2012; 132(11): 1343-7. Khan S K, Kalra S, Khanna A, Thiruvengada M M, Parker M J. Timing of surgery for hip fractures: a systematic review of 52 published studies involving 291,413 patients. Injury 2009; 40(7): 692-7. Murphy D K, Randell T, Brennan K L, Probe R A, Brennan M L. Treatment and displacement affect the reoperation rate for femoral neck fracture trauma. Clin Orthop Relat Res 2013; 471(8): 2691-702. Nguyen B N T, Hoshino H, Togawa D, Matsuyama Y. Cortical thickness index of the proximal femur: a radiographic parameter for preliminary assessment of bone mineral density and osteoporosis status in the age 50 years and over population. Clin Orthop Surg 2018; 10(2): 149-56. Nyholm A M, Gromov K, Palm H, Brix M, Kallemose T, Troelsen A. Time to surgery is associated with thirty-day and ninety-day mortality after proximal femoral fracture. J Bone Joint Surg Am 2015; 97-A(16): 1333-9. Nyholm A M, Palm H, Sandholdt H, Troelsen A, Gromov K, Collaborators D. Osteosynthesis with parallel implants in the treatment of femoral neck fractures: minimal effect of implant position on risk of reoperation. J Bone Joint Surg Am 2018; 100-A(19): 1682-90. Palm H, Teixidor J. Proximal femoral fractures: can we improve further surgical treatment pathways? Injury 2015; 46(2015): S47-51. Palm H, Jacobsen S, Krasheninnikoff M, Foss N B, Kehlet H, Gebuhr P. Influence of surgeon’s experience and supervision on re-operation rate after hip fracture surgery. Injury 2007; 38(7): 775-9. Palm H, Gosvig K, Krasheninnikoff M, Jacobsen S, Gebuhr P. A new measurement for posterior tilt predicts reoperation in undisplaced femoral neck fractures: 113 consecutive patients treated by internal fixation and followed for 1 year. Acta Orthop 2009; 80(3): 303-7. Palm H, Krasheninnikoff M, Holck K, Lemser T, Foss N B, Jacobsen S, Kehlet H, Gebuhr P. A new algorithm for hip fracture surgery. Acta Orthop 2012; 83(1): 26-30. Papageorgiou M, Sathyapalan T, Schutte R. Muscle mass measures and incident osteoporosis in a large cohort of postmenopausal women. J Cachexia Sarcopenia Muscle 2019; 10(1): 131-9. Parker M, Gurusamy K. Internal fixation versus arthroplasty for intracapsular proximal femoral fractures in adults. Cochrane Library 2006; (4): 1-122. R CT. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; 2017. Rogmark C, Johnell O. Primary arthroplasty is better than internal fixation of displaced femoral neck fractures: a meta-analysis of 14 randomized studies with 2,289 patients. Acta Orthop 2006; 77(3): 359-67. Rogmark C, Kristensen M T, Viberg B, Rönnquist S S, Overgaard S, Palm H. Hip fractures in the non-elderly: who, why and whither? Injury 2018; 49(8): 1445-50. Sah A P, Thornhill T S, LeBoff M S, Glowacki J. Correlation of plain radiographic indices of the hip with quantitative bone mineral density. Osteoporos Int 2007; 18(8): 1119-26. Strömqvist B, Nilsson L T, Thorngren K G. Femoral neck fracture fixation with hook-pins: 2-year results and learning curve in 626 prospective cases. Acta Orthop 1992; 63(3): 282-7. Viberg B, Ryg J, Overgaard S, Lauritsen J, Ovesen O. Low bone mineral density is not related to failure in femoral neck fracture patients treated with internal fixation. Acta Orthop 2014; 85(1): 60-5. Yang J, Lin L, Chao K, Chuang S, Wu C, Yeh T, Lian Y. Risk factors for nonunion in patients with intracapsular femoral neck fractures treated with three cannulated screws placed in either a triangle or an inverted triangle configuration. J Bone Joint Surg 2013; 61-9.

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Comparison of the 10-year outcomes of cemented and cementless unicompartmental knee replacements: data from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man Hasan R MOHAMMAD 1,2, Gulraj S MATHARU 1,2, Andrew JUDGE 1,2, and David W MURRAY 1 1 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences 2 Musculoskeletal Research Unit, Bristol Medical School, University of Bristol, Level 1

Correspondence: hasanmohammad@doctors.org.uk Submitted 2019-04-24. Accepted 2019-09-13.

Background and purpose — Unicompartmental knee replacement (UKR) offers advantages over total replacement but has higher revision rates, particularly for aseptic loosening. The cementless Oxford UKR was introduced to address this. We undertook a registry-based matched comparison of cementless and cemented UKRs. Patients and methods — From 40,552 Oxford UKRs identified by the National Joint Registry for England, Wales, Northern Ireland and Isle of Man (NJR) we propensity score matched, based on patient, surgical, and implant factors, 7,407 cemented and 7,407 cementless UKRs (total = 14,814). Results — The 10-year cumulative implant survival rates for cementless and cemented UKRs was 93% (95% CI 90–96) and 90% (CI 88–92) respectively, with this difference being significant (HR 0.76; p = 0.002). The risk of revision for aseptic loosening was less than half (p < 0.001) in the cementless (0.42%) compared with the cemented group (1.00%), and the risk of revision also decreased for unexplained pain (to 0.46% from 0.74%; p = 0.03) and lysis (to 0.04% from 0.15%; p = 0.03). However, the risk of revision for periprosthetic fracture increased significantly (p = 0.01) in the cementless (0.26%) compared with the cemented group (0.09%). 10-year patient survival rates were similar (HR 1.2; p = 0.1). Interpretation — The cementless UKR has improved 10-year implant survival compared with the cemented UKR, independent of patient, implant, and surgical factors. This improved survival in the cementless group was primarily the result of lower revision rate for aseptic loosening, unexplained pain, and lysis, suggesting the fixation of the cementless was superior. However, there was a small increased risk of revision for periprosthetic fracture with the cementless implant.

University of Oxford, Nuffield Orthopaedic Centre, Oxford; Learning and Research Building, Southmead Hospital, Bristol, UK

Over 100,000 primary knee replacements are performed annually in the United Kingdom, with these numbers rapidly increasing (National Joint Registry 2018). This includes both total knee replacement (TKR) and unicompartmental knee replacement (UKR). Although UKR offers significant advantages over TKR including faster recovery, fewer complications, improved function, and lower mortality (Liddle et al. 2014, 2015, Burn et al. 2018), its revision rate is higher in the National Registries (New Zealand Joint Registry 2016, Australian Orthopaedic Association 2018, National Joint Registry 2018). The most commonly used UKR is the Phase 3 Oxford (Zimmer Biomet, Swindon, UK), which has a fully congruent mobile bearing and is implanted using a minimally invasive approach (Pandit et al. 2006). The cemented version was introduced in 1998. The commonest reasons for revision include aseptic loosening and pain (Mohammad et al. 2018). Radiolucent lines, also known as physiological radiolucencies, are indicative of fibrocartilage at the interface and are seen in over half of cemented UKR tibial components (Gulati et al. 2009). In the presence of pain, these can be misinterpreted as aseptic loosening and lead to revisions despite studies showing no relation (Gulati et al. 2009). In an attempt to decrease the revision rate a cementless version was introduced in 2004, with the only changes to the implant being a porous coating of titanium and hydroxyapatite, and the femoral component having an additional peg. Randomized controlled trials comparing cemented and cementless UKRs found no statistically significant difference in functional outcomes, but the prevalence of partial and complete radiolucencies was reduced with cementless implants (Pandit et al. 2013). These trials were too small to compare revision rates. However, data from the New Zealand Joint Reg-

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istry (NZJR) suggest that the cementless UKR has a lower revision rate than the cemented UKR (New Zealand Joint Registry 2016). It is not clear whether the difference in revision rate seen in the NZJR is due to differences in the implants or to other factors. For example it could be that more experienced surgeons, who are doing larger numbers and therefore have lower revision rates, are predominantly using cementless components. The National Joint Registry for England, Wales, Northern Ireland and Isle of Man (NJR) was established in April 2003 and is now the world’s largest arthroplasty register with over 2 million joint replacements recorded and is linked to the UK’s Office of National Statistics (ONS) mortality data (National Joint Registry 2018). Unfortunately, the NJR does not report the revision rates of cemented and cementless UKR separately in its Annual Report. We used NJR data to compare the revision rates following cemented and cementless Oxford UKRs. Our null hypothesis was that there would be no difference between cemented and cementless UKR implant survival. To ensure that any difference in implant performance was due to the fixation rather than other factors, we propensity matched cemented and cementless cases on patient, surgeon (including caseload), and implant factors.

Patients and methods A retrospective observational study was performed using NJR records and was approved by the NJR Research SubCommittee (National Joint Registry 2018). The NJR collects data on patient factors (including age, sex, BMI, ASA grade), implant factors (including component design, sizes, and manufacturer type), and surgical factors (surgical approach, cemented or cementless fixation (for femoral and tibial components), indication, caseload, operating surgeon grade) for each replacement procedure, which are provided by the operating surgeon. The NJR database is linked to the Office of National Statistics, which provides data on patient mortality. The NJR achieves high levels of patient consent (93%) and linkability (95%) to subsequent operations (National Joint Registry 2018). Anonymized patient data were extracted from the NJR database which included all primary Oxford UKRs implanted between January 1, 2005 and December 31, 2016 (n = 50,334). After data cleaning involving removal of lateral UKRs, hybrids, complex primaries, old tibial sizes, and missing/inconsistent component missing/inconsistent, there were 40,522 UKRs (30,814 cemented and 9,708 cementless) eligible for study inclusion (Figure 1). Given the potential for factors other than the type of fixation to affect the revision rate (Prempeh et al. 2008, Memtsoudis et al. 2009, Selby et al. 2012, Judge et al. 2013, Elmallah et al. 2015, Lim et al. 2015, Hamilton et al. 2016, Liddle et al. 2016, Bayliss et al. 2017, Hosaka et al. 2017, Murphy et al. 2018, Picard

All primary Oxford UKRs implanted between 1st January 2005 to 31st December 2016 n = 50,334 Excluded (n = 9,812): – complex primary surgery, 81 – lateral UKRs, 1,820 – hybrid UKRs, 430 – missing/inconsistent component details, old tibial sizes or titanium niobium nitride implants, 7,481 UKRs available for matching n = 40,522 Number of matched UKRs n = 14,814

Figure 1. Data flowchart of NJR database cleaning.

et al. 2018, Deere et al. 2019, Lenguerrand et al. 2019) we a priori matched the cemented and cementless groups for multiple known confounders using propensity scores. These propensity scores were generated from patient demographics, surgical factors (including surgeon caseload) and implant factors. Surgical factors included surgeon caseload, defined as the average number of UKRs done per year and stratified into low (< 10 cases/year), medium (10 to < 30 cases/year) and high volume (≥ 30 cases/year) as described previously (Liddle et al. 2016). By controlling for these covariates the use of propensity score matching would allow the true effect of implant fixation on revision surgery to be accurately assessed. This a priori approach was supported by the substantial differences in patient, surgical, and implant factors between the unmatched cemented and cementless groups (Table 1, see Supplementary data). Statistics Logistic regression was used to generate a propensity score representing the probability that a patient received a cementless UKR. All patient, surgical, and implant factors in Table 1 (see Supplementary data) were used for matching, apart from BMI, which had a large proportion of missing data. This approach is consistent with previous studies (Matharu et al. 2018a and b), and our data demonstrated BMI was similar between the 2 fixation groups both before and after matching. The algorithm used matched on the logit of the propensity score with a 0.02SD caliper width. The matching ratio was 1:1. We used greedy matching without replacement. This approach has been shown to have superior performance for estimating treatment effects (Austin 2009). Standardized mean differences (SMDs) were examined both before and after matching to assess for any covariate imbalance between the cemented and cementless UKRs, with SMDs of 10% or more considered suggestive of covariate imbalance (Austin 2009). After matching, 14,814 UKRs (7,407 cemented and 7,407 cementless) were included for analysis.

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Implant survival probability (%)

Patient survival probability (%)

Prevalence (%)

100

Cemented Cementless

1.2 a

1.0

94 92

94 c

0.8

90 0.6

88 86

0.4

c 0.2

Cemented Cementless

82 80 0

Years since index operation

Figure 2. Kaplan–Meier implant survival rates for matched cemented (n = 7,407) and cementless (n = 7,407) UKR implants up to 10 years.

Cemented Cementless

82 80 Aseptic loosening

Pain

Lysis

Indication for revision

Periprosthetic fracture

Figure 3. Comparison of the reasons for revision between matched cemented and cementless implants that were statistically significant. a p < 0.001, b p = 0.01, and c p = 0.03 (chi-square test with Yates’ correction).

Outcomes of interest were: (1) implant survival, (2) indications for revision surgery, and (3) patient survival. Cumulative survival was determined using the Kaplan–Meier method. The endpoint for implant survival was revision surgery (any implant component removed, exchanged, or added) and the endpoint for patient survival was mortality. Implant and patient survival rates were compared between the cemented and cementless groups, using Cox regression models, with the proportional hazards assumptions assessed and satisfied in all analyses. A multi-level frailty model was used in the regression models to control for patient clustering within surgeons. Additionally, to account for clustering within the matched cohort, a robust variance estimator was used in regression models. Univariable and adjusted models were also assessed. The adjusted models included covariates with residual imbalance after matching (SMD of 10% or more) (Austin 2009). The proportional chi-square test with Yates’ correction was used to compare the frequency of revisions for specific indications between the cemented and cementless UKR groups. All statistical analyses were performed using Stata (Version 15.1; StataCorp, College Station, TX, USA) except propensity score matching, which was performed using R (Version 3.4.0; R Foundation for Statistical Computing, Vienna, Austria). P-values of < 0.05 were considered significant, with 95% confidence intervals (CI) presented. Ethics, funding, and potential conflicts of interest This study was based entirely on existing patient records acquired during routine clinical care and thus did not require ethical approval (Wade 2005). This project was fully approved by the NJR Research Sub Committee. This research did not receive any specific grant from funding agencies in the public, commercial, or not for profit sectors. Institutional and Personal funding has been received from Zimmer Biomet.

Years since index operation

Figure 4. Kaplan–Meier patient survival for matched cemented (n = 7,407) and cementless (n = 7,407) UKR implants up to 10 years.

Results The matched cohort included 14,814 UKRs with 7,407 cemented UKRs and 7,407 cementless UKRs. The mean age at surgery was 65 years (SD 9.5), with 6,155 women (42%) and 8,659 men (58%). The mean BMI was 30 (SD 5.0) with the primary indication for surgery being osteoarthritis in 14,633 knees (99%). Patient, surgical (including caseload), and implant characteristics became well balanced between the cemented and cementless groups after propensity score matching (Table 1, see Supplementary data). The only covariate with residual imbalance was year of primary surgery, which when adjusted for in the regression models did not change the findings presented below. In the matched cohort, the mean follow-up for both cemented and cementless implants was 4 years (SD 2). 507 knees, 218 (2.9%) cementless and 289 (3.9%) cemented, underwent revision surgery. The 10-year cumulative implant survival rates were 93% (CI 90–96) and 90% (CI 88–92) for cementless and cemented respectively (Figure 2). The corresponding cumulative revision rates were 7% (CI 4–10) and 10% (CI 8–13) at 10 years respectively. Cementless UKRs had a significantly reduced revision rate compared with cemented UKRs (HR = 0.76, CI 0.64–0.91; p = 0.002). The most common reasons for revision in the cemented group were aseptic loosening (n = 74, 1.00%), pain (n = 55, 0.74%), and osteoarthritis progression (n = 72, 0.97%) (Table 2, see Supplementary data). In the cementless group the most common reasons for revision were osteoarthritis progression (n = 55, 0.74%), pain (n = 34, 0.46%), and aseptic loosening (n = 31, 0.42%) (Table 2, see Supplementary data). 4 specific revision indications were significantly different between cemented

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and cementless groups: revision for aseptic loosening was 1.0% versus 0.42% (p < 0.001); for pain 0.74% versus 0.46% (p = 0.03); and for lysis 0.15% versus 0.04% (p = 0.03), respectively (Figure 3). The risk of revision for periprosthetic fracture was significantly higher (p = 0.01) in the cementless group (n = 19, 0.26%) compared with the cemented (n = 7, 0.09%). There were 517 (276 cementless and 241 cemented) patient deaths. 11 deaths occurred within 90 days of surgery (7 cementless and 4 cemented). The cumulative 10-year patient survival rates for cementless UKR were 85% (CI 81–89) and 88% (CI 85–90) for cemented UKR (Figure 4). This difference was not statistically significant (HR = 1.2, CI 0.98–1.4; p = 0.1).

Discussion The early cementless UKR had poor outcomes, but the results have improved with time (Bernasek et al. 1988, Lindstrand et al. 1988, Harilainen et al. 1993, Bergenudd 1995, Mohammad et al. 2018). Data from the NZJR has shown that the revision rate of the cementless Oxford is substantially less than the cemented. However, as this is raw unmatched data, we cannot be certain why this is, and many factors such as more experienced surgeons tending to use the cementless implant may contribute. We have now shown in approximately 15,000 UKRs that are propensity matched to exclude other potential patient, surgical (including surgeon caseload), and implant confounders that the revision rate of the cementless Oxford UKR is 24% less (HR 0.76, p = 0.002) than the cemented out to 10 years. This therefore suggests that the cementless Oxford UKR is a better performing implant than the cemented. The primary reason for this difference is that the rates of revision for aseptic loosening, pain, and lysis were all substantially lower in the cementless group. Indeed, the combined revision rate from these causes was about half for cementless compared with cemented fixation. Previous randomized studies have shown the incidence of narrow tibial radiolucent lines (otherwise known as physiological radiolucencies) is much lower with cementless rather than cemented fixation, suggesting that the fixation is much better (Kendrick et al. 2015). This would explain why the revision rate for aseptic loosening and lysis has decreased. It is, however, not clear why the revision rate for pain has decreased. It could be that the incidence of pain is less with cementless fixation. Alternatively it could be that in the presence of pain surgeons are more likely to revise a component that has a radiolucent line, even though the evidence would suggest that the radiolucent line is not a cause of pain and is not indicative of loosening (Gulati et al. 2009). The only reason for revision that occurred statistically significantly more frequently with the cementless than the cemented group was peri-prosthetic fracture, with the rates of revision being respectively 0.26% and 0.09% (p = 0.01). The difference is 0.17% which is relatively small compared

with the decrease in revision rate. Furthermore, the mean time to revision for peri-prosthetic fracture was one year, which is much earlier than for most other revisions, so with time and increased follow-up the proportion of revisions that are due to peri-prosthetic fracture should decrease further. Information concerning the site of the peri-prosthetic fracture is not recorded, but it is likely that the majority were tibial plateau fractures. A cadaver study has shown that the load to fracture is lower with a cementless rather than a cemented tibial component (Seeger et al. 2012), suggesting that the increased rate of fracture may relate to the interference fit between the cementless tibial component and the impaction required to implant it. As tibial plateau fractures are major complications, often requiring revision TKR with stems and wedges, surgeons should take care to avoid them when implanting cementless components. In particular they should avoid deep cuts, make the vertical cut just medial to the tibial spine, protect the posterior cortex, ensure the tibial trial can be inserted with finger pressure, and impact the tibial component with care and a light hammer. We believe that this is the first large-scale study of any type of knee replacement which has demonstrated that the cementless version has lower revision rates than the cemented, and that the difference is due to improved fixation. This may, however, relate to the design of the implant. As all ligaments are preserved and there is an unconstrained mobile bearing the loads transmitted to the bone–implant interface are predominantly compressive with minimal shear or tension, which is ideal for cementless fixation. The results may therefore not apply to all types of UKR or to TKR. The main study limitation is that it is based on Registry data and is therefore a study of revision and not reoperation or other clinical outcomes. However, many of these other outcomes have already been studied in randomized trials. Additionally, the reasons for revision in the NJR are those recorded at the time of surgery even if this subsequently changed due to histopathology and microbiology data. Registries can underreport revisions (Sabah et al. 2015, 2016) although there is no reason to believe this would differ between the groups, and it is not possible to confirm causality in registry-based studies. Another limitation is that, despite matching, there is potential for residual confounding and matching can reduce the generalizability of our findings. The groups were not perfectly matched given there was imbalance in the year of primary surgery, as the cementless components were introduced after the cemented. This was mitigated as many of the early cemented cases were excluded as they had different shaped tibial components (numerical sizes). Although operating techniques improve with time, there were no differences in our findings when we adjusted the regression models for year of primary surgery. There was a substantial proportion of BMI data missing so we did not match on BMI. However, the BMI distribution between cemented and cementless UKR was the same both before and after propensity matching. The only way

to achieve balance with respect to both known and unknown confounders is with a randomized trial. However, to compare revision rates would require very large numbers and long follow-up, which would be impractical; we believe propensity matching offers the next best alternative. In conclusion, in this propensity matched registry-based study, the observed risk of revision of the cementless Oxford UKR was 24% less than that of the cemented out to 10 years. This was primarily because the risk of revision for aseptic loosening, pain, and lysis all decreased in the cementless, suggesting that it is due to improved fixation. Supplementary data Tables 1 and 2 are available as supplementary data in the online version of this article, http://dx.doi.org/10.1080/17453674. 2019.1680924 We thank the patients and staff of all the hospitals in England, Wales, Northern Ireland and Isle of Man who have contributed data to the National Joint Registry. We are grateful to the Healthcare Quality Improvement Partnership (HQIP), the NJR Research Sub-committee and staff at the NJR Centre for facilitating this work. The authors have conformed to the NJR’s standard protocol for data access and publication. The views expressed represent those of the authors and do not necessarily reflect those of the National Joint Registry Steering Committee or the Healthcare Quality Improvement Partnership (HQIP) who do not vouch for how the information is presented. HRM holds the Henni Mester Scholarship at University College, Oxford University and the Royal College of Surgeon’s Research Fellowship. AJ was supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. HRM, GSM, AJ, and DWM designed the study. HRM and GSM analyzed the data with statistical support from AJ. HRM, GSM, AJ, and DWM helped with data interpretation. HRM wrote the initial manuscript draft which was then revised appropriately by all authors.

