Men’s Bones Break Too: Role of Liver Disease in Cause of Osteoporosis

Although less common in men than women, osteoporosis affects approximately 16% of men aged 50 years and older, and 1 in 4 men older than 50 years will break a bone because of osteoporosis.1,2 Outcomes of fragility fractures are worse in men than in women; 1 in 3 men who experience a hip fracture at age 75 to 84 years will die within the first year.3-5 However, few men consider themselves at risk for osteoporosis despite having risk factors for this condition including obesity, diabetes, sedentary lifestyle, smoking, alcohol use disorder, kidney disease, and liver disease.6 Men are also less frequently screened for bone mineral density (BMD) loss at midlife compared with women.6

This review will focus on liver disease as a risk factor for osteoporosis in men as both of these conditions typically progress asymptomatically until fracture, abnormal liver enzymes, or steatosis on imaging are detected. Screening and treatment recommendations for osteoporosis in all men will be outlined.

Osteoporosis in Patients With NAFLD

Nonalcoholic fatty liver disease (NAFLD) affects approximately 30% of the US population, with the subtype of nonalcoholic steatohepatitis affecting 5%.7,8 The condition affects up to 75% of those who are overweight and one-third to two-thirds of people with type 2 diabetes.8-10 The number of people in the US with NAFLD is expected to reach 100 million by 2030 owing to the projected increase in obesity and type 2 diabetes rates.8

The prevalence and severity of NAFLD are higher in men than in premenopausal women; however, postmenopausal women have higher rates than men.11 The disease is most commonly found among Hispanic individuals followed by non-Hispanic White individuals and Asian Americans.9 Non-Hispanic Black patients have a significantly lower risk of NAFLD compared with non-Hispanic White patients.9,12

Multiple pathogenic pathways exist in NAFLD that contribute to a proinflammatory state, placing the individual at higher risk for osteoporosis. Individuals with NAFLD often can be described as those with an expanded and inflamed visceral adipose tissue and accompanying metabolic syndrome, including obesity. This dysfunctional inflamed tissue plays a role in targeting the liver, which can be a source of proinflammatory, procoagulant, and profibrogenic factors.7 These inflammatory processes can affect both the bone and the metabolic/hormonal processes that often affect those with NAFLD.The release of proinflammatory cytokines and hormones from this inflamed adipose tissue is also involved in developing systemic insulin resistance, which can adversely affect bone structure and quality.7

Chronic inflammation is interesting when considering the pathogenesis of osteopenia/osteoporosis.Tumor necrosis factor (TNF)-alpha stimulates osteoclastogenesis while also inhibiting

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osteoblastic activity.7 Tumor necrosis factor-alpha also inhibits osteoclast apoptosis, inhibits osteoblast differentiation, and increases apoptosis for these cells.13 An inverse association exists between TNF-alpha and vitamin D levels, which also could inversely affect skeletal metabolism.14

Osteopontin enhances bone resorption and reduces bone deposition. In NAFLD, osteopontin is overexpressed. Osteoprotegerin is a glycoprotein impacting bone turnover in part because of its role as a decoy receptor for the receptor activator of nuclear factor kappa-B ligand (RANK-L), which inhibits osteoclast differentiation and activation.15 Osteoprotegerin also promotes cell survival by inhibiting TNFrelated apoptosis-inducing ligand (TRAIL)-induced apoptosis.15

It is not surprising that decreased osteoprotegerin levels are linked to abdominal obesity, insulin resistance, and NAFLD.16

Osteocalcin, which is a noncollagen protein within the bone matrix, is primarily expressed by osteoblasts. Decreased osteocalcin levels are linked in a graded relationship with the presence and severity of NAFLD.7 The hormone leptin plays a role in the bone microarchitectural process and has a possible antisteatotic but also a proinflammatory and profibrogenic action, which exerts regulatory effects on BMD in individuals with NAFLD.7

