During the past year several review articles have been published on the topic of osteoporosis in men. These reviews have highlighted recommendations for measuring bone mineral density (BMD) in older men as a means of screening for osteoporosis, use of the World Health Organization’s Fracture Risk Assessment Tool for predicting the risk of hip and major osteoporotic fractures, frequency of secondary causes of osteoporosis, useful laboratory tests to evaluate these conditions, newer treatments for men with osteoporosis that increase BMD and may reduce the risk of fractures, and new data on the prevalence of low BMD and osteoporosis in men.
During the past year several review articles have been published on the topic of osteoporosis in men. These reviews have highlighted recommendations for measuring bone mineral density (BMD) in older men as a means of screening for osteoporosis, use of the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) for predicting the absolute risk of hip and major osteoporotic fractures in men, the frequency of secondary causes of osteoporosis in men, laboratory tests that are useful in evaluating men for these conditions, and newer treatments (ie, zoledronic acid and denosumab) for men with osteoporosis that increase BMD and may reduce the risk of fractures. In addition, new data on the prevalence of low BMD and osteoporosis in men in the United States have been published. Finally, readers are recommended to keep abreast of this broad topic by accessing relevant sections in UpToDate.
Epidemiology
Osteoporosis, an asymptomatic disease of low bone mass, has received recognition as a public health problem in men, which is attributable not only to the expected increase in the aging population allowing men more years to experience bone loss, but also to the estimated increase in the consequences of low BMD, particularly the increased risk of suffering a fracture.
According to the National Osteoporosis Foundation (NOF), 10 million Americans older than 50 years are afflicted with osteoporosis (defined as a BMD less than 2.5 standard deviations below the mean [comprising young normals at peak BMD] or T score <−2.5 SD ) and 34 million with low bone mass, or osteopenia (−2.5 SD ≤ T score ≤−1.0 SD). While women are much more likely than men to be diagnosed with osteoporosis and osteopenia, men are also at risk of developing osteoporosis or low bone mass as they age. A more recent methodology for estimating the prevalence of osteoporosis in men applied the NOF guidelines for treatment. These guidelines are based on the WHO FRAX, which estimates a person’s 10-year fracture risk based on 10 risk factors. Using these new guidelines, Berry and colleagues found that 17% of men over the age of 50 years met treatment criteria. Dawson-Hughes and colleagues also applied the NOF guidelines to National Health and Nutrition Examination Survey (NHANES) data and found that an estimated 20% of men met the criteria for treatment of low bone mass.
Like women, men have an increasing prevalence of osteoporosis and osteopenia with increasing age; however, the prevalence of osteoporosis is low until 80 years and beyond. NHANES data showed that 27.4% of men aged 50 to 59 years had osteopenia and none had osteoporosis. These percentages rose to 49.1% and 16.6%, respectively, in men older than 80 years. The NOF estimates that the overall prevalence of osteoporosis will increase by almost 50% by the year 2020, when 61.4 million adults in the United States are expected to be affected. The overall prevalence of osteoporosis in men is also expected to increase by 50% in the next 15 years.
The prevalence of osteoporosis differs by race in both genders. White non-Hispanics still have the highest prevalence in both females and males (19%–20% female, 4%–5% male), and among men, non-Hispanic black men (3%) have a slightly higher prevalence than Hispanic men (2%).
Fractures
Having osteoporosis increases the susceptibility to fracture. Approximately 1.5 million fractures a year in the United States are attributable to low bone mass. The most common types of fractures are vertebral, hip, and wrist. The lifetime risk of any fracture for men after the age of 60 years is 25%, and the risk increases to 42% for men diagnosed with osteoporosis. Although diminishing bone strength increases the risk of fracture, the majority of fractures occur in individuals with osteopenia.
The estimated annual cost of fractures in the United States is upwards of $20 billion a year in medical costs. The cost for fractures associated with low bone mass in white men is about $3.2 billion per year. Even though vertebral fractures are the most prevalent of the fragility fractures, hip fractures are the most costly and are associated with the most serious outcomes.