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Patients report inferior quality of care for knee osteoarthritis prior to assessment for knee replacement surgery – a cross-sectional study of 517 patients in Denmark Lina H INGELSRUD 1, Ewa M ROOS 2, Kirill GROMOV 1, Sofie S JENSEN 2, and Anders TROELSEN 1 1 Department

of Orthopedic Surgery, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark; 2 Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark Correspondence: lina.holm.ingelsrud@regionh.dk Submitted 2019-08-07. Accepted 2019-09-24.

Background and purpose — Clinical care pathways for knee osteoarthritis (OA) are not always in line with clinical guidelines. We investigated (1) the patient-perceived quality of OA management, (2) which physiotherapist-delivered treatments patients with knee OA have attempted, and (3) patients’ expected subsequent treatment, at the time of referral to an orthopedic surgeon. Patients and methods — This cross-sectional study included all patients with scheduled first-time appointments for knee OA at an orthopedic outpatient clinic from April 2017 to February 2018. Postal questionnaires included the 16-item OsteoArthritis Quality Indicator (OA-QI) questionnaire and questions about physiotherapist-delivered treatment for knee OA. Results — 517 of 627 (82%) eligible patients responded. Responders’ (63% female) mean age was 67 years. The mean pass rate for the 16 independent quality indicators was 32% (8–74%). Sub-grouped into 4 categories, pass rates for independent quality indicators ranged from 16–52% regarding information, 9–50% regarding pain and functional assessment, 8–35% regarding referrals, and 16–74% regarding pharmacological treatment. While half of responders felt informed of physical activity benefits, only one-third had consulted a physiotherapist during the past year. Commonest physiotherapist-delivered treatments were exercise therapy for 22% and participation in the Good Life with osteoArthritis in Denmark (GLA:D) program for12% of responding patients. 65% expected surgery as subsequent treatment. Interpretation — Patients with knee OA are undertreated in primary care in Denmark; however, our findings may only reflect healthcare settings that are comparably organized. Our results call for better structure and uniform pathways for primary care knee OA treatment before referral to an orthopedic surgeon.

According to national and international clinical guidelines, first-line treatment strategies for knee osteoarthritis (OA) should have been offered prior to referral for knee replacement surgery (Danish Health Authority 2012, American Academy of Orthopaedic Surgeons 2013, Fernandes et al. 2013, National Clinical Guideline Centre 2014, Bannuru et al. 2019). In Scandinavia, several implementation strategies have been undertaken to optimize the adherence to clinical guideline recommendations for non-operative treatment of OA (Thorstensson et al. 2015, Skou and Roos 2017, Moseng et al. 2019). In Denmark, the focus on patient education and exercise has been strengthened with the physiotherapist-led treatment program Good Life with Osteoarthritis in Denmark (GLA:D) that was launched in 2013. Results from the GLA:D registry are promising and show that patients experience pain relief, and improved physical function and quality of life after attending the program (Skou and Roos 2017). Clarifying what patients expect from their subsequent treatment may help understand what drives patients to seek referral to an orthopedic surgeon. We therefore (1) evaluated the patient-perceived quality of OA management, (2) described which physiotherapist-delivered treatments patients with knee OA have attempted, and (3) described the patients’ expectations of their subsequent treatment, at the point in time when patients are referred to an orthopedic surgeon in Denmark.

Patients and methods We followed the STROBE guidelines for the reporting of this study. In this cross-sectional study, we consecutively included patients from 1 outpatient orthopedic department at a public hospital in Denmark. The inclusion criterion was patients having been referred for first-time appointments with an

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Invited patients N = 699 Excluded (n = 72): – cancelled the consultation, 35 – dead before the consultation, 1 – non-Danish speakers, 36 Eligible patients n = 627 Non-responders (n = 110): – refused participation, 15 – could not be contacted before the consultation, 95 Responders n = 517 (82%)

Figure 1. Flow diagram.

orthopedic surgeon for an assessment of knee OA. Patients unable to speak or read Danish and patients who cancelled their consultation were excluded. In the period March 2018 to February 2019, patients were sent a postal invitation and were asked to respond to a self-reported questionnaire and return this in a pre-stamped envelope before the appointment with the orthopedic surgeon. Questionnaire The questionnaire included the patient-reported OsteoArthritis Quality Indicator questionnaire (OA-QI). The 17-item OA-QI was developed in 2010 by Østerås et al. (2013, 2015), who found it to have acceptable validity and moderate reliability in patients with knee, hip, or hand OA. The OA-QI includes quality indicators related to patient education and information, assessment of pain and function, referrals, and pharmacologic treatment for OA. For this study, we adjusted the OA-QI to specifically reflect knee OA and removed the item regarding referral to an orthopedic surgeon. We further asked about the number of physiotherapy consultations for knee OA the patient had attended during the past year. Patients who had consulted a physiotherapist were asked which types of treatments they had received from a predefined list and could add other treatments in free text, if relevant. Patients also responded to a question about their expectations of subsequent treatment following the consultation with the orthopedic surgeon. The following 6 response options were given: surgical intervention, exercise therapy recommendation, weight loss recommendation, pain intervention recommendation, no further treatment recommended, or other, with the opportunity to expand on other expectations in free text. The patients’ knee pain and functional limitations due to knee problems were measured using the Oxford Knee Score (OKS). The OKS was developed in 1998 as an outcome measure for people having total knee replacement, and its reliability and validity characteristics were later confirmed in nonoperatively treated patients with knee OA. The 12 items are

Table 1. Patient characteristics. Values are frequency (%) unless otherwise specified Factor

Responders Respons

Age, mean (SD) 515 67 (11) Female 517 324 (63) BMI, mean (SD) 503 30 (5) Education level 498 Primary 129 (26) Secondary 141 (28) Tertiary 228 (46) Current smoker 515 74 (14) Occupation 514 Working full-time or part-time 141 (27) Unemployed 28 (5) Sick leave 23 (4) Retired 322 (63) Living alone 517 208 (40) Comorbidities 517 None 105 (20) Heart disease 54 (10) Hypertension 231 (45) Cerebral vascular disease 18 (3) Peripheral artery disease 62 (12) Lung disease 55 (11) Diabetes 58 (11) Kidney disease 13 (3) Neurologic disease 9 (2) Liver disease 7 (1) Cancer within 5 years 35 (7) Depression 39 (8) Spinal arthritis or other spinal condition 172 (33) Other arthritides 92 (18) Knee OA duration 512 0–6 months 43 (8) 6–12 months 49 (10) 1–2 years 73 (14) 2–5 years 105 (21) 5–10 years 122 (24) > 10 years 120 (23) Knee pain (VAS) median (IQR) 486 7 (5–8) OKS, mean (SD) 501 23 (8) KL grade 459 0 1 (0) 1 29 (6) 2 89 (19) 3 171 (37) 4 169 (37) The number of missing items varied across the variables, thus the specific numbers of included observations are presented. Abbreviations: BMI: body mass index, OA: osteoarthritis, VAS: visual analogue scale, OKS: Oxford Knee Score, KL grade: Kellgren and Lawrence classification system.

each scored from 0 to 4, summed to a total score of 0 (worst) to 48 (best) (Dawson et al. 1998). Additionally, patients reported their average knee pain intensity during the past week on a 0–100 mm VAS scale ranging from no pain to worst pain imaginable. Finally, patient demographics—height, weight, age, education level, employment status, smoking, residential status, comorbidities, and symptom duration—were collected. The degree of radiographic OA was evaluated for patients with routinely obtained anteroposterior, weight-bearing radio-

graphs available, and classified with the Kellgren and Lawrence (KL) classification system, ranging from grade 0 to 4 OA. For patients who reported problems with both knees, the most severe KL grade was recorded.

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Table 2. Patient self-reported quality indicator pass rates for knee osteoarthritis treatment during the past year at the point of referral to an orthopedic surgeon for an evaluation of surgical appropriateness. Values are frequency (%) unless otherwise specified OA-QI (n = 508) a Yes No Missing 1. Information about disease development 2. Information about treatment modalities 3. Information about self-management 4. Information about lifestyle adaptation 5. Information about physical activity 6. Referral for physical activity 7. Information about weight reduction 8. Referral for weight reduction 9. Assessment of problems in daily activities 10. Assessment for walking aid 11. Assessment for other daily living aids 12. Assessment of pain 13. Recommended paracetamol 14. Offered stronger pain killers 15. Information about NSAIDS (side) effects 16. Offered joint injection 17. Referral to orthopedic surgeon

128 (25) 148 (29) 72 (14) 100 (20) 247 (49) 167 (33)

Pass rate (95% CI) b

Do not remember 319 (63) 50 (10) 11 (2) 29 (25–33) 320 (63) 23 (5) 17 (3) 32 (28–36) 390 (77) 28 (6) 18 (4) 16 (13–19) 364 (72) 23 (5) 21 (4) 22 (18–26) 228 (45) 15 (3) 18 (4) 52 (48–56) 310 (61) 12 (2) 19 (4) 35 (31–39) Not overweight 247 (49) 140 (28) 8 (2) 31 (27–36) 326 (64) 139 (27) 14 (3) 8 (6–11) Do not have this problem 319 (63) 48 (9) 24 (5) 27 (23–31) 335 (66) 84 (17) 17 (3) 18 (14–22) 345 (68) 109 (21) 21 (4) 9 (6–12) Do not have pain 241 (47) 11 (2) 14 (3) 50 (46–55) 125 (25) 11 (2) 23 (5) 74 (69–77) 276 (54) 23 (5) 27 (5) 40 (35–44) 232 (46) 29 (6) 28 (6) 49 (44–53) 386 (76) 25 (5) 25 (5) 16 (13–19) Not applicable in this study

Pilot study To test the feasibility of the questionnaire, we conducted a pre-test of the questionnaire on 6 patients 113 (22) who completed the questionnaire 29 (6) in the waiting room, prior to their consultation with an orthope117 (23) 72 (14) dic surgeon. The patients were 33 (6) observed while completing the questionnaire, followed by a semi242 (48) 349 (69) structured interview to assess the 182 (36) feasibility, comprehensibility, and 219 (43) relevance of the questions. The 72 (14) time to complete the questionnaire ranged from 9 to 20 minutes. We Abbreviations: OA-QI: OsteoArthritis Quality Indicator questionnaire. a 9 of the 517 responders had not answered any of the questions in the OA-QI. subsequently conducted a pilot b Pass rates were calculated as the percentage of patients responding “yes” out of the total number study to test the feasibility of the responding either “yes” or “no.” data collection procedure. Of 114 patients who were sent a postal questionnaire, only 52 (46%) responded and 3 items had more than 10% missing responses. was not required. The study was conducted in accordance with Based on the pilot study, we made smaller wording edits to the the WMA Declaration of Helsinki. The study was funded by items with large degrees of missing items. the Danish Rheumatism Association and by the Orthopaedic Department at the Copenhagen University Hospital Hvidovre. Statistics ER is co-founder of GLA:D. The authors declare no other Data are presented as mean (SD) for normally distributed con- potential conflicts of interest. tinuous data and median with 25th and 75th quantiles for nonnormally distributed data. Categorical data are presented as numbers and percentages. Results from the OA-QI are reported as pass rates for each of the 16 quality indicators separately, Results and as summary pass rates across all quality indicators for each 517 of 627 (82%) eligible patients responded (Figure 1). The patient, as described in the original publication. Separate quality responders had a mean (SD) age of 67 (11) and 63% were indicator pass rates were calculated as the percentage of patients female. In comparison, the non-responders’ mean (SD) age responding “yes” out of the total number responding either “yes” was 63 (12) years and 65% were female (Table 1). or “no,” combined, taking the relevance of the quality indicator into account. Summary pass rates for each individual patient Quality indicators for knee OA treatment were calculated as the percentage of indicators with the response The mean pass rate for the 16 independent quality indicators “yes” out of the total number of indicators with responses “yes” was 32% (8–74) (Table 2). Sub-grouped into 4 categories, the or “no,” combined (Østerås et al. 2013). Statistical analyses pass rates were 16–52% related to OA information, 9–50% were performed with the statistical package R, version 3.4.1 (R related to assessment of pain and function, 8–35% related to Foundation for Statistical Computing, Vienna, Austria). referrals, and 16–74% related to pharmacological treatment (Table 2). The median (25th to 75th quantile) summary pass Ethics, funding, and potential conflicts of interest rate, i.e., the percentage of fulfilled quality indicators overall The study was approved by the national data protection per patient, was 29% (18–50). 1% of patients reported “yes” agency (Journal number AHH-2015-093). Since only ques- to all the quality indicators that were relevant to them, while tionnaire-based data were used, ethical committee approval 6% had not achieved any of the relevant quality indicators.

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Table 3. Number of physiotherapy consultations due to knee osteo arthritis received during the past year prior to consulting with an orthopedic surgeon Physiotherapy consultations a None 1–3 4–6 7–9 10–12 > 12 a

n (%) 309 (63) 66 (13) 31 (6) 30 (6) 21 (4) 36 (7)

23 of 517 did not respond to this question (n = 494).

Table 4. Type of physiotherapist-delivered treatments for knee osteoarthritis during the past year

Physiotherapist- delivered treatment n

Percentage of a total those consulting responders a physiotherapist b (n = 513) (n = 184)

GLA:D participation 61 12 OA information 44 9 Any type of exercise 114 22 Stretching 45 9 Massage 47 9 Electrotherapy 24 5 Acupuncture 37 7 Insoles 34 7 Gait assessment 17 3 Other 43 8

33 24 62 24 26 13 20 18 9 23

Abbreviations: GLA:D: Good Life with Osteoarthritis in Denmark (the combination of patient education and supervised groupbased exercise therapy). a Percentages do not add up to 100% across the treatment types because some patients received several treatments in combination. b 4 patients out of the total 517 responders did not answer the question about type of physiotherapist-delivered treatments.

Physiotherapist-delivered treatment 184 of 494 (37%) responders who completed the question regarding the number of physiotherapy consultations during the past year had had at least 1 consultation. Of these, 66 had seen the physiotherapist 1 to 3 times (Table 3). The 2 most frequently reported physiotherapist-delivered treatments were “any type of exercise therapy” for 22% and participation in the GLA:D program (the combination of patient education and supervised group-based neuromuscular exercise therapy) for 12% of the 513 patients who had completed the question. Furthermore, OA information, stretching, and massage where each reported by 9% of the responding patients (Table 4). Most patients had received several treatments in combination. Patients’ expectations of treatment suggested by the orthopedic surgeon Prior to their consultation with the orthopedic surgeon, the majority (65%) expected to be offered a surgical intervention, followed by expecting to be recommended exercise therapy (30%), pain management (22%), or weight loss intervention (15%) (Table 5).

Discussion We investigated the quality of care delivered in primary care for patients with knee OA, prior to referral for an orthopedic surgeon. We found that while quality indicators regarding pharmacological pain relief were fulfilled by one-third to two-

Table 5. Patients’ expectations of their subsequent treatment after consulting with the orthopedic surgeon Expectations a Surgery Exercise Weight loss Pain management No treatment Other

n (%) b 324 (65) 150 (30) 76 (15) 108 (22) 22 (4) 101 (20)

a 20

of 517 did not respond to this question (n = 497). b Percentages do not add up to 100% because patients may have responded to several expectations.

thirds, most quality indicators relating to patient information, exercise, weight loss, and functional assessment were fulfilled for at most one-third of patients. Of special note is that less than 1 in 3 felt informed about the way the OA disease develops, possible treatment modalities, how to self-manage their disease, and how to change their lifestyle. Furthermore, even though 1 in 2 felt informed about the importance of physical activity and exercise, only 1 in 3 had consulted a physiotherapist during the past year before referral to an orthopedic surgeon. Our results support prior studies reporting suboptimal quality of knee OA care in Denmark and other countries. In a study of hand, knee, and hip OA in a primary care setting in 1 municipality in Norway, the median summary pass rate was 27%, which is comparable to our finding of 29% (Østerås et al. 2013). Our results further confirm the results from the smaller (n = 49) Danish knee OA cohort in a study comparing the quality of knee OA care across 4 European countries (Østerås et al. 2015). In that study, quality indicators regarding OA information were fulfilled by only 17% to 38% in the Danish cohort, which is comparable to the 16% to 32% from our study. Furthermore, Østerås et al. found that around half the responders had received referrals for supervised exercise (i.e., physiotherapy) in Norway, Portugal, and the UK, while that proportion was only 21% in Denmark. In comparison, in our study, only 35% were referred, even though they were at a later stage of disease. These findings highlight that access to physiotherapists should be facilitated since physiotherapists have a core role in prescribing and supervising exercise therapy for patients with knee OA. A financial barrier may be present for patients in Denmark. Although patients can directly access private physiotherapy clinics they then have to

pay the full treatment cost, while those with a referral from a general practitioner are reimbursed approximately 40%. Skou et al. (2015b) suggested that knee replacement can be postponed, even in those with moderate to severe OA, and also that patients undergoing a structured and optimized non-operative treatment program may be better prepared for a surgical decision. In their clinical trial, comparing an optimized non-operative treatment strategy with an optimized non-operative treatment strategy combined with total knee replacement, only 26% of those in the non-operative group subsequently decided to undergo surgery during the following 12 months. Rheumatologists, orthopedic surgeons, and general practitioners considered that a barrier to referring patients with OA to physiotherapy is that patients receive non-evidence-based passive treatment modalities, instead of exercise therapy (Selten et al. 2017). Correspondingly, only 2 in 3 patients in our study had received exercise as part of their physiotherapy treatment. 10 years ago, Holden et al. (2009) found that physiotherapists in the UK were concerned about the real benefits of exercise for knee OA, and moreover many believed that exercise would potentially be harmful for the osteoarthritic joint. More recent studies have, however, established that patients with severe radiographic OA grades can also achieve pain relief and functional improvement with exercise (Juhl et al. 2014, Skou et al. 2015a), and even large exercise loads do not seem to be harmful for the cartilage in the osteoarthritic knee (Bricca et al. 2018). Even though a more recent report suggests that physiotherapists are convinced by this contemporary knowledge (Spitaels et al. 2016), another study pointed at several healthcare providers doubting the real benefits of exercise (Selten et al. 2017). Furthermore, lack of support, or conflicting information from different healthcare providers, were found to be important barriers for patients to adhere to exercise therapy (Kanavaki et al. 2017). Motivating patients to exercise is challenging if they believe that their joint is worn down, which may partly explain our finding of low adherence to exercise therapy. While providing patient education on OA and self-management strategies is crucial for long-term adherence, only 1 in 4 patients in our study had received information about OA from the physiotherapist. A lack of established self-management and patient education tools amongst physiotherapists (Holden et al. 2009) may explain why few patients experienced OA information as being part of the physiotherapist-delivered treatment. The GLA:D program does incorporate a structured approach and specific tools for patient education (Skou and Roos 2017); however, only 1 in 3 patients from our study who had consulted a physiotherapist had participated in the GLA:D program. We found that 2 in 3 patients expected to be waitlisted for surgery at their consultation with the orthopedic surgeon. This may reflect that 1/3 of patients see the orthopedic surgeon as the OA expert providing a second opinion instead of a professional carrying out surgery. This proportion might have

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been higher had the OA education for general practitioners and physiotherapists been improved, and had the non-operative treatment strategy been optimized. This hypothesis is strengthened by our additional finding that 1 in 3 expected to be referred for exercise therapy. A commonly elaborated response to the question regarding expectations of the following consultation was that they hoped to “find out what is wrong with my knee” (data not shown). These statements may indicate that the patients had not received a clinical OA diagnosis in general practice and support the idea that the surgeon is seen as the OA expert. Differences in healthcare systems across countries may limit the external validity of our findings. The generalizability is, however, strengthened by the high response rate of consecutively invited patients from a large-volume orthopedic department with a large area of uptake that includes both rural and urban settlement. Despite our consecutive approach, there is a risk of selection bias since non-responders were on average 4 years younger than the responders. A possible explanation could be that younger patients with knee problems often did not consider their OA diagnosis definitive, and therefore did not consider it relevant to answer the questionnaire. Further limitations involve a risk of recall bias (Basedow and Esterman 2015). Patients may have forgotten which specific type of physiotherapist-delivered treatment they had received, and the number of physiotherapy consultations. Furthermore, patients may have had previous 1st-time appointments due to their knee OA at other specialist centers than ours, or at our center due to OA in the opposite knee. However, we hypothesize that any previous specialist consultations would have led to an improved pass rate. Finally, there may be a discrepancy between the degrees of fulfilled quality indicators from the patients’ perspective, in comparison with the healthcare professional’s perspective. Quality assessment based on reviewing medical records is commonly used to reflect the professionals’ perspectives (Basedow and Esterman 2015). A shortcoming of this approach, however, is that it may lead to both under- or overestimating the usage of healthcare processes due to inaccurate information in the medical records (Luck et al. 2000).The self-reported OA-QI has demonstrated adequate content and construct validity (Østerås et al. 2013), and is a feasible option to capture patient-perceived quality of care. In conclusion, patients with knee OA are undertreated in primary care; however, our findings may only reflect healthcare settings that are comparably organized. Only about 1/3 had consulted a physiotherapist during the last year, and only 1/4 were informed about the disease and its management options prior to seeing an orthopedic surgeon. Our results calls for better structure and uniform pathways for knee OA treatment in the primary sector before referral to an orthopedic surgeon. Future studies should investigate whether optimizing the quality of care in the primary health care sector has a positive effect on the outcomes of knee OA treatment across treatment sectors.

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Conception and design: LHI, ER, AT. Collection and assembly of data: LHI, SS. Analysis: LHI. Interpretation of the data: LHI, ER, KG, SST, AT. Drafting of the manuscript: LHI, AT. Critical revision and final approval of the article: LHI, ER, KG, SST, AT. The authors would like to thank all the patients for their time and effort in replying to our questionnaire. They further thank Fie Tillie Schlippe, Anne Birgitte Larsen, and Ina Hjortkjær Stark for contributing to the data collection. Acta thanks Thea Vliet Vlieland for help with peer review of this study.