Vitamin D3 has a wide variety of effects on the body including bone mineralization. Noncirrhotic NAFLD individuals with low levels of serum 25-hydroxyvitamin D3 have greater severity of NAFLD fibrosis/steatosis, independent of other risk factors.7 In addition to the cellular changes associated with NAFLD linked to osteoporosis, the population of individuals with NAFLD is typically more sedentary than healthy control groups, which reduces mechanical stress loading that aids bone strengthening.7

Osteoporosis in Alcoholic Liver Disease

Alcoholic liver disease (ALD) is also linked to an increased risk for osteoporosis and is more common in men than women. The term ALD is used to describe a spectrum of diseases ranging from alcoholic fatty liver disease (AFLD) to advanced ALD (including alcoholic hepatitis, cirrhosis, and cirrhosis complications). The overall prevalence of ALD in the US is estimated at 8.1% in the general population and 9.0% among men.17 The prevalence of alcoholic-fatty liver disease in the US is 4.3% (60.6% men).18

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The incidence of osteoporosis among patients with ALD ranges from 11% to 22% in those without liver cirrhosis to 20% to 50% among those with liver cirrhosis.7

Changes in bone architecture in individuals with ALD and pancreatitis are similar to those with NAFLD, but heavy alcohol consumption could directly harm and reduce osteoblasts.19 Altered vitamin D, testosterone, and parathyroid hormone levels are also sequelae of chronic alcohol consumption, which leads to decreased bone formation.19 In addition to the proinflammatory cytokines that are increased in NAFLD, sclerostin (which regulates part of the bone formation pathway) is increased in end-stage ALD patients.19 In both cirrhotic and noncirrhotic liver disease, bone deterioration is part of the disease process. Cirrhotic patients develop metabolic bone disease and alcoholic or viral cirrhosis patients frequently have osteodystrophy.7 Young patients with cirrhosis (particularly related to alcoholism) have an excess risk of bone fractures.7

Caution should be used in overgeneralizing findings to those patients with non-alcoholic steatohepatitis (NASH)-cirrhosis, but it is worth studying to see if these patients have similar risks for bone fractures and decreased BMD.

Osteoporosis Screening in Men

Osteoporosis screening tools appear to have equal predictive value in both men and women.20 However, insufficient evidence is available to inform guidelines on when men should first receive a dual-energy x-ray absorptiometry (DEXA) or BMD testing.4 Indications for BMD testing are listed in Table 1, however, chronic liver disease is not usually mentioned as a risk factor.20,21

The United States Preventative Services Task Force (USPSTF) changed their recommendation for screening of men to only include those with the following risk factors for osteoporosis20:

• Low body mass

• Chronic corticosteroid use

• Heavy alcohol consumption

• Current smoking

• Previous fractures

• Recent falls

The National Osteoporosis Foundation (NOF), rebranded as the Bone Health and Osteoporosis Foundation (BHOF) in October 2021, recommends screening for men aged 50 to 59 years with risk factors or aged 50 years and older with a history of adult-aged fracture.21

In a cohort of men who had sustained a fragility fracture, 92.8% had not previously received an osteoporosis diagnosis and only 6% had undergone a DEXA screening 2 years prior to their fracture.4 Even among men with additional high-risk characteristics, including use of β-blocker medications, mobility impairment, or opioid use, screening rates were low.4 Less well-known risk factors for osteoporosis now include hypogonadism, NAFLD, hemochromatosis, and biliary disease.7,22

Osteoporosis Treatment in Men

Studies assessing the efficacy of osteoporosis medications in men are lacking and the USPSTF noted that assumptions cannot be derived from studies in postmenopausal women as the underlying biology of bones may differ based on differences in sex hormone.20 In the American College of Physicians (ACP) 2023 updated guideline on the pharmacologic treatment of primary osteoporosis, the group now recommends that clinicians preferentially use bisphosphonates as first-line therapy in both women and men with osteoporosis (Table 2, page 18).23 The ACP also suggested that the RANK ligand inhibitor (denosumab) can be used as a second-line pharmacologic treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis who have contraindications to or experience adverse effects from bisphosphonates. Both of these recommendations were considered conditional and are based on low-certainty evidence.

