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Calcif Tissue Int (2010) 86:82–89 DOI 10.1007/s00223-009-9317-8

Strontium Ranelate Enhances Callus Strength More Than PTH 1-34 in an Osteoporotic Rat Model of Fracture Healing Bjoern Habermann • Konstantinos Kafchitsas • Gavin Olender • Peter Augat • Andreas Kurth

Received: 6 May 2009 / Accepted: 26 October 2009 / Published online: 4 December 2009 Ó Springer Science+Business Media, LLC 2009

Abstract Treatment of an underlying disease is often initiated after the occurrence of an osteoporotic fracture. Our aim was to investigate whether teriparatide (PTH 1-34) and strontium ranelate affect fracture healing in ovariectomized (OVX) rats when provided for the first time after the occurrence of an osteoporotic fracture. We combined the model of an OVX rat with a closed diaphyseal fracture. Sixty Sprague Dawley rats were randomly assigned to four groups. Fracture healing in OVX rats after treatment with pharmacological doses of strontium ranelate and PTH 1-34 was compared with OVX and sham-treated control groups. After 28 days, the femur was excised and scanned by micro computed tomography and the callus evaluated, after which biomechanical torsional testing was performed and torque and toughness until reaching the yield point were analyzed. Only treatment with strontium ranelate led to a significant increase in callus resistance compared to the OVX control rats, whereas both PTH 1-34 and strontium ranelate increased the bone volume/tissue volume ratio of the

B. Habermann (&)  K. Kafchitsas  A. Kurth Department of Orthopaedics and Orthopaedic Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany e-mail: K. Kafchitsas e-mail: A. Kurth e-mail: G. Olender  P. Augat Biomechanical Research Laboratory, Traumacenter Murnau, Murnau, Germany e-mail: P. Augat e-mail:


callus. The PTH 1-34–increased trabecular bone volume within the callus was even higher compared to sham. As for the callus tissue volume, the increase induced by strontium ranelate was significant, contrary to the changes induced by PTH. Callus in strontium ranelate–treated animals is more resistant to torsion compared with OVX control rats. To our knowledge, this is the first report of the enhancement of fracture healing by strontium ranelate. Because both treatments enhance bone and tissue volume within the callus, there may be a qualitative difference between the calluses of PTH 1-34– and strontium ranelate–treated OVX rats. The superior results obtained with strontium ranelate compared to PTH in terms of callus resistance could be the consequence of a better quality of the new bone formed within the callus. Keywords OVX rats  Osteoporosis  Fracture healing  PTH  Strontium ranelate

Osteoporosis leads to a reduction of the trabecular structure in cancellous bone and to an increase in bone fragility. As a result of these structural changes, a higher incidence of bone fractures after inadequate trauma occurs in those patients. In addition to the treatment of the fracture, it is essential to initiate adequate treatment of the underlying disease, i.e., osteoporosis. Because in most cases osteoporosis is diagnosed at the time of fracture occurrence, information on the influence of antiosteoporotic drugs on fracture healing is essential. Strontium ranelate has proven its efficacy in reducing the risk of vertebral, nonvertebral, and hip fracture in women with postmenopausal osteoporosis [1, 2]. This efficacy of strontium ranelate is independent of baseline risk factors [3] and is maintained during 5 [4] and even