American Academy of Orthopaedic Surgeons. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd ed. Adopted by the American Academy of Orthopaedic Surgeons Board of Directors. Am Acad Orthop Surg; 2013. Bannuru R R, Osani M C, Vaysbrot E E, Arden N K, Bennell K, BiermaZeinstra S M A, Kraus V B, Lohmander L S, Abbott J H, Bhandari M, Blanco F J, Espinosa R, Haugen I K, Lin J, Mandl L A, Moilanen E, Nakamura N, Snyder-Mackler L, Trojian T, Underwood M, McAlindon T E. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage 2019. doi: 10.1016/j. joca.2019.06.011. [Epub ahead of print] Basedow M, Esterman A. Assessing appropriateness of osteoarthritis care using quality indicators: a systematic review. J Eval Clin Pract 2015; 21(5): 782-9. Bricca A, Struglics A, Larsson S, Steultjens M, Juhl C B, Roos E M. Impact of exercise therapy on molecular biomarkers related to articular cartilage and inflammation in people at risk of, or with established, knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Arthritis Care Res 2018; 26: S314-15. Danish Health Authority. Knæartrose: nationale kliniske retningslinjer og faglige visitationsretningslinjer (Knee osteoarthritis: National clinical guidelines and visitation guidelines) [in Danish]; 2012. Dawson J, Fitzpatrick R, Murray D, Carr A. Questionnaire on the perceptions of patients about total knee replacement. J Bone Joint Surg 1998; 80(1): 63- 9. Fernandes L, Hagen K B, Bijlsma J W J, Andreassen O, Christensen P, Conaghan P G, Doherty M, Geenen R, Hammond A, Kjeken I, Lohmander L S, Lund H, Mallen C D, Nava T, Oliver S, Pavelka K, Pitsillidou I, da Silva J A, de la Torre J, Zanoli G, Vliet Vlieland T P M. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis 2013; 72(7): 1125-35. Holden M A, Nicholls E E, Young J, Hay E M, Foster NE. UK-based physical therapists’ attitudes and beliefs regarding exercise and knee osteoarthritis: Findings from a mixed-methods study. Arthritis Care Res 2009; 61(11): 1511-21.

Juhl C, Christensen R, Roos E M, Zhang W, Lund H. Impact of exercise type and dose on pain and disability in knee osteoarthritis: a systematic review and meta-regression analysis of randomized controlled trials. Arthritis Rheumatol 2014; 66(3): 622-36. Kanavaki A M, Rushton A, Efstathiou N, Alrushud A, Klocke R, Abhishek A, Duda J L. Barriers and facilitators of physical activity in knee and hip osteoarthritis: a systematic review of qualitative evidence. BMJ Open 2017; 7:e017042. Luck J, Peabody J W, Dresselhaus T R, Lee M, Glassman P. How well does chart abstraction measure quality? A prospective comparison of standardized patients with the medical record. Am J Med 2000; 108(8): 642-9. Moseng T, Dagfinrud H, Østerås N. Implementing international osteoarthritis guidelines in primary care: uptake and fidelity among health professionals and patients. Osteoarthritis Cartilage 2019; 27:1138-47. National Clinical Guideline Centre. Osteoarthritis care and management in adults. Clin Guidel CG177; 2014. Østerås N, Garratt A, Grotle M, Natvig B, Kjeken I, Kvien T K, Hagen K B. Patient-reported quality of care for osteoarthritis: development and testing of the osteoarthritis quality indicator questionnaire. Arthritis Care Res 2013; 65(7): 1043-51. Østerås N, Jordan K P, Clausen B, Cordeiro C, Dziedzic K, Edwards J, Grønhaug G, Higginbottom A, Lund H, Pacheco G, Pais S, Hagen K B. Selfreported quality care for knee osteoarthritis: comparisons across Denmark, Norway, Portugal and the UK. RMD Open 2015; 1(1): 1-9. Selten E M H, Vriezekolk J E, Nijhof M W, Schers H J, Van Der MeulenDilling R G, Van Der Laan W H, Geenen R, Van Den Ende C H M. Barriers impeding the use of non-pharmacological, non-surgical care in hip and knee osteoarthritis: the views of general practitioners, physical therapists, and medical specialists. J Clin Rheumatol 2017; 23(8): 405-10. Skou S T, Roos E M. Good Life with osteoArthritis in Denmark (GLA:DTM): evidence-based education and supervised neuromuscular exercise delivered by certified physiotherapists nationwide. BMC Musculoskelet Disord 2017; 18(1): 1-13. Skou S T, Derosche C, Andersen M M, Rathleff M S, Simonsen O. Nonoperative treatment improves pain irrespective of radiographic severity. Acta Orthop 2015a; 86(4): 1-6. Skou S T, Roos E M, Laursen M B, Rathleff M S, Arendt-Nielsen L, Simonsen O, Rasmussen S. A randomized, controlled trial of total knee replacement. N Engl J Med 2015b; 373(17): 1597-606. Spitaels D, Hermens R, Van Assche D, Verschueren S, Luyten F, Vankrunkelsven P. Are physiotherapists adhering to quality indicators for the management of knee osteoarthritis? An observational study. Man Ther 2016; 27:112-23. Thorstensson C A, Garellick G, Rystedt H, Dahlberg L E. Better management of patients with osteoarthritis: development and nationwide implementation of an evidence-based supported osteoarthritis self-management programme. Musculoskeletal Care 2015; 13(2): 67-75.

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The Forgotten Joint Score-12 in Swedish patients undergoing knee arthroplasty: a validation study with the Knee Injury and Osteoarthritis Outcome Score (KOOS) as comparator Siri HEIJBEL 1, Josefine E NAILI 2, Axel HEDIN 1, Annette W-DAHL 3,4, Kjell G NILSSON 5, and Margareta HEDSTRÖM 1,6 1 Department

of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm; 2 Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm; 3 Lund University, Department of Clinical Sciences Lund, Skåne University Hospital, Department of Orthopedics, Lund; 4 The Swedish Knee Arthroplasty Register; 5 Department of Surgical and Perioperative Sciences, Orthopedics, Umeå University, Umeå; 6 Reconstructive Orthopedics, Karolinska University Hospital Huddinge, Stockholm, Sweden Correspondence: siri.heijbel@stud.ki.se Submitted 2019-06-07. Accepted 2019-10-11.

Background and purpose — Having patients self-evaluate the outcome is an important part of the follow-up after knee arthroplasty. The Forgotten Joint Score-12 (FJS-12) introduced joint awareness as a new approach, suggested to be sensitive enough to differentiate well-functioning patients. This study evaluated the Swedish translation of the FJS-12 and investigated the validity, reliability, and interpretability in patients undergoing knee arthroplasty Patients and methods — We included 109 consecutive patients 1 year after primary knee arthroplasty to assess construct validity (Pearson’s correlation coefficient, r), internal consistency (Cronbach’s alpha [CA]), floor and ceiling effects, and score distribution. The Knee injury and Osteoarthritis Outcome Score (KOOS) was the comparator instrument for the analyses. Further, 31 patients preoperatively and 22 patients postoperatively were included to assess test– retest reliability (intraclass correlation coefficient [ICC]). Results — Construct validity was moderate to excellent (r = 0.62–0.84). The FJS-12 showed a high degree of internal consistency (CA = 0.96). The ICC was good preoperatively (0.76) and postoperatively (0.87). Ceiling effects were 2.8% in the FJS-12 and ranging between 0.9% and 10% in the KOOS. Interpretation — The Swedish translation of the FJS-12 showed good validity and reliability and can be used to assess outcome after knee arthroplasty. Moreover, the FJS-12 shows promising results in its ability to differentiate wellfunctioning patients. Future studies on unidimensionality, scale validity, interpretability, and responsiveness are needed for a more explicit analysis of the psychometric properties.

Traditionally, the evaluation of outcome following knee arthroplasty has focused to involve objective parameters, such as the range of motion or the risk for revision surgery over a 10-year period. In line with patient-centered health care, supplementary evaluation with subjective parameters using patient-reported outcome measures (PROMs) has increased in popularity during the last decades (Rolfson et al. 2016). The Swedish Knee Arthroplasty Register (SKAR) collects a set of questionnaires that, among other measurements, includes the disease specific PROM Knee injury and Osteoarthritis Outcome Score (KOOS). The KOOS is a well-established 42-item PROM, which address issues of pain and other symptoms along with functionality in daily living, sports and recreational activities, and perceived knee-related quality of life (Roos et al. 1998, Roos and Toksvig-Larsen 2003). Joint awareness was introduced by Behrend et al. (2012) as a new approach for assessment of outcome following joint arthroplasty. Complete unawareness, put on a par with a joint without problems, has been suggested as the ultimate goal after arthroplasty and, moreover, a sensitive enough measurement to differentiate well-functioning patients (Behrend et al. 2012). A discerning PROM could benefit the evaluation of potential improvements in the surgical techniques or advantageous course of treatments. Such characteristics might become more relevant in the future, as the indications for knee arthroplasty extend and the number of younger patients increases along with the total number of annually performed surgeries (Nemes et al. 2015). The Forgotten Joint Score-12 (FJS-12) is a concise and userfriendly 12-item PROM that evaluates patients’ ability to forget their joint in daily life. The FJS-12 has previously been translated into several languages with promising results regarding the validity and reliability after knee arthroplasty (Behrend et

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al. 2012, Thompson et al. 2015, Baumann et al. 2016, Shadid et al. 2016, Thomsen et al. 2016, Cao et al. 2017, Hamilton et al. 2017, Robinson et al. 2018). However, the FJS-12 has not yet been validated for Swedish knee arthroplasty patients. We evaluated the Swedish translation of the FJS-12 and assessed the validity, reliability, and interpretability in patients undergoing knee arthroplasty, more specifically by assessing the construct validity, internal consistency, test–retest reliability, and floor and ceiling effects. Furthermore, we compared floor and ceiling effects and score distribution between the FJS-12 and the KOOS.

an interval of at least 2 weeks. No upper time limit for completion was determined.

Patients and methods

KOOS The KOOS consists of 42 items divided into 5 domains: Symptoms, Pain, Function in Daily Life (ADL), Function in Sport and Recreational Activities (Sport/Rec), and Kneerelated Quality of Life (QoL) (Roos et al. 1998). Each item is answered within a 5-point Likert scale. Initial raw data from each of the domains had been converted to a scale ranging from 0 to 100 (worst to best).

Content validity of the translated version The developers of the FJS-12 provided a Swedish-language version of the questionnaire, which had been translated in accordance with the report “Principles of Good Practice for the Translation and Cultural Adaption Process for Patient Reported Outcomes (PRO) Measures” (Wild et al. 2005). The Swedish translation was tested in a group of 19 patients with verified knee osteoarthritis at the Departments of Orthopedics at Nyköping and Umeå University Hospitals. The patients were interviewed regarding their perception and the relevance of the FJS-12. Thereafter, all items were tested in their final form and an updated version of the FJS-12 was sent back and accepted by the developers. Study setting and patients This validation study was performed at the Department of Reconstructive Orthopedics at Karolinska University Hospital Huddinge in Stockholm, Sweden. All Swedish-speaking patients, regardless of underlying diagnosis, who underwent primary knee arthroplasty (unilateral knee arthroplasty (UKA) or total knee arthroplasty (TKA)) between June 1, 2016 and December 31, 2017, were eligible for inclusion. Patients were excluded if more than 4 items were missing in the FJS-12, in accordance with Behrend et al. (2012), and if the KOOS data provided by the SKAR were incomplete. Data collection The clinics’ routine 1 year after knee arthroplasty is to provide a set of questionnaires (including the KOOS) to patients by postal mail, which is subsequently reported to the SKAR. To carry through this study, the FJS-12 was added to the regular set of questionnaires in 2017 and collected until March 2019. The FJS-12 data were extracted manually from completed questionnaires returned to the clinic. The KOOS data, sex, age at surgery, BMI, and ASA classification were extracted from the SKAR. Furthermore, for assessment of test–retest reliability, there were 31 patients preoperatively and 22 patients 1 year postoperatively who received and completed the FJS-12 twice with

FJS-12 The FJS-12 consists of 12 items that are related to joint awareness in daily life (Behrend et al. 2012). Each item is answered within a 5-point Likert scale with the following response options: never (0 p); almost never (1 p); seldom (2 p); sometimes (3 p); and mostly (4 p). The initial raw data were converted to a scale ranging from 0 to 100 (worst to best), by dividing the summarized score by the number of completed items, which subsequently was multiplied by 25 and thereafter subtracted from 100.

Statistics Construct validity was assessed by Pearson’s correlation coefficient (r). The FJS-12 was correlated to each of the KOOS domains. The correlations were classified as little or no correlation (0–0.25); fair degree of correlation (0.25–0.50); moderate to good correlation (0.50–0.75); and very good to excellent correlation (0.75–1) (Dawson and Trapp 2004). The correlations were expected to be at least 0.5 to all of the KOOS domains. Internal consistency was assessed by Cronbach’s alpha, which was considered as adequate if the value was between 0.70 and 0.95 (Terwee et al. 2007). Test–retest reliability was assessed by calculating the intra-class correlation coefficient (ICC) for a 2-way random effect model with measures of absolute agreement. The ICC was calculated for each group (preoperatively and postoperatively) and was thereafter classified as poor (0–0.5), moderate (0.5–0.75), good (0.75–0.9), or excellent (0.9–1) (Koo and Li 2016). Floor and ceiling effects were assessed and compared for the FJS-12 and for each of the KOOS domains. Floor and ceiling effects were determined to be pronounced if the percentage of patients, with a total score of either 0 or 100, was > 15% respectively (Terwee et al. 2007). Score distributions were investigated with histograms. For test of normality, the Shapiro–Wilk test was used. Mean values and standard deviation (SD) are given for normally distributed data and median and range are given, in addition, for non-normally distributed data. Construct validity and test– retest reliability are presented with 95% confidence interval (CI). The statistical analyses were performed with SPSS Statistics 25.0 (IBM Corp, Armonk, NY, USA) and Microsoft Excel (Microsoft Corp, Redmond, WA, USA).

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Table 1. Demographic data, postoperative mean (SD) and median (range) score of the FJS-12 and the KOOS domains Characteristics TKA UKA Number of patients (%) 86 (79) 23 (21) Women, n (%) 51 14 Age at surgery Mean (SD) 69 (9) 71 (7) Mean BMI (SD) 30 (5) 28 (3) ASA classification, n (%) 1 6 3 2 42 11 3 37 9 N/A 1 – Median score (range) FJS-12 33 (0–100) 40 (0–100) KOOS Symptoms 75 (25–100) 75 (46–100) KOOS Pain 83 (5–100) 81 (31–100) KOOS ADL 79 (10–100) 78 (36–100) KOOS Sport/Rec 25 (0–100) 40 (0–95) KOOS QoL 53 (0–100) 63 (19–100) Mean score (SD) FJS-12 37 (30) 50 (33) KOOS Symptoms 72 (18) 79 (15) KOOS Pain 76 (23) 79 (20) KOOS ADL 70 (25) 77 (21) KOOS Sport/Rec 32 (29) 43 (28) KOOS QoL 57 (26) 64 (25)

All patients 109 (100) 65 (60) 69 (9) 30 (7) 9 (8) 53 (49) 46 (42) 1 (1) 35 (0–100) 75 (25–100) 83 (6–100) 78 (10–100) 30 (0–100) 56 (0–100) 40 (31) 74 (18) 77 (22) 72 (24) 34 (29) 58 (26)

BMI = Body Mass Index; ASA = American Society of Anesthesiologists; FJS-12 = Forgotten Joint Score-12; KOOS = Knee injury and Osteoarthritis Outcome Score; ADL = Functions in daily life; Sport/Rec = Functions in sport and recreational activities; QoL = Knee-related quality of life.

Ethics, funding and potential conflicts of interests The study was approved by the Regional Ethical Review Board in Stockholm (2014/1895-31/3) and was supported by grants provided by Region Stockholm (NSV project). No competing interests were declared.

Results Content validity After patient debriefing in the test group, item number 12 “... when you are doing your favorite sport?” was changed to “... when you exercise?”. All other questions were regarded as relevant and easily understood. In the phrase “Are you aware of your affected joint...”, the word “affected” was originally translated to the Swedish word “drabbad”. The word “drabbad” is something undesirable or unpleasant and was therefore changed to the more neutral word “berörd”. Validation process During the study period there were 177 primary knee arthroplasties performed, from which 145 patients returned the questionnaires to the clinic. There were 36 patients with incom-

Table 2. Number (%) of patients with floor effect (0 points), ceiling effect (100 points) out of 109 patients Questionnaire FJS-12 KOOS Symptoms KOOS Pain KOOS ADL KOOS Sport/Rec KOOS QoL

Floor effect 10 (9) 0 0 0 19 (17) 1 (1)

Ceiling effect 3 (3) 6 (6) 11 (10) 6 (6) 1 (1) 6 (6)

For abbreviations, see Table 1.

plete questionnaires excluded from the study, leaving a set of 109 (62%) questionnaires available for the analyses. From the included questionnaires 11 items were missing, distributed over 6 of the questions. The mean time from surgery to completion of the questionnaires was 13.5 months (10–20). From the included patients there were 86 who underwent TKA and 23 who underwent UKA. Demographic data and scores of the FJS-12 and the KOOS are summarized in Table 1. Construct validity Pearson’s correlation coefficient of the FJS-12 to the KOOS ranged from moderate to excellent: Symptoms, r = 0.62 (CI 0.48–0.71); Pain, r = 0.72 (CI 0.63–0.79); ADL, r = 0.74 (CI 0.66–0.80); Sport/Rec, r = 0.65 (CI 0.55–0.74) and QoL, r = 0.84 (CI 0.79–0.88). Reliability and reproducibility The interrelatedness amongst the items of FJS-12 was investigated and a high level of internal consistency was found (Cronbach’s alpha 0.96). The test–retest reliability of the FJS-12 was classified as good with an ICC of 0.76 (CI 0.55– 0.87) in the preoperative group and 0.87 (CI 0.72–0.94) in the postoperative group. Interpretability There were no pronounced ceiling effects in the FJS-12 or in the KOOS whereas a pronounced floor effect (17%) was found in the domain Sport/Rec (Table 2). Figure 1 presents the score distribution over the scales in the FJS-12 and the KOOS domains.

Discussion In the FJS-12 the patients are asked to rate their level of joint awareness during common activities in daily life. The findings in this study suggest that the FJS-12 has good validity and reliability. Furthermore, when comparing score distribution and floor and ceiling effects between the FJS-12 and the KOOS, the results indicates that the FJS-12 is an appropriate PROM to use for differentiation of well-functioning patients.

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Frequency

100

Postoperative score FJS–12

100

Postoperative score KOOS Symptoms

Frequency

100

Postoperative score KOOS ADL

100

Postoperative score KOOS Sport/Rec

100

Postoperative score KOOS Pain

Postoperative score KOOS QoL

Figure 1. Distribution of scores 1 year after knee arthroplasty in FJS-12 and KOOS domains: Symptoms; Pain; Functions in daily life (ADL); Functions in sport and recreational activities (Sport/Rec), and Knee-related quality of life (QoL).

To further investigate and strengthen the validity of the FJS12, future studies exploring the unidimensionality, scale validity, interpretability, and responsiveness are needed. Construct validity Joint awareness has been suggested to integrate a variety of variables such as pain, stiffness, and functionality in daily living (Behrend et al. 2012). Therefore, the correlations between the FJS-12 and the KOOS are expected to be at least moderate but not absolute. We found moderate to excellent correlations (r = 0.62–0.84), findings that are similar to those found by Cao et al. (2017) and Thompson et al. (2015), who reported strong correlations between the FJS-12 and the KOOS. We found the strongest correlation between the FJS-12 and the KOOS domain QoL. This particular domain includes items of a more general character, compared with the more explicitly characterized items in the other domains, and may in that aspect be more like the FJS-12. The conceptual generality of joint awareness may be a disadvantage with the FJS-12. Although the versatility is likely to provide a sensitive measurement of both improvement and deterioration, as well as differences that can occur between patients, it may also allow for psychological factors to influ-

ence the scores, such as insecurity and fear of complications (Loth et al. 2018). Reliability and reproducibility If the value of Cronbach’s alpha exceeds the upper limit for positive rating (0.95) according to Terwee et al. (2007), this could indicate a redundancy between the items. In this study, the value of Cronbach’s alpha was 0.96, similar to the majority of the previous FJS-12 validation studies (Behrend et al. 2012, Baumann et al. 2016, Thomsen et al. 2016, Hamilton et al. 2017, Robinson et al. 2018). The high value of Cronbach’s alpha may be due to the similarity of the questions, since they all begin with the same phrase, “Are you aware of your joint...”. It may be that some patients conceptualize joint awareness as something constant rather than situation dependent. The ICC was investigated for both the preoperative patients and the postoperative patients separately, since the value of the coefficient depend partly on the sample variation (Terwee et al. 2007). The results were classified as good test-retest reliability, which is similar to previous findings (Thompson et al. 2015, Thomsen et al. 2016, Cao et al. 2017, Robinson et al. 2018). Furthermore, a true value of the ICC requires that the patients are free from clinical changes that interfere with the measure-

ments. Given this, the ICC that was calculated in the postoperative patient group (0.87) may be closer to the true value compared with the ICC in the preoperative patient group (0.76). Interpretability A pronounced floor effect was found in the KOOS domain Sport/Rec (see Table 2). This may be caused by specific movements, i.e., squatting, running, kneeling, jumping, and pivoting/twisting, that are difficult to perform by a large number of patients who have undergone knee arthroplasty. Previous reports of the FJS-12 ceiling effects after knee arthroplasty range from 0% to 9.2% (Baumann et al. 2016, Thienpont et al. 2016, Hamilton et al. 2017, Robinson et al. 2018). The present study showed that the FJS-12 had lower ceiling effects than the KOOS (Table 2), which has similarly been found in other studies (Thompson et al. 2015, Thienpont et al. 2016). Our findings on ceiling effects (2.8%) are considerably lower compared with recently published results (21%) by Larsson et al. (2019) for the FJS-12 in patients undergoing total hip arthroplasty (THA). This might limit the usability of the FJS-12 in THA patients, which has previously been discussed by Thienpont et al. (2016), who found a higher ceiling effect in patients undergoing THA compared with TKA. Figure 1 suggests that the scores have a greater spread over the scale in the FJS-12 compared with the KOOS. This may be because complete unawareness of a knee with a joint implant is more difficult to achieve, compared with an outcome such as a satisfying degree of pain relief. Our findings indicate a comprehensiveness in the FJS-12 that enables detection of differences between patients, which may indicate that the FJS-12 provide attributes with high discriminatory power in this patient group. Feasibility The conciseness of the FJS-12 may be more appealing for patients than the extensiveness of the KOOS. Cao et al. (2017) reported a mean completion time of 85 seconds, which is considerably shorter than the approximate 10 minutes’ completion time for the KOOS. Although joint awareness may be conceptually challenging for some patients to interpret, the opinions that were expressed in the pilot study regarding the relevance and understanding of the FJS-12 were positive. Strengths and limitations A strength of the present study is that the sample size for construct validity, internal consistency, and floor and ceiling effects met the criteria proposed by Terwee et al. (2007). Further, the study comprises a consecutive group of patients and all arthroplasties were performed according to the clinics’ everyday routine, altogether minimizing the risk of selection bias in the sample. However, the sample could have been affected by the response rate. Further, this was a university hospital-based study while a large proportion of the knee arthroplasties in the Stockholm

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region are provided by private-driven healthcare facilities, which may affect the generalizability of the score distribution and floor and ceiling effects. While the mean age in our study sample was comparable to the mean age of the Swedish knee arthroplasty patients, the mean KOOS scores were somewhat lower (SKAR 2018). This may be explained by the higher proportion of patients with ASA ≥ 3 and BMI 35+ who were referred to the hospital concerned, as compared with the general knee arthroplasty population (SKAR 2018). We did not investigate the structural validity of the FJS12, which decreases the reliability of the internal consistency measurement (Terwee et al. 2007). Although Cronbach’s alpha indicates that the items are related to one another, the internal consistency of the FJS-12 is not completely explored unless the items have been evaluated with factor analysis. To avoid the ICC being affected by the heterogeneity of the preoperative and postoperative patient groups, we performed separate calculations for each, which resulted in rather small sample sizes. When the test–retest reliability is evaluated, there is no consensus regarding the exact time period between the first and second response. In this study, a period of at least 2 weeks was chosen to prevent recall bias. However, there was no upper time limit for completion, which may have falsely lowered the result for the ICC analysis due to possible clinical changes in the patients. Conclusion Our study shows that the FJS-12 has good validity and reliability and may be used after knee arthroplasty in clinical practice, or as a supplement to the KOOS in the SKAR. Furthermore, the results indicate that the FJS-12 may provide attributes that differentiate well-functioning patients. This might be especially useful for future clinical research on improving the treatment for patients who undergo knee arthroplasty.

