Osteoporosis, a metabolic bone disease characterized by low bone mass, microarchitectural deterioration of bone tissue, and increased susceptibility to fracture now is recognized to be a disease of men and women.7 Based on bone mineral density (BMD) measurements established by the World Health Organization (WHO), approximately 8 million women and 2 million men in the United States currently are affected.26 The prevalence of osteoporosis is lower in men than in women for several reasons: a greater accumulation of skeletal mass during growth, a greater bone size, an absent midlife menopause, a slower rate of bone loss, and a shorter male life expectancy.2 Nevertheless, osteoporosis in men is an increasing public health concern. Men sustain approximately 30% of all hip fractures worldwide.41 These hip fractures in men are associated with a greater morbidity and mortality than in women. In fact, 20% of the annual $20 billion directed to the treatment of osteoporotic fractures in the United States goes to the treatment of men.17 As the current population ages and the life expectancy of men improves, this figure will increase.
Testosterone had been assumed to be the key sex steroid involved in bone metabolism in men. However, as a result of two case reports, estrogen is now known to be necessary for normal skeletal maturation and for maintenance of adult bone mass in men.4,44 In fact, the reason for the age-related decline in BMD in men seems to be an age-related decline in the levels of bioavailable estrogen.24
Osteoporosis is a multifactorial, polygenic disease.16 As this review will show, many types of genes are involved in bone metabolism. Such genes include those coding for structural proteins, such as Type I collagen and the vitamin D receptor, and genes involved in sex steroid metabolism. These categories of genes, and others, are referred to as osteoporosis candidate genes.16 Polymorphisms have been discovered in these genes, and investigations into their associations with a male osteoporotic phenotype are in their early stages.37
The hypothesis that BMD is a determinant for fracture risk is well established. In 1994, the WHO established diagnostic criterion for the detection of osteoporosis based on BMD values attained in women.2 The applicability of these criteria to men has not been accepted, largely because no official consensus has been reached yet. As we will explain, at issue is whether gender differences in the BMD-fracture risk relationship necessitate different BMD guidelines for women and men.
Treatment of osteoporosis involves prevention and intervention. General prevention strategies aim to maximize peak bone mass and minimize bone loss. Studies have identified alendronate as an effective treatment of osteoporosis in men.1,34 Another important treatment of osteoporosis in men is intermittent parathyroid hormone (PTH), the first bone forming agent approved for the treatment of osteoporosis.3
Information about the pathogenesis, diagnosis, and treatment of osteoporosis in men is accumulating. Specific topics to be addressed include the role of sex steroids and genetics in the development of osteoporosis in men, risk factors for low bone mass and fracture, the sensitivity of bone density in predicting fractures in men, gender differences in fracture patterns, and treatments for osteoporosis in men.
The Role of Sex Steroids on Bone Mass in Men
It has been recognized that estrogen plays a crucial role in the maintenance of bone mass in women. The role of sex steroids on the male skeleton has a more controversial history. Testosterone had been assumed to be the key sex steroid involved in bone metabolism in men. However, the report of two cases of rare genetic disorders associated with estrogen resistance and estrogen deficiency showed that androgens are not the only sex steroids responsible for achieving peak bone mass in males.4,44 A 24-year-old man with aromatase deficiency presented with reduced bone mass, immature bone age, unfused epiphyses, and an undetectable serum estradiol concentration (aromatase activity is necessary for conversion of testosterone to estradiol).4 Subsequent estrogen treatment dramatically increased this patient’s bone mass and led to epiphyseal fusion. Another case report described a 28-year-old man with decreased bone mass and unfused epiphyses who had estrogen resistance.44 This patient did not respond to estrogen replacement therapy. Therefore, the importance of estrogen for normal skeletal maturation and maintenance of adult bone mass in men became clear.