B. Habermann et al.: Strontium Ranelate Enhances Callus Strength

8 years [5]. Strontium ranelate has a dual mode of action [6, 7]. In vitro, it increases bone formation by enhancing preosteoblast replication, differentiation, and activity [8– 10] and decreases bone resorption by inhibiting osteoclast differentiation, activity and stimulating osteoclast apoptosis [10–13]. In vivo, strontium ranelate increases bone strength in intact rats or totally prevents its decrease in ovariectomized (OVX) rats as a result of its positive effects on microarchitecture and intrinsic bone quality [14, 15]. Teriparatide (PTH 1-34) has anabolic effects on bone and increases bone strength [16–19]. A continuous infusion of PTH 1-34 has catabolic effects, whereas its intermittent administration has anabolic effects on bone formation. In osteoporotic women, its intermittent administration leads to an increase in bone mineral density (BMD) and a reduction in vertebral and nonvertebral fracture incidence [20]. It was shown in nonosteoporotic rats that daily administration of PTH 1-34 enhances fracture healing [21]. Furthermore, PTH 1-34 enhances callus formation in young, aged, and OVX rats [22–25]. As the population ages, the prevalence of osteoporotic fractures increases. Although most fractures heal, approximately 5 to 10% are associated with impaired healing, including delayed healing or nonunion. Fracture healing is a long and difficult process, which includes a first phase of inflammation and resorption and a second phase of bone formation. Considering the poor quality and quantity of bone in the elderly, there is a potential for the use of pharmaceutical agents to enhance fracture healing. The purpose of the present study was to determine the effect of two antiosteoporotic treatments on fracture healing in osteoporotic OVX rats 28 days after fracture occurrence. PTH, which has been proven to influence fracture healing in OVX rats [24], was taken as a control treatment. Strontium ranelate, which acts on both resorption and formation, is a good candidate to enhance fracture healing. We combined the rat model of a closed, standardized diaphyseal fracture of the femur, as introduced by Bonnarens and Einhorn [26], with the model of a postovariectomy osteopenic rat, mimicking postmenopausal bone loss [27].

Materials and Methods Forty-five animals were ovariectomized at the age of 12 weeks, and a further 15 underwent sham operation. At the age of 24 weeks, osteopenia in the OVX rats was diagnosed by means of dual-energy x-ray absorptiometry (DXA). Then, in all animals, a standardized mid-diaphyseal fracture was induced. Under general anesthesia (100 mg ketanest [Ketavet], 1 mg midazolam [Dormicum], and 10 mg xylazine [Rompun], i.p.), a 0.8-mm Kirschner


wire was introduced into the left femoral canal through a medial parapatellar incision and arthrotomy of the knee. After closing the wound, a mid-diaphyseal fracture was produced by using a falling weight of 650 g over a threepoint bending mechanism. In all groups, the drop height of the weight was 14 cm and induced by lateral loading. The fracture was radiographically documented. In all cases, a straight mid-diaphyseal fracture was induced. The animal experiments were approved by the Regierungspraesidium Darmstadt, Germany. At the time of fracture, the animals were divided into four groups. Group 1 was the sham control group, and groups 2, 3, and 4 were the OVX treatment groups. Groups 1 and 2 were treated with NaCl 0.9% s.c. daily, group 3 was treated with 600 mg/kg/d strontium ranelate (purchased from Servier Deutschland GmbH) p.o. daily, and group 4 received 20 lg PTH 1-34 (purchased from Lilly Deutschland GmbH) three times a weeks.c. (equivalent to a dose of 20 lg/kg/d). The fracture was radiographically documented. The dose of 600 mg/kg/d of strontium ranelate leads to a blood strontium concentration close to the human exposure after a therapeutic dose of 2 g/d [15]. The dose of 20 lg/kg/d PTH 1-34 leads to higher human therapeutic exposure but is a pharmacological dose used in rats. The rats were liberated to calcium-reduced food and water ad libitum (EF R/M, Sniff GmbH). They were killed after 28 days and the left femurs were immediately excised, wrapped in NaCl-soaked gauze, and frozen at -80°C. The samples were then scanned by MicroCT 80 by Scanco Medical, Zurich, Switzerland. The whole bone was scanned, and 600 slices 40 lm in thickness were placed through the former fracture area. The center of the fracture callus was defined manually as the point where the previous organization of the cortical bone in the fracture area was nearly inexistent. One hundred slices of 40 lm were placed above and below. The threshold for calluses was 155–320, whereas it was 320– 1000 for cortical bone and 155–210 for bone marrow. The evaluation of the data focused on outer callus contour, cortical contour, and marrow contour, as well as cortical thickness and polar moment of inertia. BMD, tissue volume (TV), bone volume (BV), and the BV/TV ratio were recorded. BMD was achieved by measuring mean voxel values. Mean voxel values (1/mm) could be equalized to the bone mineral content when the scan was calibrated for bone. The manufacturer’s software package was used for image processing and data evaluation (version 4.04). After embedding the samples in methylmethacrylate cement (Technovit, Heraeus Sulzer, Wehrheim, Germany), torsion testing on the bones was carried out with the axialtorsional 8874 system by Instron (Darmstadt, Germany).