Hip Fractures
In 2004 there were approximately 329,000 hip fractures in the United States and about 28% (93,000) occurred in men. At age 50 years, the lifetime incidence of hip fracture for men is 6% to 11%. Chang and colleagues found that for men the rate increased from zero per 100,000 person years in the 60- to 64-year age group to 1187 per 100,000 person years in the 85 years and older group. Whereas the incidence of hip fracture in women appears to be stabilizing, the incidence in men is on the increase. Cummings and colleagues reported from the Study of Osteoporotic Fractures in Men (MrOS) that a lower total hip BMD is associated with an increased risk of hip fracture, and this association is stronger in men than in women despite the higher incidence of hip fractures in women.
Outcomes of Hip Fracture
The consequences of a hip fracture can be severe. In general, men have poorer outcomes after hip fracture than women. Mortality rates are doubled in men. In a large study of more than 43,000 veterans, Bass and colleagues found that 32% of men died within a year of fracturing a hip. One explanation for the disparity in mortality rate is that men are often sicker at the time of the fracture than women. Men also have been found to have significantly more postoperative complications than women, which contribute to the increased mortality. Non-Hispanic whites in both genders have been found to have a better survival rate than other races after a hip fracture.
In addition, the risk of suffering a subsequent fracture increases 1.62-fold. Bischoff and colleagues found that in hip fracture patients, 10.3% of participants had a second fracture within 3 years and that men were more likely than women to sustain a second hip fracture (14.4% vs 9.5%). Functional recovery can be lengthy and in some instances, prefracture functional levels are not attained. Of those who were not institutionalized before fracture, 25% remain in an institution a year or longer after fracture, and as many as half of those who were functioning independently before fracture do not recover. Men have poorer function in physical activities in the 12 months after the hip fracture. In addition, having a diagnosis of osteoporosis can affect men’s perception of health. Men with the diagnosis of osteoporosis rated poorer mental health, vitality, and physical functioning according to the SF-36 health questionnaire compared with men without the diagnosis.
Risk factors for osteoporosis in men
Low Bone Mineral Density
Peak bone mass occurs for most individuals in their early 20s. Factors that influence peak bone mass are genetics, nutrition, exercise, smoking, and alcohol use ; however, McGuigan and colleagues found that exercise was the most important predictor for peak bone mass in men. Other significant predictors of peak bone mass in men are weight and alcohol intake. In general, at peak bone mass men have larger bones with greater mass than women.
Gender and race also have an impact on bone loss with age. While men lose bone mass with age, the average rate of bone loss in older men can reach 1% per year. In old age, men have lost about one-third of their trabecular bone mass. Studies have found that in both genders, blacks have a slower rate of decline in bone mass than whites.
There are several risk factors that appear to be more predictive of developing osteoporosis or osteopenia in men than others. Age, smoking, low body weight, weight loss, positive family history, prior fracture, alcohol use, long-term glucocorticoid use, physical inactivity, and inadequate calcium intake have all been found to be predictive of low bone density in men. The MrOS study also reported frailty, falls (factors that contribute to limitations of physical function), and low serum 25-hydroxyvitamin D as risk factors for low BMD in men. Overall, the evidence appears to be strongest for smoking, low body weight, weight loss, age, and long-term glucocorticoid use. It is estimated that up to 1 in 6 cases of male osteoporosis is related to glucocorticoid use.
Two additional risk factors have been found to be related to loss of bone mass in men: androgen deprivation therapy for prostate cancer and low testosterone levels. Androgen deprivation therapy has been found to decrease bone density in men receiving the treatment at 5 to 10 times the rate of healthy men or those not receiving treatment. The loss is most rapid during the first year of treatment and reverts back to normal age-associated loss after several years. Several studies have found that low testosterone levels in older men are also associated with bone loss. The majority of the literature now shows that whereas young men with low testosterone levels are at risk for low bone density, low testosterone levels in older men are not associated with bone loss ; rather, it is declining estradiol levels that are more correlated with bone loss in older men. Two studies found that the men with the greatest risk for hip fracture were those with both low estradiol and low testosterone levels, suggesting there may be a synergistic effect. It is postulated that the low testosterone levels contribute more to risk factors for falls through muscle mass or balance, and therefore increase the risk of fracture but not risk of low bone density.