SH drafted the manuscript, performed the statistical analyses, and managed the data. JEN drafted the manuscript. AH managed the data and was involved in conception of the pilot study. AWD drafted the manuscript. KGN was involved in conception of the pilot study. MH was involved in in conception and design, drafted the manuscript, and conception of the pilot study. All authors have made substantial contributions in the interpretation of data and revision of the manuscript. The authors would like to thank Kristina Staaf MD at Nyköpings Hospital for her contribution to the conception of the pilot study. Acta thanks Lina Holm Ingelsrud and Yvette Pronk for help with peer review of this study.

Baumann F, Ernstberger T, Loibl M, Zeman F, Nerlich M, Tibesku C. Validation of the German Forgotten Joint Score (G-FJS) according to the COSMIN checklist: does a reduction in joint awareness indicate clinical improvement after arthroplasty of the knee? Arch Orthop Trauma Surg 2016; 136(2): 257-64.

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Behrend H, Giesinger K, Giesinger J M, Kuster M S. The “forgotten joint” as the ultimate goal in joint arthroplasty: validation of a new patient-reported outcome measure. J Arthroplasty 2012; 27(3): 430-6. Cao S, Liu N, Han W, Zi Y, Peng F, Li L, Fu Q, Chen Y, Zheng W, Qian Q. Simplified Chinese version of the Forgotten Joint Score (FJS) for patients who underwent joint arthroplasty: cross-cultural adaptation and validation. J Orthop Surg Res 2017; 12(1): 6. Dawson B, Trapp R G. summarizing data & presenting data in tables & graphs. In: Basic & clinical biostatistics, 4th ed., Chapter 3. New York: McGraw-Hill; 2004. Hamilton D F, Loth F L, Giesinger J M, Giesinger K, MacDonald D J, Patton J T, Simpson A H R W, Howie C R. Validation of the English language Forgotten Joint Score-12 as an outcome measure for total hip and knee arthroplasty in a British population. Bone Joint J 2017; 99-B(2): 218-24. Koo T L, Li M Y. A guideline of selecting and reporting intraclass correlation coefficients for reliability research. J Chiropr Med 2016; 15(2): 155-63. Larsson A, Rolfson O, Karrholm J. Evaluation of Forgotten Joint Score in total hip arthroplasty with Oxford Hip Score as reference standard. Acta Orthop 2019; 90(3): 253-57. Loth F L, Liebensteiner M C, Giesinger J M, Giesinger K, Bliem H R, Holzner B. What makes patients aware of their artificial knee joint? BMC Musculoskelet Disord 2018; 19(1): 5. Nemes S, Rolfson O, W-Dahl A, Garellick G, Sundberg M, Karrholm J, et al. Historical view and future demand for knee arthroplasty in Sweden. Acta Orthop 2015; 86(4): 426-31. Robinson P G, Rankin C S, Lavery J, Anthony I, Blyth M, Jones B. The validity and reliability of the modified forgotten joint score. J Orthop 2018; 15(2): 480-5. Rolfson O, Eresian Chenok K, Bohm E, Lübbeke A, Denissen G, Dunn J, Lyman S, Franklin P, Dunbar M, Overgaard S, Garellick G, Dawson J; Patient-Reported Outcome Measures Working Group of the International

Society of Arthroplasty Registries. Patient-reported outcome measures in arthroplasty registries. Acta Orthop 2016; 87(eSuppl 362): 3-8. Roos E M, Toksvig-Larsen S. Knee injury and Osteoarthritis Outcome Score (KOOS): validation and comparison to the WOMAC in total knee replacement. Health Qual Life Outcomes 2003; 1: 17. Roos E M, Roos H P, Lohmander L S, Ekdahl C, Beynnon B D. Knee Injury and Osteoarthritis Outcome Score (KOOS): development of a self-administered outcome measure. J Orthop Sports Phys Ther 1998; 28(2): 88-96. Shadid M B, Vinken N S, Marting L N, Wolterbeek N. The Dutch version of the Forgotten Joint Score: test–retesting reliability and validation. Acta Orthop Belg 2016; 82(1): 112-8 SKAR. Swedish Knee Arthroplasty Register Annual Report; 2018. ISBN 97891-88017-20-8 Terwee C B, Bot S D, de Boer M R, van der Windt D A, Knol D L, Dekker J, Bouter L M, de Vet H C W. Quality criteria were proposed for measurement properties of health status questionnaires. J Clin Epidemiol 2007; 60(1): 34-42. Thienpont E, Vanden Berghe A, Schwab P E, Forthomme J P, Cornu O. Joint awareness in osteoarthritis of the hip and knee evaluated with the “Forgotten Joint” Score before and after joint replacement. Knee Surg Sports Traumatol Arthrosc 2016; 24(10): 3346-51. Thompson S M, Salmon L J, Webb J M, Pinczewski L A, Roe J P. Construct validity and test re-test reliability of the Forgotten Joint Score. J Arthroplasty 2015; 30(11): 1902-5. Thomsen M G, Latifi R, Kallemose T, Barfod K W, Husted H, Troelsen A. Good validity and reliability of the forgotten joint score in evaluating the outcome of total knee arthroplasty. Acta Orthop 2016; 87(3): 280-5. Wild D, Grove A, Martin M, Eremenco S, McElroy S, Verjee-Lorenz A, Erikson P. Principles of good practice for the translation and cultural adaptation process for patient-reported outcomes (PRO) measures: report of the ISPOR Task Force for Translation and Cultural Adaptation. Value Health 2005; 8(2): 94-104.

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Weight and height separated provide better understanding than BMI on the risk of revision after total knee arthroplasty: report of 107,228 primary total knee arthroplasties from the Swedish Knee Arthroplasty Register 2009–2017 Erdem A SEZGIN 1, Annette W-DAHL 2,3, Lars LIDGREN 2,3, and Otto ROBERTSSON 2,3 1 Gazi

University, Faculty of Medicine, Department of Orthopedics and Traumatology, Ankara, Turkey; 2 Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, Orthopedics, Lund, Sweden; 3 The Swedish Knee Arthroplasty Register, Lund, Sweden Correspondence: easezgin@gazi.edu.tr Submitted 2019-08-19. Accepted 2019-10-16.

Background and purpose — Obesity defined as increased BMI is commonly associated with higher revision rates following total knee arthroplasty (TKA). We examined the effect of BMI on the rate of revision after TKA, for both infection and other reasons, and analyzed weight and height separately to provide better understanding of the risk profile. Patients and methods — The Swedish national knee arthroplasty register was used to identify 107,228 patients operated with primary TKA for osteoarthritis between 2009 and 2017. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for BMI (categories: < 18.5, 18.5–24.9, 25–29.9, 30–34.9, 35–39.9, ≥ 40), weight (categories: < 65, 65–89, 90–114, ≥ 115 kg) and height (categories: < 160, 160–179, ≥ 180 cm Results — There were 2,503 revisions in the followup period; 1,036 for infection and 1,467 for other reasons. Higher BMI and weight categories were associated with a similar and statistically significantly increased risk of revision for all causes and for infection. The risk of revision for infection was almost twice in the highest BMI and highest weight group: HR = 3.4 (CI 2.3–4.7) and HR = 3.1 (CI 2.5–3.9) respectively. For BMI and weight categories there was no statistically significant association between revision for other reasons than infection, contrary to the tallest height category where it was statistically significant (HR = 1.3 [CI 1.1–1.5]). Interpretation — BMI, weight, and height may be associated with different types of risks for revision following TKA.

Patients having a total knee arthroplasty (TKA) have some modifiable risk factors that may affect surgical outcome. Obesity has reached epidemic levels mainly in the western countries and is being considered as a public health crisis (Gonzalez Della Valle et al. 2012, George et al. 2017). Obesity is considered a risk factor for both developing knee osteoarthritis (OA) and progression requiring TKA surgery at younger age (Changulani et al. 2008, Singer et al. 2018). Moreover, many studies have shown that morbid obesity is associated with increased risk of revision following TKA (Springer et al. 2013, Roche et al. 2018, Tohidi et al. 2018, Boyce et al. 2019). However, most of the studies report overall risk for revision without detailing reasons for revision. The effect of obesity on revision besides an increased risk for periprosthetic joint infection (PJI) has not been thoroughly discussed in the literature (D’Apuzzo et al. 2015, Wagner et al. 2016, Jung et al. 2017, Roche et al. 2018, Boyce et al. 2019). There might be a complex relation between weight and height, and TKA outcome. Only 1 study has shown that weight and height effect the risk of revision differently when analyzed as independent variables (Christensen et al. 2018). Therefore, this nationwide register-based study in Sweden evaluated the effect of BMI on rate of revision for PJI as well as reasons for revision other than PJI in patients operated for OA with TKA, and analyzed weight and height separately to provide better understanding of risk of revision.

Patients and methods Patients who had undergone primary TKA for OA between January 1, 2009 and December 31, 2017 were identified in the Swedish Knee Arthroplasty Register (SKAR). The SKAR, which started in 1975, is the world’s first national arthroplasty register and has high coverage and completeness (SKAR 2018).

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BMI, weight, and height at the time of surgery were identified from the SKAR as well as age and sex. TKAs lacking BMI data were excluded. The World Health Organization (WHO) classification was used to classify BMI into 6 categories: underweight (BMI < 18.5), normal weight (BMI 18.5–24.9), overweight (BMI 25–29.9), obese class I (BMI 30–34.9), obese class II (BMI 35–39.9), and obese class III (BMI ≥ 40). Weight and height were analyzed as both continuous and categorical variables. Categories for weight and height were defined arbitrarily: < 65, 65–89, 90–114, ≥ 115 kg; and < 160, 160–179, ≥ 180 cm. The outcome measures were revision for all reasons, revision for infection or suspected infection, and revision for reasons other than infection. In the SKAR, revisions are defined as a new operation in which 1 or more of the components are changed, removed, or added (including arthrodesis and amputation). Patients included in the study had a follow-up until death or December 31, 2017. Statistics Adjusted hazard ratios (HRs) were obtained for each 6 BMI categories using Cox proportional hazards regressions with 3 separate endpoints: revision for all reasons, revision for infection, and revision for reasons other than infection. Adjustments were made for differences in age and sex at the time of operation. Similarly, Cox proportional hazards regression was used to obtain adjusted HRs for weight and height as both continuous and categorical variables using the aforementioned 3 outcomes as endpoints. Reference categories were determined for BMI, weight, and height as 18.5–24.9, 65–89 kg, and 160– 179 cm respectively. Adjustments were made for differences in age, sex, weight, and height at the time of surgery. Results are reported as HRs with 95% confidence intervals (CIs). P-values of < 0.05 were considered to be statistically significant. Statistical analyses were carried out using Stata version 15 (StataCorp, College Station, TX, USA). Ethics, funding, and potential conflicts of interest The data gathering from the Swedish Knee Arthroplasty Register was approved by the Ethics Board of Lund University (LU20-02). The authors received no funding for this work. No conflicts of interest were declared.

Results From the SKAR database 108,623 TKAs were identified that met the initial eligibility criteria. 1,395 TKAs with missing data were excluded and 107,228 TKAs were included in the study cohort. For the BMI categories, 0.2% of TKAs were underweight, 18% normal weight, 43% overweight, 28% in obese class I, 8.6% in obese class II, and finally 1.9% were in obese class III. For weight and height categories 8.3% were in < 65 kg, 57% in 65–89 kg, 31% in 90–114 kg, 3.8% in ≥ 115

Table 1. Adjusted hazard ratios (HR) for different outcomes according to the 6 BMI categories Revision Revision for (all causes) infection BMI HR (CI) HR (CI)

Revision for reasons other than infection HR (CI)

< 18.5 0.3 (0.1–2.1) 18.5–24.9 Reference 25–29.9 1.1 (0.9–1.2) 30–34.9 1.3 (1.1–1.5) 35–39.9 1.3 (1.1–1.5) ≥ 40 1.6 (1.2–2)

0.8 (0.1–5.7)

Not available

1.1 (0.9–1.3) 1.5 (1.2–1.8) 2.1 (1.7–2.7) 3.3 (2.3–4.7)

1.1 (0.9–1.3) 1.2 (1.01–1.4) 0.9 (0.7–1.1) 0.9 (0.6–1.3)

CI = 95% confidence interval

kg, and 46% in < 160 cm, 68.0% in 160–179 cm, 19% in ≥180 cm. There were 2,503 (2.3%) revisions over the follow-up period, 1,036 being for infection and 1,467 for reasons other than infection. BMI and revision After Cox proportional hazard regression, considering revision for all reasons, obesity was found to be associated with higher risk starting from obese class I (Table 1). Revision for infection also demonstrated a similar increase of risk starting from obese class I. However, no such trend between obesity and revision rates for reasons other than infection was observed except for the increase in obese class I. Weight and revision Like BMI, weight also demonstrated an association with risk of revision and revision for infection, as both a continuous and a categorical variable. However, no statistically significant difference was found between the weight groups and revision for reasons other than infection (Table 2). Height and revision Although height as a continuous variable had a statistically significant association with all revisions, there were no statistically significant differences between height categories and revision. In addition, medium and tall height categories did not show statistically significant association with revision for infection; however, there was increased risk in the shortest height category. Contrary to other endpoints, we found that the tallest height category and height as a continuous variable were associated with higher risk of revision for reasons other than infection (Table 2).

Discussion We showed that obesity was associated with overall risk of revision and revision for infection, but the same relationship could not be shown for revision for reasons other than infec-

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Table 2. Adjusted hazard ratios (HR) for different outcomes according to weight and height as continuous and categorical variables Revision Revision for (all causes) infection Parameter HR (CI) HR (CI)

Revision for reasons other than infection HR (CI)

Weight (kg) Continuous 1.01 (1.01–1.01) 1.02 (1.02–1.03) 1 (1–1) < 65 0.9 (0.7–1.02) 0.7 (0.5–1) 0.9 (0.8–1.2) 65–89 Reference 90–114 1.2 (1.1–1.3) 1.4 (1.2–1.6) 1.1 (0.95–1.2) ≥ 115 1.8 (1.5–2.1) 3.1 (2.5–3.9) 1.1 (0.8–1.4) Height (cm) Continuous 1.01 (1.00–1.02) 0.99 (0.98–1.00) 1.02 (1.02–1.03) < 160 0.9 (0.8–1.1) 1.3 (1.02–1.6) 0.8 (0.7–1) 160–179 Reference ≥ 180 1.1 (1–1.3) 1 (0.8–1.2) 1.3 (1.1–1.5) CI = 95% confidence interval

tion. The 2 heaviest groups and weight as a continuous variable demonstrated a risk similar to that of obesity whereas tallest height category and 1 cm increase in height appeared to be associated with higher risk of revision for reasons other than PJI. In addition, shorter patients appeared to have increased risk of revision for PJI but there is no basis in our study and the literature to comment on this finding. The results were based on 107,228 patients from the SKAR, which has high completeness and response rate and covers the whole nation. However, we acknowledge several limitations to our study. First, despite overweight and obesity increase in the Swedish population, the percentages are still lower than in many other countries and, further, the average height of the Swedish population is higher than the world average (Hanson et al. 2009). Second, it may be argued that weight and height are naturally dependent variables. However, it should be noted that the focus of this study was not to introduce height and weight as alternative predictors of outcome; such analysis has been done recently by Christensen et al. (2018) using a similar statistical method. Moreover, as height is not a modifiable parameter, clinical relevance of height is questionable and these results can only be used as a base for further speculations on mechanical effects of height. Finally, we would like to note that the study groups were arbitrarily defined, as in other studies, due to the lack of defined weight and height categories considering the risk of revision. While deciding on the groups, we tried to portray TKA patient profiles according to orthopedic surgeons’ (EAS, LL, OR) clinical experiences. Normal and overweight BMI categories totaled approximately 70% of patients and the 65–89 kg category totaled 60% in our study. Similarly, there were 30% in both the 90–114 kg category and obese class 1. There were 4% in the heaviest category and 10% in obese class 3. Also, for height, approximately 70% were in the normal, 10% in the short, and 20% in the tall group. We acknowledge that arbitrary categories and consequent sample sizes have a considerable effect on statistical

analysis, especially for height, where this parameter showed a correlation with higher risk of overall revision as a continuous variable; however, there was no correlation between height categories for the same endpoint. By definition BMI is used to determine healthy weight and its ability to reflect body habitus is limited. Therefore, the individual variables, height and weight, used for calculation of BMI have recently drawn attention and are also suggested to be valuable as alternative predictors of risk (Lübbeke et al. 2016, Christensen et al. 2018, Gøttsche et al. 2019). Being the numerator in the calculation, weight has a positive correlation with BMI contrary to height, which is the denominator. Therefore, weight and height can have an effect on their own and not necessarily in combination. This concept has hitherto only been discussed by Christensen et al. (2018). Their single-center study consisting of more than 20,000 consecutive TKAs performed between 1985 and 2012 showed that increasing BMI, body weight, and body surface area was associated with an increased risk of infection, although height demonstrated no correlation in multivariate models. Instead, they showed that each 11 cm increase in height resulted in 14% increased risk of revision for mechanical failure. Our study supports this concept, by pointing out that height has a different effect on rate of revision for reasons other than PJI compared with weight and BMI. It can be translated as suggesting that a tall and obese individual would be more at risk for mechanical failure than a short and obese one, while both have increased risk of revision for infection after TKA. The reason behind this might be the increased lever arm, which results in higher moment of force above and below prostheses in taller patients, thus creating unfavorable mechanical loading that can lead to premature wear and loosening (Christensen et al. 2018). In addition, considering taller patients are not expected to adopt a more sedentary lifestyle like obese patients tend to do, it is plausible that height has a possible effect on mechanical complications after TKA which differs from that of BMI and weight (McClung et al. 2000, Amin et al. 2006, Overgaard et al. 2019). Weight, on the other hand, has been discussed several times in the literature. Lübbeke et al. (2016) analyzed the effect of weight on PJI rates in arthroplasty and suggested that both 35 kg/m2 and 100 kg can be regarded as thresholds for a significant 2-fold increase in PJI. Gøttsche et al. (2019) also studied effects of weight on implant survival but found no correlation between weight and revision for aseptic loosening or infection. Despite being a Danish nationwide registry study with almost 70,000 TKAs, there were only 173 (0.3%) revisions due to infection, which may explain the lack of correlation or indicate possible under-reporting in their study. In conclusion, our results could aid risk assessment and consideration of possible precautions to reduce failure but not patient selection for TKA. As height is not a modifiable factor, taller patients could be informed about the possible value of decreasing the load on the TKA by losing weight and modifying high-impact activity.

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The study was conceived by LL. OR, AWD and EAS performed the analyses and LL and EAS wrote the initial draft. All authors contributed to the interpretation of the data and to revision of the manuscript. Acta thanks Peter Nolte and Anders Troelsen for help with peer review of this study.