TABLE 1. Indications for Bone Mineral Density Testing20,21

Women ≥65 y and men ≥70 y regardless of risk factors

Younger postmenopausal women, women in the menopausal transition, and men 50-69 y with clinical risk factors for fracture

Adults with conditions (rheumatoid arthritis, autoimmune disease, or diseases affecting bone health) or medications (eg, glucocorticoids) associated with low bone mass

Heavy alcohol consumption

Smoking history

Recent falls

Adults aged ≥50 y with a history of adult-age fracture

Source: US Preventive Services Task Force et al20 and Leboff et al.21

TABLE 2. American College of Physicians Guideline on Pharmacologic Treatment of Osteoporosis23

Recommendation GRADE

Use bisphosphonates (alendronate, ibandronate, risedronate, zoledronate) as initial treatment to reduce the risk of fractures in postmenopausal females and males diagnosed with primary osteoporosis

Use bisphosphonates as initial treatment to reduce the risk of fractures in males diagnosed with primary osteoporosis

Use the RANK ligand inhibitor denosumab as a second-line pharmacologic treatment to reduce the risk of fractures in postmenopausal females and males diagnosed with primary osteoporosis who have contraindications to or experience adverse effects of bisphosphonates

Use the sclerostin inhibitor romosozumab or the recombinant PTH teriparatide followed by a bisphosphonate to reduce the risk of fractures only in females with primary osteoporosis at very high risk of fracture

Use an individualized approach to decisions regarding use of bisphosphonates in females older than 65 y with osteopenia to reduce the risk of fractures

Strong recommendation; high-certainty evidence

Conditional recommendation; low-certainty evidence

Conditional recommendation; low-certainty evidence

Romosozumab; moderate-certainty evidence Teriparatide; low-certainty evidence

Conditional recommendation; low-certainty evidence

ACP, American College of Physicians; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; PTH, parathyroid hormone

Source: Qaseem et al.23

The ACP’s recommendations on osteoporosis treatment in males are based on a systematic review of 6 randomizedcontrolled studies and 4 observational studies that included only males with osteoporosis or in which patient outcomes were stratified by sex.23 The group found no evidence of differences in treatment benefits or harms by sex. Data on bisphosphonates suggested a reduction in radiographic vertebral fractures in men (absolute risk difference, 140 fewer events per 1000 patients) compared with placebo in trials assessing outcomes at least 36 months from treatment initiation. None of the trials were designed to evaluate the effects of treatment on hip fractures in men and the ACP concluded that bisphosphonates probably did not reduce other nonvertebral fracture outcomes.

The parathyroid hormone-related peptide analog abaloparatide is the most recently approved agent for use in men with osteoporosis at high risk for fracture; the drug was first approved for use in postmenopausal women. Approval in men was based on results of a phase 3 trial in which abaloparatide significantly increased BMD at the lumbar spine (primary outcome) at 6 and 12 months and also significantly increased BMD at the hip and femoral neck at 12 months.24 At the time of publication of the ACP guideline, the group concluded that data on the benefits and harms of abaloparatide was inconclusive.23

The ACP’s review showed no difference in the risk for serious adverse events among males based on high-certainty evidence.23 Additionally, no difference in withdrawals due to adverse events or atrial fibrillation was found among males; this information was based on moderate- and low-certainty evidence, respectively.

Longer treatment with bisphosphonates in males was linked to a higher risk for atypical femoral fractures and osteonecrosis of the jaw, and zoledronate was linked to an increased likelihood of pyrexia, myalgia, and arthralgia in older males, according to the ACP.23

Conclusion

Osteoporosis is a highly underscreened and undertreated disease in men. Risk factors for osteoporosis are different in men vs women, and practitioners need to be aware of whom to screen and effective screening tools. More research is needed to determine if other newer classes of medications, such as injectable anabolic agents, would benefit men with osteoporosis who have comorbid liver diseases such as NAFLD, cirrhosis, and NASH. ■

Karen D. French, DNP, FNP-C, RN, is a practicing FNP in a large hepatology/GI practice in Southern California. She is director of the FNP program and an associate professor at Azusa Pacific University in Azusa, California.

References

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