Race is also a risk factor for men. Non-Hispanic black men have higher BMD than non-Hispanic white men and Hispanics. No evidence has been found that the risk factors for the development of osteoporosis vary within the races. However, there is some evidence that risk factors for fragility fracture vary by race, with androgen deprivation therapy being more of a risk for non-Hispanic white men and age a stronger risk factor for non-Hispanic black men.
Risk factors for osteoporosis in men
Low Bone Mineral Density
Peak bone mass occurs for most individuals in their early 20s. Factors that influence peak bone mass are genetics, nutrition, exercise, smoking, and alcohol use ; however, McGuigan and colleagues found that exercise was the most important predictor for peak bone mass in men. Other significant predictors of peak bone mass in men are weight and alcohol intake. In general, at peak bone mass men have larger bones with greater mass than women.
Gender and race also have an impact on bone loss with age. While men lose bone mass with age, the average rate of bone loss in older men can reach 1% per year. In old age, men have lost about one-third of their trabecular bone mass. Studies have found that in both genders, blacks have a slower rate of decline in bone mass than whites.
There are several risk factors that appear to be more predictive of developing osteoporosis or osteopenia in men than others. Age, smoking, low body weight, weight loss, positive family history, prior fracture, alcohol use, long-term glucocorticoid use, physical inactivity, and inadequate calcium intake have all been found to be predictive of low bone density in men. The MrOS study also reported frailty, falls (factors that contribute to limitations of physical function), and low serum 25-hydroxyvitamin D as risk factors for low BMD in men. Overall, the evidence appears to be strongest for smoking, low body weight, weight loss, age, and long-term glucocorticoid use. It is estimated that up to 1 in 6 cases of male osteoporosis is related to glucocorticoid use.
Two additional risk factors have been found to be related to loss of bone mass in men: androgen deprivation therapy for prostate cancer and low testosterone levels. Androgen deprivation therapy has been found to decrease bone density in men receiving the treatment at 5 to 10 times the rate of healthy men or those not receiving treatment. The loss is most rapid during the first year of treatment and reverts back to normal age-associated loss after several years. Several studies have found that low testosterone levels in older men are also associated with bone loss. The majority of the literature now shows that whereas young men with low testosterone levels are at risk for low bone density, low testosterone levels in older men are not associated with bone loss ; rather, it is declining estradiol levels that are more correlated with bone loss in older men. Two studies found that the men with the greatest risk for hip fracture were those with both low estradiol and low testosterone levels, suggesting there may be a synergistic effect. It is postulated that the low testosterone levels contribute more to risk factors for falls through muscle mass or balance, and therefore increase the risk of fracture but not risk of low bone density.
Race is also a risk factor for men. Non-Hispanic black men have higher BMD than non-Hispanic white men and Hispanics. No evidence has been found that the risk factors for the development of osteoporosis vary within the races. However, there is some evidence that risk factors for fragility fracture vary by race, with androgen deprivation therapy being more of a risk for non-Hispanic white men and age a stronger risk factor for non-Hispanic black men.
Diagnosis and evaluation
Measurement of Bone Mineral Density
The International Society of Clinical Densitometry (ISCD) last updated its official position statement at a Position Development Conference in 2007. The ISCD recommends BMD testing in all men aged 70 years and older, and in men younger than 70 with clinical risk factors for fracture, including a prior history of a fragility fracture, a disease or condition associated with low bone mass or bone loss, and if taking medications associated with low bone mass or bone loss.