Amin A K, Patton J T, Cook R E, Brenkel I J. Does obesity influence the clinical outcome at five years following total knee replacement for osteoarthritis? J Bone Joint Surg Br 2006; 88 (3): 335-40. Boyce L, Prasad A, Barrett M, Dawson-Bowling S, Millington S, Hanna S A, et al. The outcomes of total knee arthroplasty in morbidly obese patients: a systematic review of the literature. Arch Orthop Trauma Surg 2019; 139 (4): 553-60. Changulani M, Kalairajah Y, Peel T, Field R E. The relationship between obesity and the age at which hip and knee replacement is undertaken. J Bone Joint Surg Br 2008; 90 (3): 360-3. Christensen T C, Wagner E R, Harmsen W S, Schleck C D, Berry D J. Effect of physical parameters on outcomes of total knee arthroplasty. J Bone Joint Surg Am 2018; 100 (21): 1829-37. D’Apuzzo M R, Novicoff W M, Browne J A. The John Insall Award: Morbid obesity independently impacts complications, mortality, and resource use after TKA. Clin Orthop Relat Res 2015; 473 (1): 57-63. George J, Klika A K, Navale S M, Newman J M, Barsoum W K, Higuera C A. Obesity epidemic: is its impact on total joint arthroplasty underestimated? An analysis of national trends. Clin Orthop Relat Res 2017; 475 (7): 1798-806. Gonzalez Della Valle A, Chiu Y L, Ma Y, Mazumdar M, Memtsoudis S G. The metabolic syndrome in patients undergoing knee and hip arthroplasty: trends and in-hospital outcomes in the United States. J Arthroplasty 2012; 27 (10): 1743-9.e1. Gøttsche D, Gromov K, Viborg P H, Brauner E V, Pedersen A B, Troelsen A. Weight affects survival of primary total knee arthroplasty: study based on

the Danish Knee Arthroplasty Register with 67,810 patients and a median follow-up time of 5 years. Acta Orthop 2019; 90 (1): 60-6. Hanson L, Sperling L, Gard G, Ipsen S, Olivares Vergara C. Swedish anthropometrics for product and workplace design. Appl Ergon 2009; 40 (4): 797-806. Jung P, Morris A J, Zhu M, Roberts S A, Frampton C, Young S W. BMI is a key risk factor for early periprosthetic joint infection following total hip and knee arthroplasty. N Z Med J 2017; 130 (1461): 24-34. Lübbeke A, Zingg M, Vu D, Miozzari H H, Christofilopoulos P, Uckay I, et al. Body mass and weight thresholds for increased prosthetic joint infection rates after primary total joint arthroplasty. Acta Orthop 2016; 87 (2): 132-8. McClung C D, Zahiri C A, Higa J K, Amstutz H C, Schmalzried T P. Relationship between body mass index and activity in hip or knee arthroplasty patients. J Orthop Res 2000; 18 (1): 35-9. Overgaard A, Lidgren L, Sundberg M, Robertsson O, W-Dahl A. Patientreported 1-year outcome not affected by body mass index in 3,327 total knee arthroplasty patients. Acta Orthop 019; 90(4): 360-5. Roche M, Law T Y, Kurowicki J, Rosas S, Rush A J, 3rd. Effect of obesity on total knee arthroplasty costs and revision rate. J Knee Surg 2018; 31 (1): 38-42. Singer S P, Dammerer D, Krismer M, Liebensteiner M C. Maximum lifetime body mass index is the appropriate predictor of knee and hip osteoarthritis. Arch Orthop Trauma Surg 2018; 138 (1): 99-103. SKAR. Swedish Knee Arthroplasty Register Annual Report; 2018. ISBN 97891-88017-20-8. Springer B D, Parvizi J, Austin M, Backe H, Della Valle C, Kolessar D J, et al. Obesity and total joint arthroplasty: a literature based review. J Arthroplasty 2013; 28 (5): 714-21. Tohidi M, Brogly S B, Lajkosz K, Grant H J, VanDenKerkhof E G, Campbell A R. Ten-year mortality and revision after total knee arthroplasty in morbidly obese patients. J Arthroplasty 2018; 33 (8): 2518-23. Wagner E R, Kamath A F, Fruth K, Harmsen W S, Berry D J. Effect of body mass index on reoperation and complications after total knee arthroplasty. J Bone Joint Surg Am 2016; 98 (24): 2052-60.

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No effect of cognitive behavioral patient education for patients with pain catastrophizing before total knee arthroplasty: a randomized controlled trial Sara BIRCH 1,2, Maiken STILLING 2–4, Inger MECHLENBURG 2,4,5, and Torben Bæk HANSEN 2,3 1 Department of Physiotherapy and Occupational Therapy, Holstebro Regional Hospital, Hospital Unit West; 2 Department of Clinical Medicine, Aarhus University; 3 University Clinic for Hand, Hip, and Knee Surgery, Holstebro Regional Hospital, Hospital Unit West; 4 Department of Orthopaedic Surgery, Aarhus University Hospital; 5 Department of Public Health, Aarhus University, Denmark Correspondence: sara.birch@vest.rm.dk Submitted 2019-09-18. Accepted 2019-10-29.

Background and purpose — Pain catastrophizing contributes to acute and long-term pain after total knee arthroplasty (TKA) but currently there are only limited treatment options. This study investigates the effectiveness of patient education in pain coping among patients with moderate to high pain catastrophizing score before TKA. Secondary outcomes were physical function, quality of life, self-efficacy, and pain catastrophizing. Patients and methods — The study was a parallelgroup randomized controlled trial including patients with moderate to high levels of pain catastrophizing. 60 patients were recruited from December 2015 to June 2018. The mean age of the patients was 66 (47–82) years and 40 were women. The patients were randomized to either cognitivebehavioral therapy (CBT) based pain education or usual care. The primary outcome measure was pain under activity measured with the Visual Analog Scale (VAS). All outcomes were measured preoperatively, at 3 months, and at 1 year after surgery. Results — We found no difference in the primary outcome measure, VAS during activity, between the 2 groups but both groups had large reductions over time. The CBTbased pain education group reduced their VAS score by 37 mm (95% CI 27–46) and the control group by 40 mm (CI 31–49). We found no statistically significantly differences between the 2 groups in any of the secondary outcomes. Interpretation — Future research is warranted to identify predictors of persistent pain and interventions for the approximately 20% of patients with persisting pain after a TKA.

Up to 20% of patients report persistent pain after a total knee arthroplasty (TKA) (Beswick et al. 2012). Both physical and psychological risk factors for poor outcome after TKA are identified, highlightning the complex interaction between physiological, biological, and social factors. Psychological factors such as anxiety, self-efficacy, kinesiophobia, and pain catastrophizing are associated with persistent pain after TKA (Hirakawa et al. 2014, Bierke et al. 2017). Pain catastrophizing is defined as negative emotional and cognitive responses to actual or anticipated pain (Sullivan et al. 1995). A Cochrane Review has shown that cognitive behavioral therapy (CBT) is an effective treatment for many different chronic pain conditions (Williams et al. 2012) and interventions such as pain coping skills training based on CBT are shown to reduce pain catastrophizing and improve knee function for patients with knee osteoarthritis (OA) (Somers et al. 2012, Broderick et al. 2014, Bennell et al. 2016, Cai et al. 2018). However, only 1 recent study has examined a cognitive behavioral intervention for patients with knee OA and high levels of pain catastrophizing. Riddle et al. (2019) studied 402 patients in a 3-armed randomized clinical trial (pain coping, arthritis education, and usual care) and found no differences in any of the outcomes between the 3 treatment arms. The primary aim of this study was to investigate the effectiveness – on pain after TKA – of pre- and postoperative patient education in pain coping among patients with moderate to high pain catastrophizing score. Further, we wanted to investigate the effectiveness on postoperative physical function, quality of life, self-efficacy, and pain catastrophizing.

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Patients and methods Participants A protocol article describes the patients and methods in detail (Birch et al. 2017). This randomized controlled trial recruited patients from the orthopedic outpatient clinic at Holstebro Regional Hospital from December 2015 to June 2018. Inclusion criteria were primary knee OA, scheduled for primary total knee arthroplasty because of osteoarthritis, age ≥ 18, a score > 22 on the Pain Catastrophizing Scale (PCS), proficiency in written and spoken Danish, and informed written consent. The patients were excluded if they had severe depression as diagnosed with the Major Depression Inventory (MDI) or were planning to have a contralateral knee arthroplasty within 1 year after the operation. The patients were included consecutively and randomized 1:1 to either the intervention group or usual care in 7 blocks of 8 persons. Because of high withdrawal rate, we decided to continue including patients and randomized another 16 patients. At the predefined deadline of June 1, 2018 we stopped the inclusion of patients. The physiotherapists and nurses who did the baseline and follow-up testing where blinded for the randomization. It was not possible to blind the patients and the 2 physiotherapists who delivered the patient education. Control and intervention group Patients in the control group received usual care. Preoperatively this consisted of a multidisciplinary information meeting for patients and their relatives. Postoperative patients in the usual care group were offered a phone call after 1 week and 3 control visits at the hospital after 2, 4, and 12 weeks. In addition to usual care the intervention group participated in patient education based on CBT. The patient education consisted of 7 individual sessions of approximately 45 minutes, 3 sessions preoperatively and 4 sessions postoperatively. The 1st session was delivered approximately 2 weeks before the operation and the last session was given 3 months after the operation. The patient education was delivered by 2 physiotherapists who followed a manual describing in detail the content of each of the 7 sessions. This ensured that each session was standardized although there was room to discuss individual needs. The physiotherapists observed each other on a regular basis to make sure that they delivered the intervention in the same way. As far as possible the same physiotherapist followed the patient through all the sessions. The patient education covered 3 main components: (1) education in pain and the interaction between cognition and pain perception; (2) training in cognitive and behavioral pain coping skills; and (3) training in how to apply the learned coping skills in real-life situations. For details see the protocol (Birch et al. 2017).

Deviations from protocol In November 2016, approximately 1 year after we started including patients, we had to change the number of sessions in the patient education from 7 to 6. The reason for this was that we had to exclude too many patients because the waiting time between the outpatient surgeon consultation and the operation was too short to deliver the 3 preoperative sessions. Thus, we decided to combine the 3 sessions before the operation into 2, but without changing the content. Outcome measures and follow-up The primary outcome measure was pain during activity at 12 months measured with the Visual Analog Scale (VAS): 0 indicating “no pain,” to 100 indicating “worst pain imaginable” on a mm scale. Pain during activity was measured right after the 6-minute walk test. Secondary outcomes included physical function, quality of life, physiological factors, and pain during rest. The Oxford Knee Score (OKS) was used to measure knee-related pain and physical function. Overall scores run from 0 to 48 with 48 being the best outcome (Paulsen et al. 2012). 2 performance-based outcomes—the 6-minute walk test and sit to stand in 30 seconds—were used to measure physical function (Enright 2003, Gill and McBurney 2008). The Pain Catastrophizing Scale (PCS) was used to address feelings and thoughts related to pain. Total score ranges from 0 to 52. The higher the score, the more catastrophizing thoughts are present (Sullivan et al. 1995). The EQ-5D is a measure of self-reported general health and consists of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The Pain Self-Efficacy Questionnaire (PSEQ) measures the patient’s beliefs in his/her ability to perform activities despite pain. The score ranges from 0 to 60, with 60 being the best outcome (Rasmussen et al. 2016). Pain at rest was measured with VAS before the 2 performance-based tests. The Knee Injury and Osteoarthritis Outcome Score (KOOS) consists of 5 subscales. We used the subscale “pain.” After calculation the score ranges from 0 to 100, where 100 is indicating no symptoms (Roos et al. 1998). All outcomes were measured preoperatively, at 3 months, and at 1 year after surgery. Sample size VAS during activity was used to calculate the needed study sample. Based on former studies we used a minimal clinically important difference in VAS activity of 18 mm (Hagg et al. 2003) between the 2 groups and a standard deviation of 19 mm (Forsythe et al. 2008, Edwards et al. 2009, Papakostidou et al. 2012). With a significance level at 0.05, a power of 90%, and an expected loss to follow-up of approximately 20% of the patients, a total sample of 56 patients was needed. Statistics Normally distributed data are described by mean (SD), and data not normally distributed by median (range). In the analysis the intention-to-treat principle was used including all ran-

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domized participants. For all outcomes, between-group mean differences, changes over time, and 95% confidence intervals (CI) from baseline to 3 and 12 months were analyzed by a mixed-effects linear regression model with a random person level and systematic effects of time, group, and the interaction between time and group. In the analysis of change in the primary outcome from baseline to 12 months we included VAS during activity at baseline as a covariate. Model validation was performed by comparing observed and expected withinsubject standard deviations and correlations and by inspecting QQ plots. We tried to include morphine intake as a covariate, but this did not change the results or conclusions. We filled missing values with mean values as described in the manuals if less than half of the answers were missing in the SF-36 (PF) and if 2 or fewer of the answers were missing in the OKS, the PSEQ, and the PCS. In each questionnaire missing values were filled with mean values between 0 and 5 times. The significance level was set at < 0.05. The statistical analyses were performed using STATA 15 (StataCorp, College Station, TX, USA) software package. Ethics, registration, data sharing, funding, and potential conflict of interests The study was conducted in accordance with the Declaration of Helsinki and the CONSORT statement, and registered in the Danish Data Protection Agency (j.nr. 1-16-02-245-15). All patients gave informed written consent. The protocol was approved by the Central Denmark Regions Committee on Biomedical Research Ethics (journalno. 1-10-72-64-15, issue date March 25, 2015) and registered at ClinicalTrials. gov (NCT02587429). The study was supported by the Tryg Foundation (grant number: 113944) and the Danish Rheumatism Association (grant number: A3622). None of the funders have any role in the study other than providing funding. The authors have no competing interests. Data is available from the corresponding author on reasonable request.

Results Patient flow From December 2015 to June 2018, 324 patients were considered for inclusion. 283 patients were screened and 105 of these had a PCS score > 22. We randomized 67 patients but shortly after the randomization 7 patients decided not to participate and 60 patients were measured at baseline and included in the analysis (Figure 1). Of the 31 patients randomized to receive the patient education 6 patients received 7 sessions and 25 patients received 6 sessions because of the described change in protocol. The compliance with the intervention was high and only 2 of the 31 patients missed 1 session due to personal circumstances. The 2 groups were similar at baseline (Table 1), except that a substantially higher number of the patients in the pain education group used opioids or morphine.

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ENROLLMENT

Assessed for eligibility n = 324 Excluded (n = 219): – did not answere PCS or < 2 weeks to surgery, 41 – PCS score < 12, 92 – PCS score 12–22, 86 PCS score > 22 n = 105

Excluded (n = 38): – declined participation, 15 – severe depression, 5 – < 2 weeks to surgery, 14 – revision, 1 – inflammatory arthritis, 2 – other project, 1 Randomized n = 67 ALLOCATION

Allocated to intervention (n = 35): – withdrew consent, 4 – baseline measures , 31

Allocated to control (n = 32): – withdrew consent, 3 – baseline measures , 29

FOLLOW-UP

Declined follow-up (n = 4)

Declined follow-up (n = 3)

3 months follow-up (n = 27) 12 months follow-up (n = 27)

3 months follow-up (n = 26) 12 months follow-up (n = 26) ANALYSIS

Included in analysis (n = 31)

Included in analysis (n = 29)

Patients offered 7 sessions (n = 6) Patients offered 6 sessions (n = 25)

Figure 1. CONSORT flowchart of the trial. PCS = Pain Catastrophizing Scale

Outcome measures We found a mean difference of 3 (CI –6 to 11) mm in the primary outcome measure VAS during activity 12 months after TKA between the pain education group and the usual care group (p = 0.6). Mean VAS during activity 12 months postoperatively was 12 mm (CI 5–18) for the pain education group and 9 mm (CI 3–15) for the usual care group (Table 2). Both groups had statistically significant reductions in VAS from baseline to 12 months postoperatively. The pain education group reduced their VAS score during activity by a mean of 37 mm (CI 27–46) and the control group by a mean of 40 mm (CI 31–49) (Figure 2). The estimated group difference in change in VAS during activity from baseline to 12 months postoperatively was a mean of 3 (CI –10 to 16) mm. This difference was not statistically significant, and the CI does not include a clinically relevant difference between the 2 groups. We found no statistically significantly differences between the 2 groups in any of the secondary outcomes (Table 2). In both groups there was a significant effect of time on OKS and PCS. The mean OKS score in the pain education group and

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Table 1. Baseline demographics and characteristics. Values are mean (SD) unless otherwise specified

Pain education Usual care n = 31 n = 29

Women, n Age BMI Civil status, n Cohabiting Living alone Daily smoker, n Alcohol a, n Educational level, n No education < 3 years ≥ 3 years Other Work status, n Employed Sick leave Retired Pain medication in the past week Paracetamol, n Ibuprofen, n Morphine or opioids, n Amount of opioids/day, mg Postoperative, n Operated in knee or hip within 1 year Complications within 30 days b Rehabilitation c Primary outcome VAS during activity Secondary outcome VAS during rest OKS KOOS Pain (n = 58) EQ5D (n = 55), median (range) PSEQ PCS, median (range) 6-minute walk test STS

22 66 (9) 33 (5)

18 66 (10) 33 (7)

25 6 3 5

19 10 4 2

10 8 8 5

10 4 7 8

6 3 22

8 2 19

27 16 10 33 (32)

26 13 2 10 (0)

3 3 1 1 16 14 48 (18)

49 (21)

19 (14) 21 (7) 40 (12) 0.66 (0.16–0.83) 33 (10) 28 (23–48) 387 (106) 10.3 (3.2)

25 (17) 22 (6) 37 (17) 0.72 (–0.14 to 0.83) 34 (8) 29 (23–52) 334 (103) 9.2 (2.8)

a Consumption

above recommendations (more than 1 unit of alcohol per day for women and 2 for men). b Infection or brisement forcé. c Community-based after the operation. VAS, Visual Analog Scale; OKS, Oxford Knee Score; KOOS, Knee Injury and Osteoarthritis Outcome Score; EQ5D, EuroQol-5D; PSEQ, Pain Self-Efficacy Questionnaire; PCS, Pain Catastrophizing Scale; STS, Sit-to-stand in 30 seconds.

Table 2. Primary and secondary outcomes at baseline, 3 and 12 months. The estimates are given as mean values with 95% CI from the linear mixed effect model

Pain education n = 31 n

Primary outcome VAS during activity Baseline 48 (41–55) 3 months 22 (14–30) 12 months 12 (5–18) Secondary outcome VAS during rest Baseline 19 (13–24) 3 months 11 (6–16) 12 months 7 (1–12) Oxford Knee Score Baseline 21 (19–23) 3 months 28 (25–32) 12 months 33 (29–37) KOOS pain Baseline 40 (35–45) 3 months 64 (57–72) 12 months 75 (67–82) EQ-5D Baseline 0.58 (0.52–0.66) 3 months a 0.72 (0.65–0.79) 12 months 0.78 (0.70–0.86) PSEQ Baseline 33 (30–36) 3 months 43 (38–47) 12 months 49 (44–53) PCS Baseline 30 (28–32) 3 months 13 (9–17) 12 months 11 (7–16) 6-minute walk test Baseline 387 (350–424) 3 months 405 (372–438) 12 months 441 (402–480) Sit to stand Baseline 10 (9–11) 3 months 11 (9–13) 12 months 12 (11–14)

31 24 24

49 (42–57) 15 (8–23) 9 (3–15)

29 24 26

31 24 24

25 (19–30) 7 (3–12) 6 (1–12)

29 25 26

31 24 24

22 (20–24) 31 (27–34) 37 (33–41)

29 25 24

31 25 24

37 (32–43) 69 (61–77) 83 (75– 90)

27 22 23

29 24 24

0.62 (0.54–0.70) 26 0.82 (0.78–0.87) 23 0.86 (0.81–0.91) 24

31 25 23

34 (31–38) 47 (43–52) 52 (48–57)

29 25 25

31 25 23

31 (29–33) 11 (7–15) 9 (5–14)

29 25 25

31 24 24

334 (296–372) 375 (342–408) 406 (367–446)

29 25 26

31 24 24

9 (8–10) 10 (8–11) 11 (10–13)

29 25 26

For abbreviations, see Table 1. a p = 0.01

Mean VAS pain score (95% CI) 100 Pain education Usual care

the control group increased by a mean of 13 points (CI 9–16) and by a mean of 15 points (CI 11–18), respectively. The PCS score reduced by a mean 19 (CI 14–24) in the pain education group and by a mean of 22 (CI 17–26) in the control group.

Usual care n = 29

Discussion Participation in patient education in addition to usual care for patients with a high pain catastrophizing score did not result in better outcomes 12 months after TKA. However, for both

Follow-up, months

Figure 2. Pain during activity for the two groups over the study period. Mean Visual Analog Scale (VAS) scores with 95% CI in error bars for the pain education group (green dot) and the usual care group (red dot).

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groups OKS and VAS during activity improved statistically significantly over time indicating that knee function improves and knee pain reduces after a TKA. Recent research on the effect of CBT on pain severity has shown mixed results and meta analyses show that the effect size on pain is small (Dixon et al. 2007, Williams et al. 2012). Some studies report substantial improvements in patients with knee osteoarthritis (Somers et al. 2012, Cai et al. 2018) while others report no effect on pain when comparing a CBT group with a usual care group (Helminen et al. 2015, Broderick et al. 2016, Allen et al. 2019, Riddle et al. 2019). We found no additive effect of pain education based on CBT on pain, physical function, quality of life, self-efficacy, or pain catastrophizing. There may be several reasons for this. 1st, most of the former studies reporting an effect of a CBT intervention on these factors have included patients with knee OA and only a few studies have included patients scheduled for TKA. Cai et al. (2018) found that a CBT program was superior to standard care in reducing kinesiophobia, pain catastrophizing, and knee pain among patients with high levels of kinesiophobia before a TKA. Contrary to this result, Riddle et al. (2019) found that an internet-based pain coping skills program for patients with high levels of pain catastrophizing before TKA did not improve pain or functional outcomes more than usual care. Their conclusion is consistent with that in our study, even though there are differences in the designs. We have a different primary outcome and cut-off regarding PCS. Further, the study from Riddle et al. tested telephone-based pain coping skills training contrary to our study where the patients came to the hospital and met a physiotherapist in person at all sessions. Patients scheduled for an operation may rely on the results of the operation to a great extent, which may result in less motivation for working with cognitive behavioral therapy. These expectations are not the same among patients with chronic knee OA not scheduled for an operation. Research has shown that patients’ baseline expectations regarding the benefit of CBT-based pain coping are associated with the effect of the program, and patients with lower expectation experience only a little benefit from the program (Goossens et al. 2005, Broderick et al. 2016). 2nd, based on existing research suggesting that pain catastrophizing is a predictor of persistent pain after a TKA, we decided to use PCS as a screening tool for inclusion of patients. However, recent research has suggested that patients with elevated scores on more than 1 risk factor are more likely to develop prolonged pain and disability, and that multiple psychological factors need to be considered with respect to pain and physical disability in knee OA (Sinikallio et al. 2014). Further research in this area is needed where pain catastrophizing is not the sole screening tool. We wanted to include the one-third of our TKA population with the highest PCS score. Based on data collected in our department in the years 2011–2013 we defined a cut-off for inclusion at PCS > 22 in this study (Birch et al. 2019).