B. Habermann et al.: Strontium Ranelate Enhances Callus Strength

Between the different steps of preparation, each specimen was kept immersed in physiological solution to avoid drying of the bone that could affect the biomechanical properties. The speed of torsional testing was 1 degree per second. Biomechanical testing recorded the modulus of rigidity and torque until failure. The torque was expressed in Nm. The yield point indicated the point between the elastic and plastic phase. At this point, initial microfractures could be seen. The toughness in terms of the bone’s resistance to fracture was measured in J/m3. Before analysis of the biomechanical data, the values were normalized by combining them with the lower body weight of the sham group [28]. Data were collected in Excel (Microsoft). All data were expressed as the mean ± standard deviation. For statistical analysis, we used one-way analysis of variance, and P \ 0.05 was considered significant. Sigma Stat (SPSS) was used.

Results DXA Ovariectomy led to a significant reduction in BMD in the lumbar spine after 12 weeks (-22.07%, P \ 0.05). Biomechanical Testing In the OVX group, a huge and significant decrease in resistance to torsional load was observed compared to the sham group (OVX -33.16%, P \ 0.001) (Fig. 1; Table 1). Treatment with strontium ranelate significantly improved the mechanical properties of the callus when compared to the OVX control group, while the improvement induced by the treatment with PTH 1-34 did not reach significance (strontium ranelate ?43.8%, P \ 0.05; PTH ?20.2%, P [ 0.05). Treatment with strontium ranelate or 8

PTH 1-34 also improved the mechanical properties of the callus compared to the sham control group but did not reach significance (strontium ranelate ?30.19%, P [ 0.05; PTH 1-34 ?7.01%, P [ 0.05). In all groups, mechanical testing to the yield point showed no significant differences. Micro Computed Tomography of the Fracture Callus Ovariectomy led to a nonsignificant increase in the callus tissue volume (mm3) when compared to the sham group (?11.7%; P [ 0.05) and to a nonsignificant decrease in the callus bone volume (mm3) (-1%, P [ 0.05). As for the BV/TV ratio, ovariectomy significantly decreased the relative content of bone in callus (-7.7%; P \ 0.05) (Fig. 2). The OVX rats showed a significant decrease in BMD compared to the sham rats (-19.6%; P \ 0.05), which can be interpreted as a lower BMD (Table 2 and Fig. 3). PTH 1-34 and strontium ranelate both showed a significant increase in bone volume of the callus when compared to OVX control rats (strontium ranelate ?46.3%, P \ 0,01; PTH 1-34 ?31.9%, P \ 0.05) with no significant difference between the two treatments. As for the callus tissue volume, the increase induced by strontium ranelate was significant compared to OVX, whereas PTH induced no change (strontium ranelate ?32.4%, P \ 0.01, PTH 1-34 ?6.1%, P [ 0.05); the difference between both drugs was significant (strontium ranelate vs. PTH, ?24.8%, P \ 0.01). In both the PTH 1-34– and strontium ranelate– treated animals, BV/TV was significantly increased compared to the OVX control rats (strontium ranelate ?12.2%, P \ 0.05; PTH 1-34 ?25.6%, P \ 0.001) (Fig. 2). The BV/TV of the PTH-treated rats was even higher than in the sham rats (?10.2%, P \ 0.05). Strontium ranelate and PTH 1-34 both showed a nonsignificant increase in the bone mineral content (strontium ranelate ?2.5%, P [ 0.05; PTH 1-34 ?9.8%, P [ 0.05). The difference between them was also not significant.