BMD should be measured at the lumbar spine and total hip in all subjects. Forearm BMD should only be measured when hip and/or spine cannot be measured or interpreted or when the patient has hyperparathyroidism. A uniform reference database of Caucasian men should be used for calculation of T scores in all ethnic/racial groups. T scores should be used for diagnosis of osteoporosis in men aged 50 years and older; in men younger than 50, osteoporosis cannot be diagnosed solely based on results of BMD testing. The ISCD recommendations have been endorsed by the American Association of Clinical Endocrinologists, the American Society for Bone and Mineral Research, the Endocrine Society, the North American Menopause Society, and the NOF.
The American College of Physicians (ACP) published a clinical practice guideline for screening for osteoporosis in men in 2008. The guideline was based on a systematic literature review commissioned by the Agency for Healthcare Research and Quality. The ACP recommended (1) that clinicians periodically perform individualized assessment of risk factors for osteoporosis in older men; and (2) that clinicians obtain dual-energy x-ray absorptiometry (DXA) for men who are at increased risk for osteoporosis and are candidates for drug therapy. Factors that increase the risk for osteoporosis in men include age (>70 years), low body weight (body mass index <20–25 kg/m 2 ), weight loss (>10% [compared with the usual young or adult weight or weight loss in recent years]), physical inactivity (participates in no physical activities on a regular basis [walking, climbing stairs, carrying weights, housework, or gardening]), corticosteroid use, androgen deprivation therapy, and previous fragility fracture. The US Preventive Services Task Force (PSTF) updated its recommendations in 2010; however, despite evidence in men from longitudinal observational cohort studies that the risk of both vertebral and nonvertebral fractures increases as BMD declines, the PSTF again failed to recommend routine screening of older men for osteoporosis with DXA.
The Department of Veterans Affairs issued an Information Letter in September 2009 concerning osteoporosis in men; this letter was updated in April 2001. It is recommended that an algorithm be used as a guide to choosing which men should be screened for osteoporosis using DXA ( Fig. 1 ). Men older than 50 years with any of several underlying conditions are candidates for osteoporosis screening. Examples are men on oral glucocorticoid therapy, those who have already suffered a low-trauma fracture, men treated with androgen deprivation therapy for prostate cancer or anticonvulsants for seizure disorders, and men with malabsorption or alcohol abuse. Men with these and other risk factors need to be considered for bone density testing with DXA.
Evaluation for Secondary Causes
It is estimated that 30% to 60% of osteoporosis in men is secondary, which results from a particular disease or as a result of a medication. Hypogonadism is one such secondary cause and it is the failure of the testes to produce androgen, sperm, or both. The prevalence of hypogonadism is uncertain, although the results of one study found that prevalence varies across age groups, from 7% of men aged 40 to 60 years, 22% of men 60 to 80 years, and 36% of men 80 to 100 years. Apparent decline in total testosterone in these individuals is compounded in frequency by permanent disorders of the hypothalamic-pituitary-gonadal axis.
Classification of primary or secondary hypogonadism is determined based on the location of the abnormality on the hypothalamic-pituitary-testicular axis. Those with primary hypogonadism have low testosterone, high luteinizing hormone, and high follicle-stimulating hormone levels. The major causes of primary hypogonadism include genetic causes such as Klinefelter syndrome, congenital causes such as anorchia, toxins including alcohol and heavy metals, orchitis, trauma, infarction, and aging. A diagnosis of secondary hypogonadism means that an individual has low testosterone, low luteinizing hormone, and low follicle-stimulating hormone levels. The major causes of secondary hypogonadism include pubertal delay and hypogonadotropism, a condition caused by decreased production of gonadotropins. Despite the differences in classification and abnormalities presented between primary and secondary hypogonadism, studies have established that men with either diagnosis have significantly lower BMD relative to normal men. In a study of elderly male nursing home residents, of the 5% to 15% of residents who sustained a prior hip fracture, 66% were found to have hypogonadism (<300 ng/dL). Hypogonadism was present in up to 20% of men with vertebral crush fractures even though many of these men did not have other clinical features of hypogonadism.