Estrogen deficiency is the primary cause of the early, rapid phase of postmenopausal bone loss and increased fracture risk in women.43 The subsequent, slower phase of postmenopausal bone loss also may be secondary to these declining levels of estrogen. Men do not experience such a sudden reduction in the levels of sex steroid hormones. In fact, aging men experience only minimal reductions in the overall levels of testosterone and estrogen.43 Despite the lack of a precipitous decline in total sex steroid levels, men do experience substantial age-related decreases in BMD. The reason for this age-related decline in BMD in men seems to be an age-related decline in the levels of bioavailable estrogen.24
Bioavailable estrogen refers to the fraction of estrogen with access to tissues. In contrast, those steroids bound to steroid hormone binding globulin (SHBG) do not have ready access to tissues. Herein describes the difference between total and free estrogen. Although the levels of total estrogen remain relatively stable in aging men, the levels of estrogen available to exert influences on bone actually decline. The differences between total and free testosterone follow a similar pattern. An age-related increase of SHBG accounts for the reduced fraction of free sex steroids in aging men. It is unknown why the concentration of SHBG increases in aging males.24
Although healthy aging men do have considerable reductions in the levels of bioavailable estrogen and testosterone, only the declines of free estrogen have been shown to be consistent, independent predictors of BMD in men.24 Additional studies have offered explanations as to how this free estrogen might act on bone to prevent age-related bone loss. A cross-sectional analysis of a cohort of men who were 51–85 years showed low levels of bioavailable estrogen were correlated with high bone turnover and low BMD.47 These results suggest an antiresorptive role for estrogen in preventing bone turnover. Moreover, the results indicate that age-related bone loss in men may be the result of an increased turnover rather than a suppressed bone formation.47
In an effort to elucidate how free testosterone and estrogen act on the aging male skeleton, Falahati-Nini et al11 eliminated the endogenous production of these steroids in elderly men and then studied these subjects under conditions of selective physiologic replacement. Urinary bone resorption and formation markers were measured under three conditions, the administration of testosterone and estrogen, testosterone alone, and absence of testosterone and estrogen. Results indicate that estrogen is indeed the major sex steroid regulating bone resorption in elderly men.11 That is, the absence of estrogen was associated with the largest increase in urinary resorption markers. Testosterone and estrogen were equally effective in preventing a decrease in the bone formation marker osteocalcin, suggesting a shared role in bone formation in the aging male skeleton.11 Understanding how these sex steroid hormones function at the cellular level is an area of continuing study.
Testosterone and estrogen, as steroid hormones, bind to nuclear receptors. The steroid hormone-receptor complex then functions as a transcriptional regulator within the cell nucleus.15 Estrogen receptors α and β have been identified on osteoblasts and bone marrow stromal cells. It is unknown whether estrogen receptors exist on osteoclasts, although some reports suggest that estrogens act on osteoclasts directly. It is thought that estrogens do act on osteoclasts indirectly by suppressing the production of bone resorbing cytokines. In states of estrogen deficiency, interleuken-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α) are elevated, appearing to act cooperatively to induce bone resorption.15 Androgens may act on bone directly through the androgen receptor or indirectly through its aromatization to estrogens. Androgen receptors have been shown on osteoblasts, marrow stromal cells, and osteoclasts.15 The extent to which the effects of testosterone are indirect, mediated by the peripheral conversion of testosterone to estrogen, is unknown. Regardless, it is accepted that testosterone is necessary for the development of the sexually dimorphic male skeleton at puberty and the periosteal growth of cortical bone. This periosteal bone growth is responsible for a greater bone size and peak bone mass in males.2
Hypogonadism, either primary or acquired, is a major risk factor for secondary male osteoporosis. As indicated previously, the impact of hypogonadism on the male skeleton may be caused by the effects of decreased testosterone available for aromatization to estradiol. Men with isolated hypogonadotropic hypogonadism (IHH) present with delayed puberty and experience a period of testosterone deficiency during active growth. Such patients have been shown to have markedly decreased BMD and increased susceptibility to fracture.13 Despite normalization of their serum testosterone levels, these patients’ BMD remained below normal.19 Men with constitutionally delayed puberty also have been shown to have diminished bone mass compared with normal men.13 These observations suggest that timing of puberty is an important determinant of peak bone mass.