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The PCS user manual define patients with a PCS > 30 to be at high risk of developing chronic pain. This means that we have included patients with both moderate and high levels of pain catastrophizing. However, an additional analysis showed no correlation between preoperative PCS level and treatment effect (VAS during activity) (tested with Spearman’s rank correlation r = 0.18, p =0.4). Only limited research is available on pain catastrophizing cut-off scores for specific groups of patients. Our intervention consisted of only CBT-based pain education and consistent with the study of Riddle et al. (2019) we found no statistically significant effect of this intervention compared with usual care on any of the outcomes. However, 2 studies have found that CBT-based pain coping combined with either behavioral weight management or exercise demonstrated statistically significantly better outcomes in terms of pain and function compared with PCST (Somers et al. 2012, Bennell et al. 2016). Combining psychological treatment with exercise is in line with the biopsychological approach to chronic pain management and future research may investigate the potential in combining CBT-based pain education with exercise. For the psychological outcomes we expected a larger reduction in PCS and an increase in PSEQ among the patients in the intervention group compared with the usual care group because these issues were emphasized in the pain education. However, this was not the case and both groups achieved similar improvements after 12 months. 3 months after the operation both groups have a PCS score far under 21 points, which is the cuff point for moderate PCS. Limitations There are some limitations too. 1st we had to change the number of sessions from 7 to 6 approximately 1 year after we started including patients. This means that not all patients have received the same number of sessions, but they all received the same content and we found no difference in the primary outcome between patients who received 7 sessions and patients who received 6 sessions. Furthermore, because we wanted to design a method of patient education that fits into a hospital setting, it consisted of only 7 sessions contrary to previous studies where the CBT intervention ranged from 10 to 12 sessions (Keefe et al. 2004). This might have affected the results. 2nd is the lack of blinding to the treatment groups, which was not possible. 3rd, the rather long inclusion period at about 2.5 years. However, there was no change in practice or surgeons during this period, so we do not think this has influenced the results. 4th, only patients with moderate to high pain catastrophizing score were studied and the results of this study cannot be generalized to other populations. Conclusion This study showed that pain education based on CBT was not superior to usual care after TKA in terms of reducing pain or

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improving physical function, quality of life, self-efficacy, and pain catastrophizing. Future research is warranted to identify predictors of persistent pain and interventions for the approximately 20% of patients with persisting pain after a TKA.

The authors would like to thank all the participating patients, nurses, physiotherapists, and secretaries at the University Clinic for Hand, Hip, and Knee surgery and the Department of Physiotherapy and Occupational Therapy, Holstebro Regional Hospital, Hospital Unit West, Denmark. SB, MS, IM, and TBH participated in the conception and design of the study and helped to revise the manuscript. All authors read and approved the final manuscript. Acta thanks Johan Creutzfeldt and Kristian Kjær Petersen for help with peer review of this study.

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Incidence of distal ulna fractures in a Swedish county: 74/100,000 person-years, most of them treated non-operatively Maria MOLONEY 1, Simon FARNEBO 1,3 and Lars ADOLFSSON 2,3 1 Department

of Plastic Surgery, Hand Surgery, and Burns, Linköping University; 2 Department of Orthopaedics, Linköping University; 3 Department of Clinical and Experimental Medicine, Linköping University, Sweden Correspondence: maria.moloney@regionostergotland.se Submitted 2019-01-10. Accepted 2019-09-19.

Background and purpose — Fractures of the distal ulna can occur in isolation or in conjunction with a distal radius fracture. They may result in incongruence and instability of the distal radioulnar joint. We investigated the incidence of distal ulna fractures, whether any fracture types were more common, and the methods of treatment used. Patients and methods — Data were collected from patients 18 years or older, treated for a fracture of the distal ulna in Östergötland, Sweden, during 2010–2012. Patients were identified in the patient registry. The fractures were classified according to the AO comprehensive classification of fractures. Results — The incidence of distal ulna fractures was 74/100,000 person-years. The most common fracture type was that of the ulnar styloid Q1 (79%), followed by the ulnar neck Q2 (11%). Rarest was ulna head fracture, type Q4 (1%). Incidental findings were a mean age of 63 years (SD 18), a concomitant distal radius fracture in 92% of the patients and that 79% were caused by falling from standing height. Internal fixation was performed in 30% of the Q2–Q6 fractures. This indicates that most were considered stable without internal fixation or stable after fixation of a concomitant radius fracture. Interpretation — Our results show that fractures of the distal ulna are not very common, and some fracture types are even rare. There seem to be no consensus on treatment.

Fractures of the distal ulna may result in incongruence and instability of the distal radioulnar joint (DRUJ), which may result in chronic pain or limited forearm rotation (Kvernmo 2014). Fractures of the distal ulna most often accompany a distal radius fracture and in the majority of cases they affect the ulnar styloid process, while fractures of the ulnar head and/ or neck are less common (Ring et al. 2004). Distal radius fractures and concomitant fractures of the distal radius and ulna are commonly caused by a fall from standing height on an outstretched arm with extended wrist. Isolated ulna fractures on the other hand are most often caused by a direct trauma to the ulnar border of the wrist (Richards and Deal 2014). Among patients with a Colles fracture, excluding ulnar styloid fractures, 5.6% have a concomitant fracture of the distal ulna (Biyani et al. 1995). Internal fixation of these fractures is typically difficult (Ring et al. 2004) as the distal fragment in most cases is small, consisting to a large extent of metaphysis and has a 270° articular surface. There is no clear consensus on how fractures of the distal ulna should be treated, and there are currently very few data on healing rate, results of different treatment options, and functional results. This retrospective study investigates the incidence of distal ulna fractures in adults, whether any fracture types are more common according to the AO classification, both in relation to cause of trauma and demographics. We also investigated how frequently operative treatment was the treatment of choice related to the different fracture types.

Patients and methods Data were collected for patients treated for a fracture of the distal ulna, isolated or in combination with a fracture of the © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group, on behalf of the Nordic Orthopedic Federation. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI 10.1080/17453674.2019.1686570

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Table 1. Incidence of distal ulna fractures, divided by AO fracture class, in the region of Östergötland, Sweden, during 2010–2012 Incidence Fracture class n (%) (/100,000 person-years)

Figure 1. Classification of distal ulna fractures according to the AO comprehensive classification.

distal radius, in the county of Östergötland, Sweden, between 2010 and 2012 (430 000 inhabitants). The inclusion criteria were: (1) patients with a fracture of the distal third of ulna from January 1, 2010 to Dececember 31, 2012, (2) being 18 years or older, and (3) residing in the county of Östergötland, Sweden, at the time of injury. For patients who had visited 1 of the 3 emergency units or the 3 orthopedic departments in the area (Linköping University Hospital, Vrinnevi Hospital Norrköping, and Motala Hospital), a diagnosis code according to the ICD-10 system had been recorded in the digital journal system and in the patient registry of Östergötland. In 2015 the patient registry of Östergötland was searched for all ICD-10 codes of a distal forearm fracture (S52.50, S52.51, S52.60, S52.61, S52.20, S52.21, S52.80, S52.81). The radiographs of all patients who had received 1 of these codes were then screened in the digital radiology system to identify everyone who had sustained a fracture of the distal third of the ulna during the defined time period. The cause of trauma and the chosen treatment was also recorded using the referrals and the subsequent radiographs. All images displaying a fracture of the distal third of the ulna but with the exception of styloid fractures were passed on to an independent specialist in radiology for classification. The fractures were classified according to the comprehensive classification of fractures in accordance with the Arbeitsgemeinschaft für Osteosynthesefragen (AO) in which a Q-modifier is used (Müller et al. 1990). Throughout the paper this will be referred to as the AO fracture classification. There are 6 different Q classes of which Q1 refers to styloid fractures (Figure 1). To examine the reliability of the fracture classification a second specialist in radiology examined blinded the radiographs of 20 randomly chosen patients. The 2 radiologists had been specialists in radiology for 32 and 21 years respectively. To calculate the incidence of distal ulna fractures we related the number of fractures to the population in the county of Östergötland during 2010–2012 according to the official Swedish statistics, presented by Statistics Sweden (SCB). The mean population aged 18 or older in Östergötland 2010–2012 was 345 971. To calculate incidence of different fracture types in relation to age we subgrouped the examined patient radiographs into 3 categories: 18–34, 35–64, and 65 or older.

Q1 Q2 Q3 Q4 Q5 Q6 All

607 (79) 83 (11) 28 (4) 5 (1) 16 (2) 27 (4) 766

59 8 3 1 2 3 74

Table 2. Amount and proportion (%) of distal ulna fractures, in the region of Östergötland, Sweden, during 2010–2012, divided by age Fracture class Q1 Q2 Q3 Q4 Q5 Q6 Concomitant radius fracture

18–34 years 35–64 years ≥ 65 years (n = 67) (n = 307) (n = 392) 57 (85) 4 (6) 0 (0) 0 (0) 1 (1) 5 (7)

263 (86) 25 (8) 5 (2) 2 (1) 5 (2) 7 (2)

287 (73) 54 (14) 23 (6) 3 (1) 10 (3) 15 (4)

58 (87)

281 (92)

372 (95)

Ethics, funding, and potential conflicts of interest The study protocol was reviewed and approved by the Regional Ethical Review Board in Linköping (Dnr 2014/20031). The authors received no financial support, and declare no conflicts of interest.

Results We found 766 patients who had sustained a fracture of the distal ulna during the observation period. Of these, 607 had a fracture of the styloid process, and 159 a fracture of the distal third of the diaphysis, metaphysis, or ulnar head (Table 1). The overall incidence of distal ulna fractures in Östergötland was 74/100 000 person-years during 2010–2012. The most common fracture type was a fracture of the ulnar styloid, Q1 (79%), followed by a fracture of the ulnar neck, Q2 (11%). Ulnar head fracture Q4 (1%) was the rarest fracture type. Patients 65 years or older were less likely to have a Q1 fracture when compared with the intermediate and younger groups, as presented in Table 2. Patients aged 65 years or older more commonly than the other age groups had a Q2 fracture (14%) or a Q3 fracture (6%). In patients aged 18–34 years fracture types Q3 and Q4 were not found and only 1 patient had a Q5 fracture (Table 2). The 2 radiologists agreed 70% on classification. The most common disagreement was between Q2 and Q6 where there

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Table 3. Cause of injury in distal ulna fractures, in the region of Östergötland, Sweden, during 2010–2012, divided by AO fracture class Cause of injury

Q1 Q2 Q3 Q4 Q5 Q6 Total (%)

Motor vehicle accident Bike accident Fall from standing height Fall from height Blunt trauma Forced rotation Unknown No trauma

11 3 0 12 2 0 485 63 27 57 5 0 16 4 0 3 0 0 22 5 1 1 1 0

0 0 5 19 (2.5) 0 0 1 15 (2.0) 3 15 11 604 (79) 1 1 2 66 (8.6) 0 0 5 25 (3.3) 0 0 1 4 (0.5) 1 0 2 31 (4.0) 0 0 0 2 (0.3)

Table 4. Cause of injury in distal ulna fractures, in the region of Östergötland, Sweden, during 2010–2012, divided by age, n (%) Fracture class

18–34 years 35–64 years ≥ 65 years (n = 67) (n = 307) (n = 392)

Motor vehicle accident 13 (19) Bike accident 5 (7) Fall from standing height 27 (40) Fall from height 7 (10) Blunt trauma 10 (15) Forced rotation 1 (1) Unknown 4 (6) No trauma 0 (0)

3 (1) 5 (2) 237 (77) 31 (10) 10 (3) 3 (1) 17 (6) 1 (0)

3 (1) 5 (1) 340 (87) 28 (7) 5 (1) 0 (0) 10 (3) 1 (0)

Table 5. Treatment of distal ulna fractures AO class Q2–Q6, in the region of Östergötland, Sweden, during 2010–2012, n (%)

Table 6. Treatment of concomitant fractures of distal radius and ulna AO class Q2–Q6

Concomitant Operated Operated Operated Total Ulna radius only only radius operated Fracture fracture fracture radius ulna + ulna ulna

Radius Operated Operated Both + ulna ulna radius fractures Fracture fracture only only operated

Q2 Q3 Q4 Q5 Q6 Total

83 28 5 16 27 159

65 (78) 26 (93) 5 (100) 16 (100) 10 (37) 122 (77)

22 (27) 1 (4) 2 (40) 7 (44) 2 (7) 34 (21)

6 (7) 1 (4) 0 (0) 0 (0) 3 (11) 10 (6)

13 (16) 11 (39) 3 (60) 5 (31) 6 (22) 38 (24)

is no clear landmark defining where the ulnar neck ends and the diaphysis begins. If Q2 and Q6 are considered as the same group the assessors agreed in 90% of the cases. Disagreements were solved by consensus discussion. The mean age at the time of injury was 63 years (SD 18). 76% of the patients were women. 44% had injured their right wrist. 92% also had a fracture of the radius, almost always the distal radius. Of the fractures in the ulnar head and neck (Q2– Q6) 77% had also sustained a distal radius fracture, compared with 98% of the patients with an ulnar styloid fracture (Q1). Fracture classes Q4 and Q5 were found always to have a concomitant radius fracture whereas only one-third of class Q6 also had a radius fracture. A concomitant distal radius fracture was found in 95% of the patients aged 65 years or older, and in 87% of the patients aged 18–34 years. The main type of trauma was a fall from standing height on an outstretched arm with an extended wrist, which was the cause in 79% of the patients, followed by fall from a height. The high-energy trauma of road traffic accidents and also blunt trauma including being beaten or kicked always resulted in a simple fracture to the neck or proximal ulna (Q2 and Q6), in no case being comminuted or including the ulnar head (Table 3). In patients aged 65 years and older the fracture was a result of a fall from standing height in 87%. The second most common cause of injury in this group was fall from a height and all other causes were very rare (0–3%). High-energy trauma was more common in patients aged 18–34 years. Noticeably, a fall

19 (23) 12 (43) 3 (60) 5 (31) 9 (33) 48 (30)

65 0 22 13 26 0 1 11 5 0 2 3 16 0 7 5 10 0 2 6 122 0 34 38

from standing height was not found to result in a fracture of class Q2–Q6 in this age group, only fractures of class Q1. The trauma in patients aged between 35 and 64 years, resembled that in the older age group (Table 4). Of all the patients with Q2–Q6 fractures 30% were treated operatively with internal fixation of the ulna fracture. Fracture class Q4 (3/5) and Q3 (12/28) were most commonly surgically treated. Internal fixation was performed in 10 patients with an isolated ulna fracture. Out of these there were 6 Q2, 3 Q6, and 1 Q3 (Table 5). All operated ulna fractures that had a concomitant radius fracture also had internal or external fixation of the radius fracture, most commonly a volar plate and screws. In some cases only the radius fracture was internally fixed and the ulna fracture treated non-operatively; for example with fractures of class Q2 and Q5 it was more common only to repair the radius rather than to internally fix both fractures (Table 6).

Discussion Fractures of the distal ulna are not very common, especially when excluding fractures of the ulnar styloid, and are most often found with a concomitant distal radius fracture. Our findings showed an incidence of 74/100 000 person-years in adults living in Östergötland, Sweden, during 2010–2012. Most common were fractures of the ulnar styloid (79% Q1)

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followed by fractures of the ulnar neck (11% Q2). Herzberg and Castel (2016) found that, excluding styloid fractures, 9% of patients with a distal radius fracture also have a distal ulna fracture. They defined the distal ulna as the ulnar head and neck without further specification and not the distal third of the ulna as in the present study. 5.9% were a fracture of the ulnar neck, 1.6% a fracture of both the head and neck, and 1.4% a fracture of ulnar head (Herzberg and Castel 2016). Simultaneous fractures of both radius and ulna could negatively affect the outcome by causing problems of incongruence of the DRUJ and increase the risk of nonunion. Styloid process fractures that include metaphysis often heal; however, when the styloid process is fractured separately from the metaphysis it often does not (Biyani et al. 1995). Knowledge regarding isolated ulna fractures is limited. Williams and Friedrich. (2011) investigated isolated distal ulna fractures retrospectively and could not find any substantial difference between operative and non-operative treatment when it came to bone healing and complications. They did not investigate the functional results, which may be most important to the patient, and the follow-up was only 36 weeks. Cha et al. (2012) studied a cohort of patients above 65 years of age. They found no difference in healing, pain, or function when comparing an operative plate fixation of the ulna fracture or non-operative treatment at the same time as an internal fixation of a radius fracture. Logan and Lindau (2008) concluded that isolated fractures of the ulnar head with disruption of the articular surface or instability should be operated and internally fixed, preferably after a CT scan. For fractures within 5 cm from the ulnar head that are considered stable, and fractures that become stable after fixation of a concomitant radius fracture, non-operative treatment was recommended. For unstable fractures, on the other hand, operation with open reduction and internal fixation was considered indicated. Logan and Lindau, however, also concluded that the knowledge regarding optimal treatment for intraarticular fractures of the distal ulna is limited. The general recommendation is, however, always to try to restore and keep the ulnar head and DRUJ intact, and only as a last resort resect or replace the ulnar head with a prosthesis. The typical patient with a distal ulna fracture is a postmenopausal woman who falls from standing height on an extended wrist and suffer a fracture of the distal radius and the ulnar styloid in her left hand. When the ulnar styloid fractures are excluded, the most common fracture is that of the ulnar neck (Q2). Our finding (an incidence of 74/100 000 person-years in adults) can be compared with the incidence of distal radius fractures, which has been reported to be 258/100 000 personyears in a Finnish study from 2010 including patients aged 16 years or older. That study suggests that distal radius fractures are more than 3 times as common as distal ulna fractures (Flinkkila et al. 2011). We extended our search of diagnosis codes to all distal forearm fractures to identify potentially miscoded fractures. We therefore believe that the risk of miss-

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ing patients who sought medical care for a distal ulna fracture would be small, and it appears unlikely that patients with a fracture have not been to hospital for treatment. Every medical record of a patient seeking medical care undergoes several controls to ascertain that a diagnostic code is reported but the completeness of the registry of diagnose codes in Östergötland has not been validated, which may be considered a potential limitation of our study. Östergötland is a county with more than 2/3 of the population living in cities or densely populated areas and may be considered representative of the majority of the country. The mechanism of injury is most often a fall from standing height. In the older population this could cause fractures of all classes, whereas in the younger population almost exclusively fractures were of type Q1, indicating that more energy is needed for a fracture of class Q2–Q6 to occur in younger individuals. Not surprisingly we found the distal ulna fractures to be more common in females than males and that the average age was 63. This indicates that, just like distal radius fractures, distal ulna fractures can also at least partially be explained by osteoporosis in postmenopausal women. Isolated ulna fractures were more common in patients 34 years and younger and were more often of fracture class Q2 and Q6 when compared with all age groups. Only one-third of the ulna fractures were operated, showing that most were considered either stable without internal fixation or stable after a concomitant radius fracture was internally fixed. Proper classification may be of importance to determine the appropriate treatment and assess the prognosis for the patient. We found the AO classification we used to be incomplete in some respects. This is an obvious limitation to our study, where our radiologists for example found it difficult to separate the classes Q2 and Q6 since there is no distinguishing landmark between the 2. Also, some fractures did not fit well into either class. Often these fractures were multifragmented. Furthermore, the classification does not consider the amount of dislocation, which might be of importance when considering treatment options. Since this study was performed in 2015 the AO classification has been revised and the new version from 2018 addresses the dislocation of fractures of the ulnar neck (Meinberg et al. 2018). Whether or not it covers all distal ulna fractures in a better way is yet to be studied. A third of the fractures of the distal ulna (excluding the styloid) in our material were operated and internally fixed. We cannot from the present study conclude on appropriateness of the chosen treatment. There is a need for further studies regarding treatment, healing rate, and functional results of fractures of the distal ulna. All authors have contributed to the study and read and approved the finished manuscript before submission. MM and LA designed the study. MM collected and analyzed the data, and wrote the manuscript. SF and LA contributed with analyzing data and revising the manuscript.

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The authors would like to thank the radiologists Jan Kåredal and Tomas Persson for help with examining radiographs and classifying fractures. Acta thanks Hanne L Dalsgaard and Daniel Jerrhag for help with peer review of this study.

Biyani A, Simison A J, Klenerman L. Fractures of the distal radius and ulna. J Hand Surg Br 1995; 20(3): 357-64. Cha S M, Shin H D, Kim K C, Park E. Treatment of unstable distal ulna fractures associated with distal radius fractures in patients 65 years and older. J Hand Surg Am 2012; 37(12): 2481-7. Flinkkila T, Sirnio K, Hippi M, Hartonen S, Ruuhela R, Ohtonen P, et al. Epidemiology and seasonal variation of distal radius fractures in Oulu, Finland. Osteoporos Int 2011; 22 (8): 2307-12. Herzberg G, Castel T. [Incidence of distal ulna fractures associated with distal radius fractures: treatment options]. Hand Surg Rehabil 2016; 35S: S69-S74.

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Logan A J, Lindau T R. The management of distal ulnar fractures in adults: a review of the literature and recommendations for treatment. Strategies Trauma Limb Reconstr 2008; 3(2): 49-56. Kvernmo H D. Associated fractures of the distal ulna. In: Hove L M, Lindau T, Homer P, eds. Distal radius fractures. Berlin/Heidelberg: Springer; 2014. p. 383-90. Meinberg E G, Agel J, Roberts C S, Karam M D, Kellam J F. Fracture and dislocation classification compendium—2018. J Orthop Trauma 2018; 32(Suppl 1): S1-S170. Müller M E, Koch P, Nazarian S, Schatzker J. Radius/ulna = 2. In: The comprehensive classification of fractures of long bones. Berlin/Heidelberg. Springer; 1990. Richards T A, Deal D N. Distal ulna fractures. J Hand Surg Am 2014; 39 (2): 385-91. Ring D, McCarty L P, Campbell D, Jupiter J B. Condylar blade plate fixation of unstable fractures of the distal ulna associated with fracture of the distal radius. J Hand Surg Am 2004; 29 (1): 103-9. Williams E A, Friedrich J B. Retrospective analysis demonstrates no advantage to operative management of distal ulna fractures. Hand (NY) 2011; 6 (4): 378-83.

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20-year trends of distal femoral, patellar, and proximal tibial fractures: a Danish nationwide cohort study of 60,823 patients Veronique VESTERGAARD 1–3, Alma Becic PEDERSEN 4, Peter Toft TENGBERG 2, Anders TROELSEN 2, and Henrik Morville SCHRØDER 1 1 Department

of Orthopaedic Surgery, Slagelse Hospital, Næstved, Slagelse and Ringsted Hospitals, Slagelse, Denmark; 2 Department of Orthopaedic Surgery, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark; 3 The Harris Orthopaedics Laboratory, Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA; 4 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Correspondence: veronique.julia.vestergaard@gmail.com Submitted 2019-09-27. Accepted 2019-11-08.