While a clear association exists between the diagnosis of hypogonadism and risk of low BMD, the literature supporting the association between age-related loss of testosterone and BMD is less consistent. The role of testosterone in maintaining bone homeostasis has been examined in numerous epidemiologic studies with varying conclusions. While it is recognized that normal levels of testosterone are essential in attaining optimal peak bone mass, testosterone’s effect on bone formation and resorption is less clear. The uncertainty exists because of the different causes of low testosterone.
Age-related declines in testosterone are inevitable and result from either a defect in testicular function, hypothalamic-pituitary function, or both. Although older men have testosterone levels similar to those diagnosed with hypogonadism, they represent a special case due to the late onset of symptoms. The presence of low testosterone in later life leads to different outcomes from one who is diagnosed with primary or secondary hypogonadism. Therefore, it is important to understand the difference in the presentation of symptoms as well as the possible treatment modalities for low testosterone independent of hypogonadism. A recent cross-sectional study examining the relationship between testosterone and BMD in a diverse population of men was unable to discover any significant correlation after controlling for age (utd, 43). These results coincide with previous studies. However, results from the MrOS study suggest a significant association between testosterone (total, free, and bioavailable) and BMD. The difference in results may be attributed to the cross-sectional design and different populations.
The authors are uncertain as to the consequences of low testosterone in later life, due to a paucity of long-term prospective studies identifying individuals at risk of low testosterone at younger ages. Therefore, there remains a need for long-term cohort studies to clarify the association between these two factors and to minimize temporal ambiguity. It is also necessary to evaluate the impact of varying levels of low testosterone as opposed to no testosterone, such as is found with castrated men, to fully understand the impact of testosterone on BMD.
Treatment of osteoporosis in men
Treatment options for osteoporosis include lifestyle modification including calcium and vitamin D supplementation, weight-bearing exercise, smoking cessation and reduction in alcohol intake as well as prescription medications. According to the Institute of Medicine, the recommended dietary allowance for men aged 70 and above for calcium is 1,200 mg per day while that for vitamin D is 800 International Units (IU) per day.
The major class of prescription drugs used in the treatment of osteoporosis in men is bisphosphonates. Three of these are approved by the U.S. Food and Drug Administration (FDA) for treatment of osteoporosis in men: alendronate, risedronate, and zoledronic acid. Alendronate and risedronate are both administered as oral medications while zoledronic acid is administered as an intravenous (IV) infusion. Alendronate should be given at a dose of either 70 mg once weekly or 10 mg daily. Risedronate should be given at a dose of 35 mg once weekly; note that the 150 mg once monthly dose is not FDA approved for use in men. Zoledronic acid should be given at a dose of 5 mg once yearly by IV infusion; it is particularly useful for the patient who is unable to sit or stand upright for at least 30 minutes or with a disorder of the esophagus that impedes swallowing and complete esophageal emptying. All bisphosphonates are contraindicated in patients with hypocalcemia.
Teriparatide, recombinant human parathyroid hormone 1-34, is also approved for treatment of osteoporosis in men; it should be given at a dose of 20 mcg daily as a subcutaneous injection. Teriparatide is indicated in men with primary or hypogonadal osteoporosis at high risk of fracture. In our opinion, it should be reserved for patients who have contraindications to or are intolerant of bisphosphonates, or are considered to have failed bisphosphonate therapy. At this time, denosumab is not yet approved for treatment of osteoporosis in men. We recommend that all health care providers read the Product Information for each compound in order to familiarize themselves with the contraindications, warnings and precautions, adverse reactions and drug interactions for each compound as well as the section on Patient Counseling Information.