Acquired hypogonadism is a more common and increasingly recognized problem. Testosterone replacement therapy has been shown to reduce bone remodeling and increase trabecular BMD in these patients.23 Although men experience a gradual decrease in testosterone levels with age, testosterone replacement therapy has only been shown to improve bone mass in patients with notable hypogonadism (testosterone < 200 ng/dL).46
Osteoporosis frequently is encountered in men receiving androgen deprivation therapy for prostate cancer. Such androgen deprivation therapy accelerates bone loss and increases the risk for fracture.45 As with all malignancies, diet, activity level, and treatment-related loss of lean body mass also may contribute to fracture risk. Increased attention is being devoted to the prevention of osteoporosis and fracture in these patients through the use of bisphosphonates.45
Genetics of Male Osteoporosis
Except for rare conditions, osteoporosis is considered a multifactorial, polygenic disease in which genes are modified by hormones, environment, and nutrition.16 To date, the majority of research into the genetics of osteoporosis has been conducted in women. Much of this work has relied on population-based, case-control association studies of genes involved in bone metabolism.16 These so-called candidate genes code for sex steroid hormones and receptors, bone matrix proteins, cytokine and growth factors, and calcitropic hormones and receptors. Although studies into how these genes modulate male BMD and osteoporotic phenotype are fewer than in women, there is ample evidence to support the notion that genetic factors are an important determinant of male osteoporosis. For example, family-based studies have indicated that bone mass is considerably lower in the relatives of men with osteoporosis.5,10 In addition, two landmark case reports have described male osteoporosis syndromes resulting from mutations in the aromatase and estrogen receptor genes, respectively.4,44
It now is apparent that estrogen deficiency is one of the leading causes of osteoporosis in males and females.16 In light of this observation, the genes involved in sex steroid metabolism (those genes coding for aromatase and the sex steroid hormone receptors) all are possible sources for the observed phenotypic variation in BMD and risk of fracture.16 As mentioned previously, in some extreme conditions involving the estrogen receptor (ERα) and aromatase (CYP19) genes, an inactivating mutation can result in early onset osteoporosis in males.4,44 The occurrence of such simple Mendelian inherited osteoporotic phenotypes suggests that more subtle genetic variations could predispose men to fragility fracture. One such example involves a recently discovered CAG repeat polymorphism (CAGR) in the androgen receptor (AR) gene and its association with decreases in BMD and increased incidence of vertebral fracture in males.50,51
Steroid hormones bind to their respective receptors on the surfaces of osteoblasts, osteoclasts, and marrow stromal cells, modulating the transcription of target genes. Testosterone, operating through the androgen receptor, shows diminished action as the number of CAG repeat polymorphisms in exon 1 of the AR gene increases.50,51 This inverse association provided the impetus for studies investigating whether a greater number of CAG repeat regions was associated with a lower BMD in men.50,51 Investigations revealed that these polymorphisms were independently and negatively associated with bone density in males.50 Additionally, markers of bone turnover were positively associated with the number of CAG repeats within the AR gene. Based on these findings, one can infer that bone metabolism and bone density are influenced by genetic polymorphisms. Moreover, individuals with a high number of polymorphic repeats in the AR gene may be predisposed to an accelerated bone loss with advanced age relative to individuals with few or no such repeats.50
Osteoporosis candidate genes also include the vitamin D receptor (VDR) and genes coding for Type I collagen (COL1A1) and insulin like growth factor (IGF-1).16 Poly- morphisms have been discovered in these genes, and investigations into their associations with a male osteoporotic phenotype are in its early stages. The promise of these and other such genetic studies lie in the prospects of developing genetic markers for the assessment of fracture risk and the identification of molecules that then can be used as targets for novel drug design.37