6 5 4 3 2 1 0 SHAM


OVX+ PTH 1-34

OVX + Strontium Ranelate

Fig. 1 Torsion to bone fracture (J/m3). * P \ 0.05 compared to sham. # P \ 0.05 compared to ovariectomy (OVX)


Osteoporotic fractures in formerly untreated patients mostly lead to increased morbidity and mortality. The risk of being bedridden and experiencing further fractures is increased. Adequate and evidence-based medication for osteoporosis needs to be initiated. It is unknown whether certain osteoporotic drugs impair fracture healing or enhance it, so that patients may experience earlier mobility. Besides vitamin D and calcium administration, bisphosphonates, estrogen, raloxifen, strontium ranelate, and PTH 1-34 are commonly used antiosteoporotic drugs. Up to now, only preclinical data provided information on the

B. Habermann et al.: Strontium Ranelate Enhances Callus Strength


Table 1 Biomechanical data of fracture callusa Characteristic




OVX ? strontium ranelate

Torsional load (J/m3)

5.31 ± 0.96

4.02 ± 1.46*

4.44 ± 1.26

5.39 ± 1.68#

Yield point

0.06 ± 0.06

0.26 ± 0.48

0.11 ± 0.06

0.05 ± 0.04

OVX ovariectomized, PTH teriparatide a

Data are presented as mean ± SD

* P \ 0.05 compared to sham #

P \ 0.05 compared to OVX

0.6 ### *




0.4 0.3 0.2 0.1 0 SHAM


OVX+ PTH 1-34

OVX + Strontium Ranelate

Fig. 2 Callus bone volume/tissue volume. * P \ 0.05 compared to sham. # P \ 0.05 compared to ovariectomy (OVX). ### P \ 0.01

impact of the therapeutic agents on fracture healing. Clinical trials with antiosteoporotic agents focusing on the outcome of the fracture healing and not on the incidence of osteoporotic fractures will be necessary. The OVX rat is a model commonly used to mimic osteoporosis-induced bone loss. Shortly after ovariectomy, the changes in bone are close to those observed in human postmenopausal bone loss. Bonnarens and Einhorn [26] introduced the model of a standardized closed diaphyseal fracture, which has been used in many studies since. The advantage of a closed fracture is that the initial environment is unchanged and not influenced, as it would be after an open osteotomy. Combining both models is interesting

to study the impact of an agent on fracture healing in an osteoporotic environment. Many previous publications have studied fracture healing in osteoporotic rats, with diverse outcomes [29–34]. One reason for these diverse outcomes is most certainly the type of fracture used. These can be differentiated as closed and open fractures, as well as the type of fixation and the location, i.e. tibia, femur, or mandibula. Furthermore, there have been recent reports on fracture models that use the metaphysis [35, 36]. Such models are interesting because metaphyseal fractures are probably the most common fractures encountered in a clinical osteoporosis situation. The problem with such fractures is the mechanical evaluation of their stability and the reproducibility. The diaphyseal fracture in animal experiments is also a wellestablished method, easy to standardize, and, after explanting the bone, is suited to mechanical testing. However, the advantage of a closed fracture as it was used in our study is that the initial environment is unchanged and not influenced, as it would be after an open osteotomy. Nevertheless, another reason for a diverse outcome is the use of different endpoints. Endpoints in the literature vary between 3 and 18 weeks [21, 22, 29–33, 37]. As described by Schmidmaier et al. [38], fracture healing in rats runs through the same phases as it does in any other mammal. At day 21, the endochondral ossification phase is almost complete, and the remodeling phase has started [38, 39]. Therefore, we were of the opinion that any impact on healing would be detectable at day 28.