Background and purpose — Knee fracture treatment burden remains unknown, impeding proper use of hospital resources. We examined 20-year trends in incidence rates (IRs) and patient-, fracture-, and treatment-related characteristics of knee fracture patients. Patients and methods — This nationwide cohort study of prospectively collected data including patients with distal femoral, patellar, and proximal tibial fractures from the Danish National Patient Registry during 1998–2017, assesses IRs of knee fractures (per 105 inhabitants) as well as patient-, fracture-, and treatment-related characteristics of knee fracture patients. Results — During 1998–2017, 60,823 patients (median age 55; 57% female) sustained 74,106 knee fractures. 74% of the study population had a Charlson Comorbidity Index (CCI) of 0 and 18% a CCI of ≥ 2. 51% were proximal tibial fractures, 31% patellar fractures, and 18% distal femoral fractures. At the time of knee fracture, 20% patients had concomitant near-knee fractures (femur/tibia/fibula shaft/ hip/ankle), 13% concomitant fractures (pelvic/spine/thorax/ upper extremities), 5% osteoporosis, and 4% primary knee osteoarthritis. Over 1/3 knee fractures were surgically treated and of these 86% were open-reduction internal fixations, 9% external fixations, and 5% knee arthroplasties. The most common surgery type was proximal tibia plating (n = 4,868; 60% female). Knee fracture IR increased 12% to 70, females aged > 51 had the highest knee fracture IR, proximal tibial fracture had the highest knee fracture type IR (32) and surgically treated knee fracture IR increased 35% to 23. Interpretation — Knee fracture IRs, especially of surgically treated knee fractures, are increasing and proximal tibial fracture has the highest knee fracture type IR. Females aged > 51 and patients with comorbidity are associated with knee fracture, proximal tibial fracture, proximal tibial fracture surgery, and posttraumatic knee arthroplasty.

Knee fractures include fractures in the distal femur, patella, and proximal tibia, with a reported incidence rate (IR) of approximately 9/105 per year in the United States (Lambers et al. 2012). Knee fractures vary in type and complexity and often result in lower function, work performance, and healthrelated quality of life (Van Dreumel et al. 2015, Sluys et al. 2016). Previous studies are limited to small sample sizes, lower extremity fractures, tibial plateau fractures, patellar fractures, or proximal tibia fractures (Court-Brown and Caesar 2006, Scholes et al. 2014, Elsoe et al. 2015, Larsen et al. 2016, Wennergren et al. 2018). To our knowledge, there are no population-based studies describing IRs of knee fractures over time, either overall or according to sex, age, knee fracture type, and treatment type. Estimation of treatment burden of knee fractures for subsequent allocation of hospital resources requires knowledge of epidemiology and IRs. We conducted a national cohort study to examine 20-year trends in incidence rates (IRs) and patient-, fracture-, and treatmentrelated characteristics of knee fracture patients in Denmark during 1998–2017.

Patients and methods Study design and data sources The study was designed as a nationwide cohort study of prospectively collected data from the Danish Civil Registration System (CRS) and Danish National Patient Registry (DNPR) (Schmidt et al. 2014, 2015). The CRS contains complete information on Danish Civil Personal Register (CPR) number, residency, and emigration and is updated daily with vital status. The DNPR contains information on hospital admissions, emergency department visits, admission date, CPR number, age, sex, WHO ICD-10 classification, and the Danish version of the Nordic Medico-Statistical Committee Classification of Surgical Proce-

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dures (NOMESCO) (WHO 2019, NOMESCO 2019). The current NOMESCO classification was implemented in 1995; we therefore excluded the years before 1996 to reduce surgery code bias, and years 1996–1997 to exclude a potential backlog of already prevalent knee fracture cases with hospital follow-up. Data on the population were divided by sex and age for each calendar year of 1998–2017 (Statistics Denmark 2019). Study population The study population consisted of patients registered in the DNPR from January 1, 1998 to December 31, 2017 with hospital contacts for ICD-10 codes DS724, DS820, and DS821 (knee fracture patients) with/without subsequent knee surgery NOMESCO code(s) (Appendix 1, see Supplementary data). Figure 1 provides a definition of new knee fracture, surgically treated knee fracture, and non-surgically treated knee fracture. Surgically treated knee fractures were divided into 3 surgery types: open reduction internal fixation (ORIF), external fixation, and knee arthroplasty. The updated version of the Charlson Comorbidity Index (CCI) was used to evaluate comorbidity (Bjorgul et al. 2010, Quan et al. 2011). Statistics The study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement guidelines (von Elm et al. 2014). Proportions, median, and interquartile range (IQR) were used to describe the study population. We estimated annual overall IRs of knee fractures with 95% confidence intervals (CIs) as the number of knee fractures per calendar year divided by the total number of individuals at risk in Denmark in that same year. All IRs were calculated/105 inhabitants. Annual IRs were calculated according to sex, age group, knee fracture type, and surgery type. Poisson regression was used to estimate incidence rate ratios (IRRs) with 1998 as year of reference. IRR expressed the relative change in IRs of knee fractures in 1999–2017 compared with year 1998 as reference IRR. All analyses were performed using the statistical software R 3.4.2 (R Foundation for Statistical Computing, Vienna, Austria). Ethics, registration, funding, and potential conflicts of interest The study was approved by Danish Data Protection Agency, record number REG-085-2017. The study was funded by P. Carl Petersen Foundation, Danish Rheumatism Association, Research Unit Naestved, Slagelse and Ringsted Hospitals, Production, Research and Innovation Naestved, Slagelse and Ringsted Hospitals, Data and Development Support Region Zealand, Naestved, Slagelse and Ringsted Hospitals’ Research Fund, and Clinical Orthopaedic Research Hvidovre, Hvidovre Hospital. Funding sources were not involved in study design, collection, analysis, interpretation, and completion. The authors declare no conflicts of interest regarding this study.

Knee fracture code/s at hospital admission No

Yes

Surgery code at hospital admission

Initiated non-surgical treatment for knee fracture No

Yes

Surgery code within 6 months of hospital admission

New knee fracture code/s within 6 months of hospital admission

New knee fracture

Yes

Non-surgical treatment for knee fracture

Surgical treatment for knee fracture

Figure 1. Definition of new knee fracture, surgically treated knee fracture and non-surgically treated knee fracture.

Results Overall incidence rates Average IR (per 105 inhabitants) for sustaining knee fracture during 1998–2017 was 63 (CI 62–63). IR for knee fracture was 64 (CI 61–66) in 1998, remaining stable in the following years and increasing from year 2010 up to 70 (CI 67–72) in 2017, corresponding to a 12% increase (Figure 2). The corresponding IRR was 1.1 (CI 1.0–1.2) in 2017 compared with 1998 (Table 1, see Supplementary data). Incidence rates by sex and age IR of knee fractures in females increased from 70 (CI 67–73) in 1998 to 83 (CI 80–86) in 2017. IR in males decreased slightly from 58 (CI 55–61) in 1998 to 57 (CI 54–60) in 2017 (Figure 3). The corresponding IRR was 1.2 (CI 1.1–1.3) for females and 1.0 (CI 0.9–1.1) for males in 2017 compared with 1998. During 1998–2017, IR for knee fractures was highest among females aged > 71 (IR decreased from 240 (CI 223–258) in 1998 to 223 (CI 209–239) in 2017). During 1998–2017, IR increased in females aged 51–70 years (IR increased from 95 [CI 87–103] to 124 [CI 116–132]), children aged 0–5 years (IR in females aged 0–5 years increased from 23 [CI 17–30] to 78 [CI 66–93] and IR in males aged 0–5 years increased from 24 [CI 19–32] to 71 [CI 60–84] and females and males aged 6–18 (IR in females increased from 31 [CI 26–37] to 38 [CI 33–44] and IRs in males increased from 57 [CI 50–65] to 70 [CI 63–79]). Incidence rates by knee fracture type During 1998–2017, average IR for proximal tibia fracture was 32 (CI 31–32), average IR for patella fracture was 21 (CI 21–21) and average IR for distal femur fracture was 12 (CI 12–12). IR for proximal tibia fracture increased over time,

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111

Incidence rate per 105 inhabitants

100

Female sex Male sex

0 2000

2005

Year

2010

Figure 2. Incidence rate of knee fractures per 105 inhabitants during 1998–2017 with 95% confidence intervals.

0 2000

2015

Proximal tibial fracture Patellar fracture Distal femoral fracture

2005

Year

2010

2015

2000

2005

Year

2010

2015

Figure 3. Incidence rates of knee fractures per Figure 4. Incidence rates of knee fractures per 105 inhabitants during 1998–2017 by knee 105 inhabitants during 1998–2017 by sex. fracture type.

Incidence rate per 105 inhabitants

Number of persons

100 90

Non-surgically treated Surgically treated

Female sex Male sex

3,000

80 2,500

70 2,000

60 50

1,500

40 1,000

30 20

500

10 0

0 2000

2005

Year

2010

2015

100

Age

Figure 5. Incidence rates of surgically and non-surgically treated knee fractures per 105 inhabitants during 1998–2017.

Figure 6. Sex and age distribution of the study population registered in the Danish National Patient Registry during 1998–2017.

especially after 2010, whereas IRs for patella fracture and distal femur fracture remained stable (Figure 4).

Patient-, fracture-, and treatment-related characteristics During 1998–2017, 60,823 patients sustained 74,106 knee fractures (Table 2, see Supplementary data). Median study population age was 55 (IQR 30–72), being 64 years (IQR 46–78) in females and 42 years (IQR 19–59) in males. 57% of knee fracture patients were female. Children aged 0–5, males aged 5–50, and females aged > 50 had highest risk of knee fracture (Figure 6). 74% of the study population had CCI 0, 8% CCI 1, and 18% CCI ≥ 2. At the time of knee fracture, 20% of knee fracture patients were registered with concomitant near-knee fractures (femur/tibia/fibula shaft/hip/ ankle), of which tibia shaft fracture (5%) and femur shaft fracture (4%) were most frequent, while 13% of knee fracture patients were registered with concomitant fractures (pelvic/ spine/thorax/upper extremities) (Appendix, see Supplementary data). At the time of knee fracture, 10% of patients were registered with lesions inside the knee, 5% with osteoporosis,

Incidence rates by treatment type Average IR for surgically treated knee fractures was 21 (CI 21–21). IR for surgically treated knee fractures was 17 (CI 16–18) in 1998 increasing to 23 (CI 22–24) in 2017, corresponding to a 35% increase (Figure 5). The corresponding IRR for surgically treated knee fracture was 1.4 (CI 1.2–1.5) in 2017 when comparing 2017 with reference year 1998. Average IR for non-surgically treated knee fractures was 42 (CI 41–42). IR for non-surgically treated knee fractures was 47 (CI 45–49) in 1998 and 47 (CI 45–49) in 2017, remaining stable during the 20-year period (Figure 5). The corresponding IRR for non-surgically treated knee fracture was 1.0 (CI 1.0–1.1) in 2017 when comparing 2017 with reference year 1998.

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Table 3. Distribution of knee fracture type in the study population including surgically and non-surgically treated knee fractures in the DNPR during 1998–2017. Values are frequency (%) Knee fracture type

Study population n = 74,106

Surgically Non-surgically treated treated n = 24,215 n = 46,397

Proximal tibia Patella Distal femur

38,080 (51) 22,689 (31) 13,337 (18)

12,175 (50) 5,977 (24) 6,063 (25)

22,411 (48) 16,712 (36) 7,274 (16)

Table 4. Frequency, age and sex distribution of most frequent knee fracture surgery types registered in the DNPR during 1998–2017 Knee fracture surgery type n

Median Female age (IQR) sex (%)

Proximal tibia plate and screws 4,868 Patella wiring 4,592 Proximal tibia screw fixation 3,635 Distal femur plate and screws 2,517 Distal femur intramedullary nail 1,350 Primary cemented knee arthroplasty 855

57 (45–67) 61 (44–72) 50 (32–63) 74 (61–85) 75 (59–85) 68 (59–76)

60 58 50 73 74 74

DNPR = Danish National Patient Registry. IQR = interquartile range.

and 4% with primary knee osteoarthritis (OA) (Appendix, see Supplementary data). The most common knee fracture type was proximal tibia fracture (51%), followed by patella fracture (31%) and distal femur fracture (18%). Table 3 shows distribution of knee fracture type in the study population including surgically and non-surgically treated knee fractures in the DNPR during 1998–2017. 90% of patients had 1 knee fracture registered and 11% patients had > 1 knee fracture registered. The total number of knee fracture treatments was 68,419 (some treatments covered multiple knee fractures). Of these 68,419 treatments, 34% were surgical treatments and 66% non-surgical treatments. 6% of knee fracture patients received both surgical and non-surgical treatments. 89% patients had 1 knee fracture surgery and 11% had > 1 knee fracture surgery. In non-surgically treated patients, the corresponding numbers were 96% with 1 non-surgical knee fracture treatment and 4% with > 1 non-surgical treatment. 22,996 surgeries were performed on 24,215 knee fractures in 20,350 patients during 1998–2017. In surgically treated patients, median population age was 59 years (IQR 42–72) and median age for females was 66 (IQR 54–77). Of surgically treated knee fractures, 86% surgeries were ORIFs, 9% external fixations, and 5% knee arthroplasties. Table 4 presents frequency, age, and sex distribution of the most frequent knee fracture surgery types registered in the DNPR during 1998–2017.

Discussion Study limitations Information bias, i.e., misclassifications of diagnosis codes and missing/incomplete data in variable and diagnosis registrations by discharging physicians, is present in registry studies. Fortunately, both ICD-10 and NOMESCO classifications are used to identify knee fracture patients, registering to DNPR is improving, reporting to DNPR is mandatory and is used for reimbursement by public and private hospitals (although knee fracture patients are not treated in the Danish private sector), and DNPR data quality is high with orthopedic diagnoses having the highest positive predictive value: 91% (Schmidt et al. 2015). Another study limitation is incomplete laterality

registration in DNPR, likely producing overestimated IRs, but random variation cannot be excluded. The same applies for ABC extensions of ICD-10 codes: only a small percentage of the study population was registered with ABC extensions, thus distributions of knee fracture subtypes could not be described (Schmidt et al. 2015). IRs calculated at the beginning of the study period might be inflated because it is unknown if they are incidences or a backlog of prevalent knee fractures with hospital follow-up. Nevertheless, the possible error in average IR for the period decreases over the long 20-year study period. The overestimations are also reduced by the 6-month washout period (Figure 1). The 6-month wash-out period is likely not too short because only 11% patients had > 1 knee fracture registered. The study was a 20-year, nationwide cohort study of knee fracture patients from a relatively homogenous population, providing results of high external validity. Overall incidence rates The knee fracture IR was approximately 9/105 per year in the United States (Lambers et al. 2012). The IR was ~60/105 inhabitants in our study (Figure 2). However, the American study included only data from emergency department visits in a population sample. Incidence rates by sex, age, knee fracture type, and treatment type In our study, increasing knee fracture IRs were seen in females aged > 51 and > 71 and both sexes aged 0–18. A national Danish study of fracture incidences reported increases in IRs of lower extremity fractures in males aged < 50, females aged > 50, and both sexes aged > 75 (Driessen et al. 2016). This was a 1-year study and did not discriminate between proximal tibia and distal femur fractures; it can therefore only partly be extrapolated to our results. A British single-center study calculated IRs/105 personyears at risk (PYRS) for distal femoral, patellar, and proximal tibial fractures in patients aged > 65 (Court-Brown et al. 2014). Their IRs ranged between 8 and 37 compared with our IRs of 12–32/105 inhabitants. As in our study, older patient groups had high knee fracture IRs, especially older females, and proximal tibia had a high knee fracture type IR.

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Our demographic data accord with a Swedish tibial fracture study in which proximal tibia fracture patients were more likely to be females (58%) with higher mean age (54) (Wennergren et al. 2018). The average IR for proximal tibia fracture was 27/105 PYRS, which is comparable to our results: 32/105 inhabitants. Our results mirror the results of the Swedish study regarding increase in proximal tibia fracture IR, higher IRs of females with increasing age compared with males, and more flatlined IR knee fracture curves in males. A Danish tibial plateau fracture study demonstrated that intra-articular proximal tibia fractures present a treatment burden, showing increased tibial plateau fracture IRs in males aged < 50 and females aged > 50 (Elsoe et al. 2015), which echoes our results of higher IRs in proximal tibia fractures and higher knee fracture IRs in females aged > 51. Driessen et al. (2016) calculated an annual patella fracture IR in Denmark: 33/105 PYRS. Larsen et al. (2016) studied patella fractures where IRs varied between 11 and 17/105 PYRS and females aged 60–80 had the highest patella fracture IR. Our results show a similar trend in high patella fracture IR (21) and that the highest knee fracture IRs are seen in females aged > 51 and > 71. Remaining discrepancies in results can be explained by different study period lengths and in geographical differences. Improvement in registrations to the DNPR, increased societal demand for invasive orthopedic treatments, i.e., surgical treatments of knee fractures and broader inclusion of comorbidly challenged patients with a lower threshold for knee fracture surgery, might explain the 35% increase in surgically treated knee fracture IR. Most patients (89%) had only 1 knee fracture surgery, making double registrations an unlikely contributor to IR increase. Patient-, fracture-, and treatment-related characteristics of knee fracture patients At the time of knee fracture, 18% patients had CCI ≥ 2, 1/5 concomitant near-knee fractures, 13% concomitant fractures, 5% osteoporosis, and 4% primary knee OA. Females aged > 51 and patients with comorbidity are associated with sustaining knee fracture, especially proximal tibial fracture, surgical treatment for knee fracture, proximal tibial fracture surgery, and posttraumatic TKA (Table 4), making our results similar to trends described in current literature with knee fractures and TKA procedures being most frequent in older females (CourtBrown and Caesar 2006, Court-Brown et al. 2014, Kremers et al. 2014, Elsoe et al. 2015, Larsen et al. 2016, Driessen et al. 2016, Krause et al. 2016, Wennergren et al. 2018). Conclusion In this 20-year nationwide cohort study, we observed that overall IR of knee fracture increased 12% to 70/105 inhabitants while IR of surgically treated knee fracture increased 35% to 23/105 inhabitants. Our findings reflect the complexity of the knee fracture population with future challenges con-

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cerning treatment burden, increasing incidences, and patient risk groups and provide the basis for proper hospital resource allocations including computing future risk-adjustment and payment models. Supplementary data Appendix and Tables 1–2 are available as supplementary data in the online version of this article, http://dx.doi.org/10.1080/ 17453674.2019.1698148. VV planned the study, wrote the protocol, obtained permission from the Danish Data Protection Agency, secured data from CRS and DNPR, performed statistical analysis, and drafted and revised the article. ABP planned the study, revised the protocol, and revised the article. PTT planned the study and revised the article. AT planned the study, revised the protocol, and revised the article. HMS planned the study, revised the protocol, and revised the article. The authors would like to thank Thomas Kallemose, MSc, and Håkon Sandholdt, MSc, for statistical groundwork. Acta thanks Charles Court-Brown for help with peer review of this study.

Bjorgul K, Novicoff W M, Saleh K J. Evaluating comorbidities in total hip and knee arthroplasty: available instruments. J Orthop Traumatol 2010: 203-9. Court-Brown C M, Caesar B. Epidemiology of adult fractures: a review. Injury 2006: 691-7. Court-Brown C M, Clement N D, Duckworth A D, Aitken S, Biant L C, McQueen M M. The spectrum of fractures in the elderly. Bone Joint J 2014; 96 B(3): 366-72. Driessen J H M, Hansen L, Eriksen S A, van Onzenoort H A W, Henry R M A, van den Bergh J, Abrahamsen B, Vestergaard P, de Vries F. The epidemiology of fractures in Denmark in 2011. Osteoporos Int 2016 ;27(6): 2017-25. Elsoe R, Larsen P, Nielsen N P H, Swenne J, Rasmussen S, Ostgaard S E. Population-based epidemiology of tibial plateau fractures. Orthopedics 2015; 38(9): e780-6. Krause M, Preiss A, Müller G, Madert J, Fehske K, Neumann M V, Domnick C, Raschke M, Südkamp N, Frosch K H. Intra-articular tibial plateau fracture characteristics according to the “Ten segment classification.” Injury 2016; 47(11): 2551-7. Kremers H M, Larson D R, Crowson C S, Kremers W K, Washington R E, Steiner C A, Jiranek W A, Berry D J. Prevalence of total hip and knee replacement in the United States. J Bone Joint Surg Am 2014; 97(17): 1386-97. Lambers K, Ootes D, Ring D. Incidence of patients with lower extremity injuries presenting to US emergency departments by anatomic region, disease category, and age. Clin Orthop Relat Res 2012; 470(1): 284-90. Larsen P, Court-Brown C M, Vedel J O, Vistrup S, Elsoe R. Incidence and epidemiology of patellar fractures. Orthopedics 2016; 39(6) :e1154-8. NOMESCO. http//medinfo.dk/sks/brows.php. Accessed March 9, 2019. Quan H, Li B, Couris C M, Fushimi K, Graham P, Hider P, Januel J M, Sundararajan V. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol 2011; 173(6): 676-82. Schmidt M, Pedersen L, Sørensen H T. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol 2014: 541-9. Schmidt M, Schmidt S A J, Sandegaard J L, Ehrenstein V, Pedersen L, Sørensen H T. The Danish National patient registry: a review of content, data quality, and research potential. Clin Epidemiol 2015: 449-90.

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Scholes S, Panesar S, Shelton N J, Francis R M, Mirza S, Mindell J S, Donaldson L J. Epidemiology of lifetime fracture prevalence in England: a population study of adults aged 55 years and over. Age Ageing 2014; 43(2): 234-40. Sluys K P, Shults J, Richmond T S. Health related quality of life and return to work after minor extremity injuries: a longitudinal study comparing upper versus lower extremity injuries. Injury 2016; 47(4): 824-31. Statistics Denmark. https//m.statbank.dk/. Accessed March 9, 2019. Van Dreumel R L M, Van Wunnik B P W, Janssen L, Simons P C G, Janzing H M J. Mid- to long-term functional outcome after open reduction and

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internal fixation of tibial plateau fractures. Injury 2015; 46(8): 1608-12. von Elm E, Altman D G, Egger M, Pocock S J, Gøtzsche P C, Vandenbroucke J P. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Int J Surg 2014; 12(12): 1495-9. Wennergren D, Bergdahl C, Ekelund J, Juto H, Sundfeldt M, Möller M. Epidemiology and incidence of tibia fractures in the Swedish Fracture Register. Injury 2018; 49(11): 2068-74. WHO Family of International Classifications. www.who.int/classifications/ en/. Accessed March 9, 2019.

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Mechanical instability induces osteoclast differentiation independent of the presence of a fibrous tissue interface and osteocyte apoptosis in a rat model for aseptic loosening Rune Vinther MADSEN 1,4, Denis NAM 2, Jörg SCHILCHER 3,5, Aleksey DVORZHINSKIY 1, James P SUTHERLAND 1, F Mathias BOSTROM 1, and Anna FAHLGREN 1,3 1 Hospital

for Special Surgery, New York, USA; 2 Rush University Medical Center, Chicago, USA; 3 Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; 4 Department of Orthopaedic Surgery, Zealand University Hospital, Køge, Denmark; 5 Department of Orthopedic Surgery, University Hospital Linköping, Sweden Correspondence: anna.fahlgren@liu.se Submitted 2018-09-14. Accepted 2019-09-23.

