INTRODUCTION — Osteoporosis is a common disease that is characterized by low bone mass with microarchitectural disruption and skeletal fragility, resulting in an increased risk of fracture. It is a leading cause of morbidity and mortality in older people.
The disorders that cause osteoporosis in men are similar to those in women (table 1). Epidemiologic surveys suggest that causes or contributing factors for osteoporosis can be identified in 40 to 60 percent of men who have osteoporotic fractures [1-3]. Hypogonadism, glucocorticoid therapy, gastrointestinal disease, vitamin D deficiency, antiseizure medication therapy, hypercalciuria, and alcohol use disorder were among the most common identifiable causes of osteoporosis in these surveys [2-5].
The etiology of osteoporosis in men will be reviewed here. The epidemiology of osteoporosis, fracture risk assessment, and the evaluation and treatment of osteoporosis in men are discussed separately. (See "Screening for osteoporosis in postmenopausal women and men", section on 'Epidemiology' and "Osteoporotic fracture risk assessment" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men" and "Treatment of osteoporosis in men".)
PATHOPHYSIOLOGY — Decreased bone mass can occur either because pubertal bone accretion is reduced or because the rate of bone resorption is accelerated after peak bone mass is achieved. Both of these processes are likely to contribute, in varying degrees, to osteoporosis in individual patients. (See "Pathogenesis of osteoporosis".)
Peak bone mass acquisition — Peak bone mass is the maximum bone mass achieved in life. The time of peak bone mass is not known with certainty, but probably occurs in the third decade of life in most individuals, with differences in timing due to genetic, hormonal, and environmental variables. (See "Pathogenesis of osteoporosis", section on 'Peak bone mass acquisition'.)
In men, bone mineral density (BMD) increases markedly during puberty in response to increasing sex steroid production [6,7]. Much of this apparent increase, particularly for cortical bone, is due to an increase in bone size. Peak spinal bone density is reached at approximately 20 years of age [8-10], while the peak density of the radius and femoral shaft is reached somewhat later [9-11].
●Sex steroids – The importance of normal sex steroid production in the acquisition of peak bone mass is illustrated by the findings of low bone mass in young men with idiopathic hypogonadotropic hypogonadism (IHH), a congenital disorder of gonadotropin-releasing hormone (GnRH) deficiency (see "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)"). In studies of men with IHH who do not undergo puberty unless they are treated appropriately, both cortical and trabecular bone density are markedly reduced [12,13]. Bone mass is reduced even during the period of rapid bone accrual before peak adult BMD is reached, suggesting that the finding of low BMD in adult men with IHH is due to inadequate pubertal bone accretion rather than excessive post-maturity bone loss. Although the observation that peak BMD is reduced in men with IHH illustrates the importance of gonadal steroids in pubertal bone accrual, that finding does not indicate whether androgens, estrogens, or both are primarily responsible for the pubertal increase in BMD.
●Androgens versus estrogens – Both estrogens and androgens have profound effects on bone homeostasis in men. Individuals with mutations that lead to complete estrogen or androgen insensitivity provide valuable insights into the independent roles of androgens and estrogens in the attainment of peak bone mass. For example, the observation that BMD is markedly reduced in men with null mutations in the estrogen receptor gene demonstrates that estrogens play a key role in the attainment of peak bone mass in men. Similarly, the marked reduction in BMD in men with null mutations in the androgen receptor gene demonstrates that androgens also play a key role in the attainment of peak bone mass. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Complete androgen insensitivity (CAIS)' and "Pathogenesis of osteoporosis", section on 'Sex steroid deficiency'.)
●Timing of puberty – Another important determinant of peak bone density is the timing of puberty. In adult men with a history of constitutionally delayed puberty, BMD of the radius, lumbar spine, and proximal femur is significantly lower than in age-matched normal men, and BMD does not appear to normalize even after sex steroid production is restored [14,15]. Similar findings have been reported in adolescent boys with delayed puberty [16]. These observations suggest that there is a critical period of time during which gonadal steroids are needed in order to achieve optimal peak BMD in men. (See "Approach to the patient with delayed puberty".)