The detection and treatment of osteoporosis has been found to be cost-effective and lower mortality in both women and men. NOF recommends that men aged 50 years and above with either (1) a hip or vertebral fracture, (2) osteoporosis based on BMD testing (T-score of -2.5 or below at either the lumbar spine or femoral neck, or (3) low BMD (T-score between -1.0 and -2.5) and a 10-year probability of fracture of ≥20 percent for major osteoporotic fractures or ≥3 percent for hip fracture be treated with pharmacologic agents to reduce their fracture risk.
In spite of the evidence that men are at risk for low bone mass and fractures, there is a gap in care that exists. Men and racial minorities are less likely to be treated for low bone mass post-fracture than non-Hispanic white women. Currently no state or federal coverage for screening or education about osteoporosis exists for men.
As previously mentioned, low serum testosterone may be a risk factor for low BMD and osteoporosis. As a result of this association, testosterone has been used as a possible treatment for low BMD and osteoporosis. Testosterone therapy should provide physiologic range serum testosterone levels (280–800 ng/dL) and physiologic range dihydrotestosterone and estradiol levels. These testosterone levels have been successful in providing optimal virilization and normal sexual function for men.
Some clinical trials that have been performed to test the efficacy of testosterone treatment for low BMD have shown efficacy. In adolescent male patients with hypogonadotropic (primary) hypogonadism, testosterone therapy increased BMD in comparison with that in male patients with hypogonadism not receiving testosterone. In men with prepubertal-onset hypogonadotropic hypogonadism, however, diminished bone mass may be only marginally improved by testosterone replacement. The number of studies that have analyzed the effect of testosterone therapy on BMD levels in older men is limited.
Clinical trials performed to identify whether or not testosterone replacement therapy is beneficial in increasing BMD, and reducing fracture risk and rate of bone loss have been limited in sample size and design, as many trials have not utilized a randomized design. In addition to improved study characteristics, contraindications for testosterone therapy need to be considered. Hormone therapy may be contraindicated by age. While no limit has been definitively established, it is possible that this contraindication exists for men older than 80 years old. Other contraindications for testosterone therapy include the presence of prostate cancer, male breast cancer, and untreated prolactinoma, as treatment for these diseases can stimulate tumor growth in androgen-dependent neoplasm. Further understanding of the contraindications and risks of testosterone treatment should be evaluated before this treatment is advised for the overall male, low-testosterone population.
Glucocorticoid-induced Osteoporosis
The man with glucocorticoid-induced osteoporosis (GIOP) presents a special problem, particularly for the rheumatologist. Adler and Hochberg recently reviewed the pathophysiology of GIOP and the evaluation and management of men receiving glucocorticoid therapy. The American College of Rheumatology revised its recommendations for the prevention and management of men aged 50 and above with GIOP in 2010. Men are stratified on risk to either a low, medium or high risk group. High risk is defined in men as a BMD T-score of -2.5 or below or a 10-year risk of major osteoporotic fracture greater than 20% using the FRAX algorithm. Medium risk is defined in men as a 10-year risk of major osteoporotic fracture between 10 and 20% with a BMD T-score between -1 and -2.5 (except in Caucasian men aged 80 and above wherein the BMD T-score can be as high as -0.5); and low risk is defined in men as a 10-year risk of major osteoporotic fracture less than 10%. All men at either medium or high risk should receive pharmacologic therapy in addition to calcium and vitamin D supplementation and lifestyle modification. For men at low risk, pharmacologic therapy is recommended only for those receiving daily glucocorticoid doses of 7.5 mg or above prednisone equivalent. Men below the age of 50 years are treated with pharmacologic therapy only if they have a prevalent fragility fracture. Finally, men receiving glucocorticoids who have low serum testosterone levels should be considered for testosterone therapy, in the absence of contraindications, as data suggest that testosterone replacement increases BMD.
Disclosures: Dr Orwig, Ms Chiles, and Mr Jones have nothing to disclose. Dr Hochberg is a consultant to Amgen, Eli Lilly and Co., Genentech/Roche, Merck & Co., Inc and Novartis Pharma AG.
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