Background and purpose — Insufficient initial fixation or early micromotion of an implant is associated with a thin layer of fibrous tissue at the peri-implant interface. It is unknown if bone loss is induced by the fibrous tissue interface acting as an active biological membrane, or as a membrane that will produce supraphysiologic fluid flow conditions during gait, which activates the mechanosensitive osteocytes to mediate osteoclast differentiation. We investigated whether mechanically induced osteolysis is dependent on the fibrous tissue interface as a biologically active scaffold, or if it merely acts as a conduit for fluid flow, affecting the mechanosensitive osteocytes in the peri-prosthetic bone. Methods — Using a rat model of mechanically instability-induced aseptic loosening, we assessed whether the induction of osteoclast differentiation was dependent on the presence of a peri-implant fibrous interface. We analyzed the amount of osteoclast differentiation, osteocyte apoptosis, pro-resorptive cytokine expression and bone loss using immunohistochemistry, mRNA expression and micro-CT. Results — Osteoclast differentiation and bone loss were induced by mechanical instability but were not affected by the presence of the fibrous tissue membrane or associated with osteocyte apoptosis. There was no increased mRNA expression of any of the cytokines in the fibrous tissue membrane compared with the peri-implant bone. Interpretation — Our data show that the fibrous tissue membrane in the interface plays a minor role in inducing bone loss. This indicates that the peri-implant bone adjacent to loose bone implants might play an important role for osteoclast differentiation.

Implant micromotion during the first 6 months after implantation is associated with an increased risk of later prosthetic loosening (Pijls et al. 2012, Streit et al. 2016). The synoviallike fibrous tissue membrane in the peri-prosthetic interface has been made responsible for this loosening process through several mechanisms: a reservoir for wear debris particles; accumulation of inflammatory cells including release of proosteoclastic factors (Ingham and Fisher 2005); a tissue layer causing mechanical instability and increased micromotion. Because the amount of wear debris particles does not correlate with bone loss severity at the peri-prosthetic interface, the fibrous tissue membrane may serve as a conduit transmitting pressurized fluid flow with or without wear-debris particles to the bone–implant interface (Alidousti et al. 2011) leading to osteoclastogenesis (Cyndari et al. 2017, Holding et al. 2006, Mandelin et al. 2005). Resorption typically starts at the implant (or cement)–bone interlock and progresses from there into the surrounding bone (Goodheart et al. 2017). Because this interlock and specifically osteolytic zones are exposed to supraphysiologic levels of fluid shear stress (Mann and Miller 2014), these areas might be responsible for the initiation of bone loss. This pressurized fluid flow already induces osteoclast differentiation and bone loss within five days (Skripitz and Aspenberg 2000, Fahlgren et al. 2010, Aspenberg et al. 2011, Nilsson et al. 2012). However, it is still unknown whether the fibrous tissue initiates the osteolytic response in the peri-implant bone or if the signals come from elsewhere such as osteocyte apoptosis (Matsumoto et al. 2013, Kennedy et al. 2014). We hypothesized that osteolysis depends on osteoclast differentiation induced through the peri-implant fibrous tissue interface. To test this hypothesis and whether mechanically induced osteoclast differentiation is associated with osteocyte apoptosis, we used a rat model for instability-induced aseptic loosening.

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Figure 1. Overview of implants for instability-induced osteolysis and the studied rat tibia. A. The central screw (S) and the pressure piston (P) that are placed in the titanium plate and implanted in the proximal tibia. Retrieved proximal tibia demonstrating the fibrous tissue that forms beneath the piston. B. Histological section with the central (Ce) cortical bone underneath the pressure piston and the peripheral (Pe) cortical bone at the periphery. MicroCT images illustrating the central and peripheral bone volumes.

Material and methods Animal model and surgical procedure We used 45 Sprague-Dawley male rats (mean weight 404 g, SD 24 g) in our previously described model (Skripitz and Aspenberg 2000, Fahlgren et al. 2010) (Figure 1). General anesthesia was induced by intra-peritoneal injection of a mixture of ketamine (80–90 mg/kg) and xylazine (5 mg/kg), and prolonged by the administration of inhaled isoflurane via a nose cone. A depression in the tibial cortex was milled out to correspond to the pressure area under the piston. After the depression was prepared, an implant with the central screw (S) was secured to the predominantly cortical bone. The central plug was replaced by the pressure piston (P) (Figure 1A) during a second surgery, after 5 weeks of osseointegration. Buprenorphine at 0.01–0.05 mg/kg was given twice daily for the first 2 postoperative days.

Presence or absence of fibrous tissue (Figure 2) 5 weeks after the implant with the central plug was inserted, we divided all animals into 2 groups. In the first group no piston was inserted for the first 5 days before we initiated mechanical instability. During these 5 days a fibrous tissue layer forms in the space between the piston and the bone surface (Figure 1A) (Skripitz and Aspenberg 2000, Fahlgren et al. 2010). In the second group, mechanical instability was initiated the day after the piston was placed, thus preventing fibrous tissue formation. Each of the 2 groups was further divided into a group with mechanical instability and one unloaded group (controls). In the groups of mechanical instability, the piston was loaded with 0.6 MPa twice daily for 2 minutes at a frequency of 0.17 Hz. This mode of loading is associated with similar levels of osteoclast differentiation in mechanical instability and wear debris particles (Nilsson et al. 2012, Amirhosseini et al. 2018). Animals were killed 5 days after the first loading episode and at the same time in surgically treated non-loaded controls. MicroCT We used micro-computed tomography (μCT) using a Scanco uCT 35 (Scanco Medical, Bruttisellen, Switzerland) to scan the experimental area under the piston with a resolution of 15 μm. The tibiae were placed in a saline-filled tube and scanned at 55 kV and 145 mA. The Scanco μCT software (HP, DECwindows Motif 1.6) was used for 3D reconstruction and viewing of the images. There were 2 regions of interest for each specimen: (1) a central zone (Ce), comprising a 3 mm area down to 1.2 mm depth underneath the piston; (2) a peripheral zone (Pe), 0.75 mm from the periphery of the central zone down to 1.2 mm deep (Figure 1B). The bone volume (BV) was measured in each zone. First surgery: Implant with central screw 5 weeks osseointegration n = 59 Second surgery: Replacement of central screw with pressure piston n = 59

5 days latency period –> Fibrous tissue formation n = 36 Mechanical instability twice daily for 2 min, 0.17 Hz n=7

Stable control n=7

Killed after 24 hours Methodology: mRNA expression

Mechanical instability twice daily for 2 min, 0.17 Hz n = 11

No latency period –> No fibrous tissue formation n = 23 Stable control n = 11

Mechanical instability twice daily for 2 min, 0.17 Hz n = 11

Stable control n = 12

Killed at Day 5 Methodology: MicroCT, histology (osteoclasts and osteocytes)

Figure 2. Study design. The role of fibrous tissue for mechanically induced osteoclast differentiation and osteolysis (left arm), and the association between osteocyte apoptosis and osteoclast differentiation (right arm). Micro-CT performed at day 5.

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Histological analysis and immunolocalization of osteoclasts and osteocytes Proximal tibiae were decalcified, embedded in paraffin, and cut in transverse sections of 7 μm thickness (Nilsson et al. 2012). Each specimen was stained for rabbit-anti rat Cathepsin K (1:600) (Zenger et al. 2007) to identify the number of osteoclasts, and Cleaved Caspase-3 (#9661, Cell Signaling Technologies, Carpinteria, CA, USA) to identify apoptotic osteocytes. Detection of Cathepsin K was done as previously described (Nilsson et al. 2012). For Cleaved Caspase-3, sections were treated for 30 minutes with a methanol-NaOH solution for antigen retrieval (DeCal, Biogenex, San Ramon, CA, USA), then blocked for another 30 minutes with serum free Protein Block. Sections were incubated overnight at 4°C with primary antibodies and detected by a biotinylated antibody (1:600) for 40 minutes. Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA, USA) was applied for 30 minutes followed by 5 minutes of 3,3´diaminobenzidine (DAB) (Sigma, St Louis, MO, USA). The sections were then counterstained, dehydrated, and mounted. The number of osteoclasts was defined as multinucleated Cathepsin K positive cells within a distance of 0.1 mm from the bone surface and counted at an objective of x10 magnification. The number of stained and unstained osteocytes was counted using x40 magnification objective. Cleaved Caspase-3 stained osteocytes were counted as apoptotic osteocytes and empty lacunae were counted as osteocyte necrosis. Apoptotic and necrotic osteocytes are shown as a percentage of total osteocytes. Osteoclast numbers and osteocyte apoptosis and necrosis were evaluated at both the central and peripheral location. A blinded investigator analyzed 1 representative section from 2 levels of the cortical bone with a distance of 450 µm. RNA isolation and gene expression analysis of the fibrous tissue and the peri-prosthetic bone Using the same animal model, 14 male Sprague-Dawley rats (mean weight 380 g, SD 16 g), were subdivided into mechanical instability and non-loaded controls. Animals in both groups were killed 24 hours after the first loading episode. For RNA isolation, custom-made trephines with diameters of 2.0 mm and 4.5 mm respectively were used to harvest bone from the central and peripheral locations in the loaded areas (Figure 1B). The bone marrow was carefully removed from the bone specimens. No periosteum was present as this was trimmed away during surgery. The fibrous tissue and the central and peripheral bone sections were snap-frozen separately in liquid nitrogen. Extraction of total RNA was performed using the TRIspin method described in detail (Nilsson et al. 2012). Primers for IL-6 (NM_012589), HIF-1α (NM_024359), SOST (NM_030584), RANKL (NM_057149), and OPG (NM_012870) were purchased from Qiagen (Germantown, MD, USA). Amplification was performed in 20 μL reactions using SyberGreen MasterMix (Qiagen). Each sample was analyzed in duplicate. Real-time (q-) PCR reactions were con-

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ducted using a standard curve methodology to quantify the specific gene targets of interest and normalized to 18SrRNA. The standard curve was made with rat spleen (Zyagen, San Diego, CA, USA) for IL-6 and HIF-1α or a rat embryo (Zyagen, San Diego, CA, USA) for SOST, RANKL, and OPG. Statistics Data were collected in a blinded fashion. Primary outcome was osteoclast number. Differences in bone volume, osteoclast number, and osteocyte variables were analyzed using a 2-way ANOVA analysis, with the presence or absence of loading and fibrous tissue as variables. The Mann–Whitney U-test was used to analyze gene expression, which was distributed in a non-parametric manner. Pearson’s correlation was used to determine the relationship between osteocyte apoptosis and osteoclast number. The expression pattern of the cytokines in the loaded fibrous tissue was within the same range as the unloaded fibrous tissue. Due to technical difficulties during tissue preparation, only 2 out of 6 of the control fibrous tissue samples were analyzed for mRNA expression. Therefore, the values are presented as absolute values and no statistics are presented. Ethics, funding, and potential conflicts of interest All experiments for the first part of the study, involving microCT, histological analysis, and immunolocalization, were carried out with IACUC approval at the Hospital for Special Surgery (Approval date: September 1, 2011, Dnr 09-11-10R). All experiments for the second part of the study, involving RNA isolation and gene expression analysis, were carried out within the context of institutional guidelines for care and treatment of experimental animals after approval from the Linköping Ethical Committee on animal research (Approval date: November 13, 2012; Dnr 99-12). The project was supported by the Swedish Research Council; Grant numbers: 521-2013-2593, 2016-01822, 2016-06097; Sweden’s Innovation Agency Grant number: 2012-04409 and the National Institutes of Health Grants R01-AR056802, R01AG028664, and P30-AR046121. The authors declare that they have no competing interests regarding this study.

Results Presence of fibrous tissue interface had no effect on instability-induced osteoclast numbers and bone loss The fibrous tissue membrane in the immediate loading group showed a fibrin clot with loose connective tissue after 5 days of loading, while the 5 days latency groups had dense richly vascularized fibrous tissue (Figure 3). Mechanical instability of the implant increased the number of Cathepsin K positive osteoclast (p < 0.05) after 5 days both underneath the implant (central area) and in the periph-

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Osteoclasts – peripheral bone

Osteoclasts – central bone

150

150 a

non-loaded loaded a

100

non-loaded loaded

100

present

absent

Fibrous tissue

present

absent

Fibrous tissue

Bone volume – peripheral bone

Bone volume – central bone

a a

Figure 3. H&E stains showing the fibrous tissue membrane in the immediate loading group (upper row) with a fibrin clot with loose connective tissue after 5 days of loading, while the 5 days latency group (lower row) had dense richly vascularized fibrous tissue.

ery (peripheral area). In the peripheral bone area mechanical instability decreased bone volume. The number of osteoclasts and bone volume did not differ whether fibrous tissue was present or absent under the bone implant (Figure 4). Osteocyte apoptosis was suppressed by mechanical instability and did not correlate with the numbers of Cathepsin K positive osteoclasts To determine whether osteocyte apoptosis or necrosis was associated with osteoclast differentiation during instabilityinduced osteolysis, we counted the amount of Caspase-3 positive osteocytes and empty osteocyte lacunae in relation to the total number of osteocytes. Osteocyte apoptosis was suppressed by mechanical instability underneath the piston (central location) compared with non-loaded controls but remained unaffected in the peripheral area. Osteocyte apoptosis and necrosis was more frequent in animals with the fibrous tissue present compared with animals without (Table 1). The percentage of apoptotic or necrotic osteocytes did not correlate with the number of Cathepsin K positive osteoclasts. The fibrous tissue had similar mRNA expression of inflammatory factors compared with the bone tissue To determine whether instability increased gene expression related to osteoblast–osteoclast differentiation, we detected the pro-osteoclastic factors IL-6, HIF-1α and VEGF and SOST, RANKL and OPG. The total expression due to exposure of mechanical instability was compared between bone and fibrous tissue. Peri-prosthetic bone exposed to mechanical instability had a 5-times higher mRNA expression of IL-6 at the central location (p < 0.05), and 7-times increased expression at the peripheral location (p = 0.07). HIF-1α mRNA expression was increased 2-times (p < 0.05) in the peripheral bone of the mechanical

2 non-loaded loaded

present

absent

Fibrous tissue

non-loaded loaded

present

absent

Fibrous tissue

Figure 3. Number of osteoclasts and bone volume in the peripheral and central cortical bone. The results are subdivided based on the presence of the fibrous tissue. Blue-colored boxes indicate loaded specimens, while green-colored boxes refer to non-loaded specimens. a indicates p < 0.05. Red lines are median, boxes IQR, and whiskers ±1.5 x IQR.

Table 1. Percentage (SD) of osteocyte apoptosis and necrosis in the peri-prosthetic bone 5 days after the first loading session and in non-loaded controls Factor/location

Loaded Non-loaded Fibrous tissue Fibrous tissue present absent present absent

Osteocyte apoptosis (%): Peripheral 6.9 (4.7) 4.0 (4.1) Central a, b, c 3.0 (0.7) 4.2 (2.7) Osteocyte necrosis (%): Peripheral b 9.8 (4.8) 6.5 (2.8) Central b 14.7 (6.0) 12.6 (8.1) a Effect b Effect c Effect

6.9 (7.0) 2.7 (1.6) 4.3 (3.1) 7.9 (4.5) 5.5 (3.3) 5.7 (2.2) 17.8 (6.7) 14.2 (4.1)

of loading: p = 0.04 of fibrous tissue: p < 0.02 of loading and fibrous tissue: p = 0.07.

instability group but remained unaffected in the central location. Mechanical instability did not affect HIF-1α in the fibrous tissue. SOST appeared suppressed 13-times (p = 0.07) in the central bone when compared with unloaded controls, while unaffected in the periphery. The fibrous tissue had a 60–600fold lower expression of SOST after being exposed to mechanical instability compared with the bone tissue. RANKL and OPG ratio was not changed by loading at 24 hours (Table 2).

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Table 2. Median of mRNA expression in the fibrous tissue and periprosthetic bone 24 hours after the first loading session Central bone Peripheral bone Fibrous tissue Loaded Loaded Loaded yes no yes no yes no Gene (n = 7) (n = 5) (n = 6) (n = 6) (n = 7) (n = 2) IL-6 HIF-1 SOST VEGF RANKL OPG

0.56 a 4.25 0.62 b 0.38 5.12 1.11

0.11 1.22 7.88 0.12 1.84 0.33

0.96 b 2.95 a 6.00 0.21 5.90 0.52

0.13 1.67 9.60 0.16 2.02 0.54

0.68 2.38 0.01 0.44 0.34 0.08

(0.09, 2.42) (0.72, 1.69) (1.88, 0.08) (0.20, 0.11) (0.29, 2.35) (0.06, 0.14)

a p < 0.05, b p < 0.07 when loaded samples were compared with non-loaded controls

Discussion We hypothesized that the peri-implant fibrous tissue membrane would be responsive to mechanical instability and excrete osteoclast-stimulating factors that would induce bone loss. Contradictory to this hypothesis, we found osteoclast differentiation and bone loss unaffected by the presence or absence of the fibrous tissue membrane. We also found that osteoclast differentiation and bone loss was independent of osteocyte apoptosis and necrosis. Furthermore, we found similar levels of pro-inflammatory gene expression in the fibrous tissue membrane and the underlying bone after mechanical instability. In a previous study, with the same design as in the current study, we tested the importance of the soft tissue membrane by tearing it apart twice daily for 5 days with rotating movements of a piston with a sharp undersurface. In that study, no pressurized fluid flow was created (Fahlgren et al. 2010). After 5 days the soft tissue underneath the piston was richly vascularized with an abundance of inflammatory cells and endothelial cells. None of the specimens with traumatized tissue showed bone resorption. However, in a control group, where mechanical instability was induced in the same way as in this study, we found peri-implant bone loss. In this peri-implant bone, increased expression of HIF-1α and IL-6 suggests an inflammatory pathway crucial for osteoclast differentiation and bone loss. Low oxygen tension and increased expression of HIF-1α is generally present at sites with increased bone resorption. Hypoxia induces the formation of blood vessel and osteoclast differentiation (Dandajena et al. 2012). An increased expression of IL-6 is likely associated with increased amount of osteoclast differentiation in instability-induced osteolysis (Nilsson et al. 2012, Amirhosseini et al. 2018). IL-6 plays a role in osteoclast and osteoblast differentiation and it has been found to be elevated in the synovial fluid of patients undergoing implant revision surgery (Wang et al. 2010). Variation of the IL-6 gene has also been shown to increase the likelihood of aseptic loosening following hip arthroplasty (Gordon et al.

2010). The current study does not allow us to differentiate properties of the fibrous tissue membrane between early failed osseointegration and late loosening. However, it demonstrates that pro-inflammatory factors in the bone tissue underneath the piston are at similar levels to those in the fibrous tissue membrane. Osteoblasts and osteocytes respond differently to fluid flow profiles, thus resulting in differences in gene expression and phenotypes (Ponik et al. 2007). In an animal model for fatigueinduced bone remodeling it was shown that neighboring cells to the apoptotic osteocytes in rat ulna trigger osteoclast differentiation and bone remodeling (Kennedy et al. 2012). However, in the current study, we were not able to demonstrate an association between osteocyte apoptosis and the number of differentiated osteoclasts. This suggests that other factors released by osteocytes or osteoblasts might affect osteoclast differentiation. The area of bone destruction is often localized near the arthroplasty implant and may not be representative of the patient’s overall bone quality. Even in the current study, we found local differences due to loading. It was established that the osteocytes beneath the loaded implant had less apoptosis than in the peripheral location. Since the bone below the piston is in effect a transversely loaded thin plate, it is likely that it is in a state of high stress and strain due to bending. This could initiate an anabolic mechanism, counteracting the osteolytic mechanism (Thompson et al. 2012). At this location, there was a tendency of almost a 13-fold mRNA down-regulation of SOST, which is secreted by osteocytes and inhibits osteoblast activity. Similarly, the obligate role of a down-regulation of SOST in osteogenesis was shown in transgenic mice with a persistently high level of SOST during loading, where loadinduced bone formation was reduced by 70–85% (Tu et al. 2012). Further, enhanced release of nitric oxide by osteocytes during loading partly regulates osteocyte apoptosis in the neighboring cells by Bcl-2 and Caspase 3 (Tan et al. 2008). This is a suggested mechanism to inhibit bone degradation due to unloading. The current study examined gene expression, knowing that gene and protein expression do not always correlate due to post-transcriptional and post-translational changes. However, it was outside this study’s capacity to elaborate on these differences. Due to technical difficulties during tissue preparation, we were only able to analyze 2 out of 6 of the control fibrous tissue samples for mRNA expression. Still, the results from these specimens were in the same range as the loaded samples. Therefore, we allowed ourselves to exclude an increased expression of mRNA in the genes of interest. The expression in the fibrous tissue membrane was not higher than in the bone tissue, neither was the expression high enough to have an impact on the number of osteoclasts. Another limitation is that the fibrous tissue used in the current animal model might not accurately represent the chronic granulation tissue seen around the loose prosthesis in human. However, it might represent soft tissue seen around implants in an earlier stage.

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Although the current study separated the fibrous tissue and the bone tissue samples for qPCR, analyses still include a mixture of cell types. Osteoblasts and osteocytes respond differently to different fluid flow profiles, thus resulting in differences in gene expression and phenotypes (Ponik et al. 2007). In conclusion, it appears that the main role of the fibrous tissue is to provide a conduit for fluid flow in instability-induced osteolysis, rather than acting as a biologically active scaffold itself. Osteoclast differentiation and bone loss were induced by mechanical instability but not affected by the presence of the fibrous tissue membrane or associated with osteocyte apoptosis. The ability of the peri-prosthetic bone to induce osteolysis even in the absence of a fibrous tissue membrane may be important. We believe that the current study can provide important information to understand the role of fibrous tissue and the peri-prosthetic bone in the early process of micromotion that later will develop into prosthetic loosening.

RVM, DN, FMB, and AF designed the study. The surgeries, specimen handling, and data collection were carried out by RVM, DN, AD, JPS, and AF. RVM, DN, and AF performed the statistical analysis. RVM, DN, JS, and AF reviewed the literature. All authors contributed to the writing of manuscript. The authors would like to thank Dr Xu Yang for technical assistance during surgery and sample preparation. Acta thanks Thomas Jakobsen, Oran Kennedy, and Kenneth Mann for help with peer review of this study.

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