Age-related bone loss — After attainment of peak bone mass, men lose approximately 30 percent of their trabecular bone and 20 percent of their cortical bone during their lifetimes. Trabecular bone loss appears to start shortly after peak BMD is reached whereas cortical bone loss begins somewhat later [17]. Acceleration of age-related bone loss can occur either when bone resorption is increased or when bone formation is impaired during skeletal remodeling.
When spine BMD is measured [18,19] using dual-energy x-ray absorptiometry (DXA) in the posterior-anterior projection, it often appears to increase in older men [20-22], likely due to degenerative changes in the posterior spinous elements (figure 1) [21]. This limitation of posterior-anterior spine DXA for evaluation of spine BMD in older men can be circumvented by measuring lateral spine BMD by DXA or by assessing spine BMD using quantitative computed tomography (QCT) to assess trabecular BMD without including the posterior spinous elements. (See "Overview of dual-energy x-ray absorptiometry", section on 'Clinical applications of DXA'.)
●Sex steroids – Although gonadal steroids appear to play a crucial role in the attainment of peak bone mass in men, whether they play a significant role in age-related bone loss is less clear. Unlike in women, in whom the menopause marks the end of robust estradiol production, the rate of age-related gonadal steroid decline is much less abrupt in men, and most men maintain normal adult levels of testosterone throughout life. As a result, men do not undergo a period of rapid bone loss as seen in women at the onset of the menopause. The skeletal impact of these more subtle declines in sex steroids is unclear. Several approaches have been used to assess the role of gonadal steroids in adult bone loss.
Numerous epidemiologic studies have reported associations between gonadal sex steroids and BMD or fractures [23-27]. Overall, these epidemiologic associations are weak, however, as might be expected when studying different populations and relating a single hormone measurement to complex endpoints like bone density and fracture.
•Testosterone – Some studies have reported significant associations between testosterone, free testosterone, and/or bioavailable testosterone and BMD, rates of bone loss, and prevalent fragility fractures [23-25] whereas others have not [26,28]. For example, in the Osteoporotic Fractures in Men Study (MrOS), a cross-sectional and longitudinal study of 2447 men over 65 years of age, the prevalence of osteoporosis in the hip or of rapid hip bone loss was threefold higher in men whose total testosterone level was <200 ng/dL (6.9 nmol/L) compared with men whose serum testosterone level was higher (figure 2) [23].
•Estrogen – In general, associations of bone density with estrogens have been slightly stronger than associations with androgens [26]. In the MrOS study, the prevalence of osteoporosis in the hip (T-score <-2.5) increased progressively as total or bioavailable estradiol levels fell (figure 2) [23]. In addition, low serum estradiol levels have been associated with an increased risk of future hip fracture in men [27]. Fracture risk appears to be even greater in men with both low serum estradiol and testosterone concentrations [26,27].
Several physiologic studies have concluded that regulation of bone turnover in adult men is primarily accomplished by estrogen [29-31]. In one physiologic study, 198 healthy men (ages 20 to 50 years) were treated with a GnRH agonist (to temporarily suppress endogenous sex steroid production) and were then randomized to receive 0 (placebo), 1.25, 2.5, 5, or 10 grams of a testosterone gel daily for 16 weeks [31]. A second group of 202 healthy men received the same doses of testosterone as well as anastrozole (to suppress aromatization of testosterone to estradiol). By comparing changes in bone turnover markers, BMD by DXA, and BMD by QCT between men who did and did not receive anastrozole, the study demonstrated that increases in bone resorption and decreases in BMD in hypogonadal men were largely due to estrogen deficiency (figure 3). The risk of developing hypogonadal bone loss appeared to be small until serum estradiol levels fell below 10 pg/mL and/or serum testosterone levels fell below 200 ng/dL.
●Other hormones – Other hormonal changes that may be associated with age-related bone loss include higher serum parathyroid hormone (PTH) concentrations and lower serum 25-hydroxyvitamin D and insulin-like growth factor 1 (IGF-1) concentrations [32-34]. Suppression of gonadal steroids in older men with a GnRH agonist increases the skeletal responsiveness to pharmacologic doses of exogenous PTH, an observation that might help to explain bone loss in men with hypogonadism [35]. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Systemic and local regulators of bone cells'.)