Table 2 Micro computed tomography data of fracture callusa Characteristic Callus tissue volume (mm3) 3

Callus bone volume (mm )



210.19 ± 46.38

234.87 ± 60.46

83.77 ± 27.24

82.95 ± 29.68


OVX ? strontium ranelate 311.18 ± 607***,##,$$

249.2 ± 4332* 109.43 ± 30.89



Callus bone volume/tissue volume

0.39 ± 0.05

0.35 ± 0.05*

0.43 ± 0.06

Bone mineral content of the callus

546.72 ± 57.62

457.27 ± 74.12***

501.96 ± 45.6*

121.37 ± 31.04*,## 0.39 ± 0.043# 468.63 ± 59.24*

OVX ovariectomized, PTH teriparatide a

Data are presented as mean ± SD

* P \ 0.05; ** P \ 0.01; *** P \ 0.001 compared to sham # P \ 0.05; ## P \ 0.01; ### P \ 0.001 compared to OVX $$

P \ 0.01 compared to PTH



B. Habermann et al.: Strontium Ranelate Enhances Callus Strength

Fig. 3 a Horizontal slice through fracture callus of an ovariectomized (OVX) Sprague Dawley (SD) rat treated with placebo. b Horizontal slice through fracture callus of an OVX SD rat treated with

strontium ranelate. c Horizontal slice through fracture callus of an OVX SD rat treated with teriparatide

The primary question addressed in this study was whether PTH 1-34 and strontium ranelate impact on fracture healing at endpoint. An impact on fracture healing, be it either an enhancement or a decrease, is evaluated by assessing the biomechanical properties of the callus. Whereas many authors use a three-point bending test [29– 32, 34], there are some reports on the torsional testing [40, 41] that we used. In torsional testing, the initial collapse of the bony structure is not so much influenced by where the main load is applied but by the structure of the whole bone itself. The fracture callus is not homogenous, and a threepoint bending test cannot be representative of the whole callus biomechanical competence. In addition to mechanical testing, micro computed tomography (lCT) has the

ability to reconstruct the fracture site in 3D and provide information on remodeling status. The present results confirm those of previous studies showing that ovariectomy impairs fracture healing in rats [24, 42–44], affecting trabecular bone formation and mineralization. The OVX group showed a significant decrease in callus resistance to torsional testing, reflecting a weaker callus strength and thus validating the model. The lCT data in our study clearly show that ovariectomy affects the callus, as previously demonstrated [24, 42–44]. Although there were no significant differences in the volume of the callus between the sham and OVX rats, ovariectomy led to a larger callus. Furthermore, the bone and mineral content of this callus were considerably and significantly reduced


B. Habermann et al.: Strontium Ranelate Enhances Callus Strength

in the OVX rats. A significant reduction in BMD 12 weeks after ovariectomy was confirmed by the DXA data. These results reflect the inhibition of trabecular bone formation and the reduction of mineralization in the later stages of fracture healing in the OVX rat model. PTH 1-34 (20 lg/kg/d) OVX-treated rats did not show a significant increase in their callus resistance compared to the OVX control rats. It had been previously demonstrated that PTH enhances bone repair in rats. Preclinical studies have shown a dose-response relationship from 10 to 800 lg/kg/d in the administration of PTH, with higher doses being more potent for enhancement of fracture healing by increasing BV/TV, bone callus volume, and finally callus resistance [45]. But the doses used in many of these studies were much higher than the recommended equivalent human doses. Many studies in normal and old rats have now clearly shown that even at dosages more in line with those corresponding to clinical exposure (5 to 10 lg/kg/d), PTH enhances fracture healing. Only one study in OVX rats with low-dose PTH 1-84 (15 lg/kg/d) showed that this agent is effective in enhancing fracture healing, improving both callus formation and resistance as assessed by a three-point bending test, whereas we used torsional testing [24]. A recent report in a rat cortical defect model showed that PTH at a clinically relevant dose is not sufficient to substantially enhance cortical bone repair over 5 weeks [46]. The dose of 20 lg/kg/d used in our study is an intermediate one when considering previous published studies. Even if in the present study PTH did not significantly increase the resistance of the callus, it significantly influenced its remodeling. The callus volume tended to increase, and the within-callus BV/TV was significantly enhanced. Indeed, as an anabolic agent, PTH has been shown to enhance callus formation by the early stimulation of proliferation and differentiation of osteoprogenitor cells [47]. Treatment with strontium ranelate (600 mg/kg/d leading to a blood strontium concentration close to the human therapeutic exposure) led to a significant increase in callus resistance compared to the OVX control rats. The increase in stability even exceeded the results of the sham group, although not significantly. The strontium ranelate effects on callus remodeling were expressed by a significant increase in BV/TV and volume of the callus. The BV/TV of the callus in strontium ranelate OVX-treated rats was identical to that of the sham rats, suggesting that strontium ranelate is able to restore a level of bone remodeling approaching that of a normal rat. Strontium ranelate has been proven to have a dual mechanism of action in vitro, acting on both osteoclasts and osteoblasts. It can be thus be hypothesized that this drug could decrease the first phase of bone resorption while improving the second phase of bone