ETIOLOGY — The medical disorders that cause osteoporosis in men are similar to those in women (table 1). Epidemiologic surveys suggest that secondary causes for osteoporosis can be identified in 40 to 60 percent of men who have osteoporotic fractures [1-3]. Hypogonadism, glucocorticoid therapy, gastrointestinal disease, vitamin D deficiency, low body mass index (BMI), antiseizure medication therapy, hypercalciuria, diabetes mellitus, current smoking, and alcohol use disorder were among the most common identifiable causes of osteoporosis in these surveys [2-5,36].
Risk factors that have been demonstrated to be most predictive of osteoporotic fractures in men include low bone mineral density (BMD), advancing age, a prior history of fragility fracture, chronic glucocorticoid use, and parental history of hip fracture (figure 4) [36,37]. (See "Osteoporotic fracture risk assessment", section on 'Clinical risk factor assessment'.)
Brief comments on some of the etiologies follow; more detailed reviews are presented elsewhere. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Bone disease with hyperthyroidism and thyroid hormone therapy" and "Bone disease in diabetes mellitus" and "Metabolic bone disease in inflammatory bowel disease" and "Drugs that affect bone metabolism".)
Hypogonadism — Gonadal steroids play an important role in attainment and maintenance of BMD in men (see 'Peak bone mass acquisition' above and 'Age-related bone loss' above). Bone turnover increases and BMD decreases in men with serum testosterone levels that are below approximately 200 ng/dL, likely because serum estradiol levels fall below 10 to 15 pg/mL [31].
Cross-sectional studies demonstrate that BMD is reduced in men with primary or secondary hypogonadism [12,38-42], constitutional delay of puberty [14,15], idiopathic hypogonadotropic hypogonadism (IHH) [12,13], and in individuals with androgen insensitivity [43,44]. (See "Causes of primary hypogonadism in males" and "Causes of secondary hypogonadism in males" and "Diagnosis and treatment of disorders of the androgen receptor".)
Osteoporosis has also been reported in hypogonadal men with hemochromatosis [39,45] and anorexia nervosa [46]. In these men, it is difficult to determine whether the osteopenia is due to concomitant liver disease and nutritional deficiencies or to hypogonadism. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)
There have been few longitudinal studies of men at risk for osteoporosis because of hypogonadism. Bone density decreases in young men who are castrated for sexual delinquency [47] and in older men with advanced prostate cancer who undergo androgen ablation therapy [48-51]. (See "Side effects of androgen deprivation therapy", section on 'Osteoporosis and bone fractures'.)
Severe hypogonadism increases the risk of fractures in men:
●In one study of 235 men with prostate cancer, 14 percent of those treated with orchiectomy (n = 59) later had osteoporotic fractures, compared with 1 percent in those who did not undergo orchiectomy (n = 176) [52]. Among the 16 men who survived for at least five years after orchiectomy, six (38 percent) had a nontraumatic fracture that was not attributable to their cancer.
●The increase in fracture risk with androgen deprivation therapy (rather than orchiectomy) may be more modest. This was illustrated in a much larger study of 50,613 men with a diagnosis of prostate cancer; 19 percent of 6650 men who survived at least five years after diagnosis (and who received androgen-deprivation therapy) had a fracture (compared with 12 percent of the 20,035 patients who did not receive androgen-deprivation therapy) [53].
Reduction in BMD can be detected after as little as six to nine months of androgen deprivation therapy. Thus, all men beginning such therapy should receive calcium and vitamin D and maintain a moderate exercise regimen [54]. Treatment with calcium and vitamin D alone, however, is not sufficient to prevent bone loss in these men. Baseline measurement of bone density and periodic reassessment during therapy are appropriate, and bisphosphonate therapy should be considered. (See "Treatment of osteoporosis in men" and "Side effects of androgen deprivation therapy", section on 'Osteoporosis and bone fractures'.)
Lifestyle factors
●Smoking and alcohol – Both cigarette smoking and excess alcohol intake are associated with increased rates of bone loss and fracture [55,56] (see "Osteoporotic fracture risk assessment", section on 'Cigarette smoking'). Alcohol intake is inversely associated with bone density in men [57,58], and osteoporotic fractures are common in men with alcohol use disorder [3,59]. The mechanism whereby alcohol reduces bone density is unknown but appears to be related to decreased bone formation.
●Calcium and vitamin D – In observational studies, vitamin D deficiency is associated with osteoporosis, poor physical performance, and an increased risk of fractures [4,33,60]. Evidence supporting the benefit of calcium and vitamin D supplementation in men with osteoporosis comes largely from prospective, randomized, placebo-controlled trials [61,62]. Although a number of trials have reported a beneficial effect of calcium or calcium plus vitamin D on bone density in postmenopausal women and older men [61-65], the data on fracture rates are more variable [66]. This topic is reviewed in detail separately. (See "Calcium and vitamin D supplementation in osteoporosis".)
●Physical activity and strength – Low levels of physical activity are associated with bone loss [1,67-69] and a higher risk of fracture in older men [70-73]. As an example, in a cohort study of 2205 men aged 49 to 51 years, low or medium levels of physical activity were associated with more than a twofold higher risk of fracture, including hip fracture, compared with high physical activity [73]. Hip fracture occurred in 20.5, 13.3, and 8.4 percent of men with sedentary lifestyle, medium physical activity, and high physical activity, respectively (hazard ratios [HRs] for low- or medium-activity compared with high-activity groups 2.56 [95% CI 1.55-4.24] and 1.61 [95% CI 1.10-2.36], respectively).
●Body weight – Body weight is positively associated with bone density in older men, and weight loss appears to increase the rate of hip bone loss, even in obese men undergoing voluntary weight reduction [74]. Low BMI is a well-known risk factor for fracture in men, just as in women [75].
Glucocorticoid excess — Both endogenous and exogenous glucocorticoid excess cause osteoporosis in men as well as in women. The osteoporosis is due primarily to the effects of glucocorticoid excess on bone, but glucocorticoid-induced hypogonadism may be a contributory factor. Glucocorticoid excess, which is nearly always caused by exogenous glucocorticoid therapy, is responsible for approximately 15 percent of vertebral fractures in men [3,76], but some of the bone disease may be due to the underlying disorders for which glucocorticoids are given rather than the glucocorticoid therapy itself. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)
Diabetes mellitus — Although type 2 diabetes mellitus is generally associated with higher bone density, men with diabetes suffer an increased risk of fractures [77-79] as compared with those without diabetes. As in women, fracture rates are highest among men with diabetes who take insulin [80], which likely reflects a combination of increased fall risk, greater diabetic severity, and microvascular disease burden, as well as compromised bone quality. (See "Bone disease in diabetes mellitus".)
Hypercalciuria — Men with hypercalciuria may have lower BMD than expected for age, particularly those in whom hypercalciuria persists despite a low calcium diet [81-86].
Idiopathic osteoporosis — The 40 to 60 percent of men with osteoporosis in whom a cause cannot be identified are said to have idiopathic osteoporosis. Histomorphometric studies suggest that many have diminished bone formation [87-89], but some have increased bone resorption [90]. Many of these men probably have a genetic predisposition to osteoporosis [91].
Serum insulin-like growth factor 1 (IGF-1) concentrations are low in some men with idiopathic osteoporosis (see "Normal skeletal development and regulation of bone formation and resorption", section on 'Growth hormone and IGFs'). Approximately 2 to 3 percent of men have a history of delayed puberty, which could be a precursor of idiopathic osteoporosis. Estrogen deficiency may also be responsible for otherwise unexplained osteoporosis in some men. (See 'Pathophysiology' above and 'Hypogonadism' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)
SUMMARY
●Pathophysiology – Low bone mass in men may be due to suboptimal peak bone mass acquisition, ongoing bone loss, or reduced bone formation during remodeling. Normal sex steroid production is necessary for the acquisition of peak bone mass in men. The rate of age-related gonadal sex steroid decline in men is much less abrupt than in women, and most men maintain normal adult levels of testosterone throughout life. (See 'Pathophysiology' above.)
●Etiology – A cause for osteoporosis can be identified in 40 to 60 percent of men who have osteoporotic fractures. Hypogonadism, glucocorticoid therapy, gastrointestinal disease, vitamin D deficiency, antiseizure medication therapy, hypercalciuria, diabetes mellitus, and alcohol use disorder are among the most common identifiable causes of osteoporosis in men (table 1). (See 'Etiology' above.)
The risk factors most predictive of osteoporotic fracture in men include low bone mineral density (BMD), advancing age, a prior history of fragility fracture, chronic glucocorticoid use, and parental history of hip fracture (figure 4).