formation by promoting the differentiation of bone marrow cells present at the callus site. Indeed, strontium ranelate was shown to promote stromal cell differentiation at the very first stage, but also during latter stages, during osteoblast differentiation [9, 10]. Whereas both PTH 1-34 and strontium ranelate increased the volume of trabecular bone within the callus, only strontium ranelate improved the resistance to torsional testing. The BV/TV of the PTH-treated rats was even higher compared to sham rats, but with no subsequent increase in mechanical resistance. As a consequence, there may be a qualitative difference between the calluses of PTH 1-34 and strontium ranelate-treated OVX rats. Indeed, in an OVX fracture rat model, the callus of PTH-treated OVX rats remained more porous than in the sham rats, showing that even if PTH treatment induced increased amounts of bone tissue in the callus, this bone has still the altered mechanical properties induced by ovariectomy [24]. As an anabolic agent, PTH increases bone remodeling and improves microarchitecture. However, the relatively huge increase in bone remodeling induced by such an agent could induce an overall decrease in the maturation of collagen fibers and lead to a poorer intrinsic bone quality. This has been shown recently in OVX rats receiving PTH by a decrease in trabecular bone hardness [48]. Strontium ranelate has been shown to improve bone remodeling, leading to better microarchitecture and intrinsic tissue quality in intact and OVX rats [14, 15]. This difference of effect of both drugs on intrinsic bone quality associated with a higher callus volume primarily after treatment with strontium ranelate could explain the better resistance of the callus after treatment with strontium ranelate compared to PTH 1-34. A histology study would be required to establish the exact mechanism of action of both drugs in this model. Moreover, this study is limited by the fact that analysis was performed only at endpoint. Nevertheless, the aim was to study and compare the enhancement of fracture healing between two drugs at a defined time point and not to study the acceleration or delay of healing, which would have required the assessment of different time points. In conclusion, this is the first report on the enhancement of fracture healing with strontium ranelate. The callus in strontium ranelate–treated animals is even more resistant to torsion in comparison to OVX and sham-untreated animals and even to those treated with PTH 1-34. PTH did not significantly enhance the resistance of the callus vs. OVX, despite a significant increase in the BV/TV ratio within the callus. The superior results obtained with strontium ranelate compared to PTH could be the consequence of a better quality of the new bone formed within the callus. Strontium ranelate might be taken into consideration in order to enhance fracture repair.


88 Acknowledgments The study was supported by Elsbeth Bonhoff Stiftung. No direct funding from any pharmaceutical company was received.

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Strontium Ranelate Enhances Callus Strength More Than PTH 1-34 in an Osteoporotic Rat Model of Fract  

Keywords OVXratsÁOsteoporosisÁFracturehealingÁ PTHÁStrontiumranelate B.Habermann(&)ÁK.KafchitsasÁA.Kurth DepartmentofOrthopaedicsandOrth...

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