Osteoporosis in men commonly is classified into primary (age-related) and secondary.42 Primary osteoporosis is described as senile or idiopathic and generally occurs in men older than the age of 70.42 Studies have suggested that reduced IGF-1 levels are associated with idiopathic osteoporosis and also may be correlated with reduced lumbar spine BMD.25 Although the relationships between IGF-1 and other growth factors are unknown, it is thought that declining IFG-1 levels are associated with osteoblastic dysfunction and diminished bone formation.25 It is this reduced osteoblast activity that is thought to be responsible for primary osteoporosis in men. Secondary osteoporosis may be related to many causes and is more common in men than women.42 Most men, approximately 60%, presenting with low bone mass or osteoporotic fracture will have a secondary cause.2,25,39,42 In addition, there are numerous comorbidities related to frail health status that influence body weight, activity level, risk of falling, and therefore, overall risk of fragility fracture.2
Modifiable risk factors for osteoporosis include cigarette smoking, dietary deficiencies of calcium and vitamin D, and physical inactivity.2,42 A low body mass index (BMI) and weight, family history of osteoporosis, alcoholism, old age, and Caucasian race also are risk factors for low BMD.2,42 Secondary causes of osteoporosis in men include hypogonadism, steroid excess, alcoholism, gastrointestinal disease and gastrectomy, idiopathic hypercalciuria, hyperthyroidism, multiple myeloma, and skeletal metastases.2,6,39 Anticonvulsants and chronic heparin therapy also can decrease bone density.39,42
Similar to women, age and decreased BMD have been shown to be important predictors of osteoporotic fractures in men.30 Numerous other important risk factors for fracture include: low BMI, glucocorticoid therapy, gastrointestinal disease, neuromuscular and cognitive dysfunction, physical inactivity, and falls.36 The Mediterranean Osteoporosis Study (MEDOS) study22 examined 730 men with hip fracture in 14 centers in Southern Europe. Low BMI, alcoholism, and a long history of smoking (duration > 49 years) were associated significantly with hip fracture incidence. History of previous fracture at the wrist, spine, and hip also were significantly associated with incidental hip fracture.22 The MEDOS study also showed a significant protective effect with amount of sunlight exposure. Above average BMI did not confer more protection than average BMI, implying that obesity is not protective for hip fractures. The MEDOS findings were similar to those reported in a previous population-based MEDOS study in women, suggesting that men and women share numerous risk factors for hip fracture.22 This information should help clinicians identify men most at risk for hip fracture.
Men and women seem to have a similar overall prevalence of vertebral deformities. However, men with multiple vertebral deformities are thought to be more likely to have underlying osteoporosis compared with men with single or dual vertebral deformities.20 In an analysis of 6937 men 50 years or older, the European Vertebral Osteoporosis Study (EVOS)20 showed that previous hip fracture (adjusted OR, 10.5), physical inactivity (OR, 2.9), low body mass (OR, 2.5) and previous steroid use (OR, 2.3) were risk factors for multiple vertebral deformities (at least three vertebral fractures). However, these risk factors were not significantly associated with single or dual vertebral deformities. The prevalence of multiple vertebral deformities in men increased exponentially after 70 years, similar to the age-specific prevalence observed in women with single deformities. In contrast, the age pattern for those men with single or dual vertebral deformities was relatively flat, showing a modest increase with age older than 75 years. Data from a subset of EVOS previously showed that the association between BMD and vertebral deformities is weaker in men with single deformities compared with men with multiple deformities.20 This likely reflects less severe osteoporosis in men with single vertebral deformities compared with men with multiple vertebral deformities.20 Therefore, it is necessary to distinguish those men with single deformities from those men with multiple deformities. It is only in the later group where the age-specific prevalence and risk factor profile is similar to that observed in women.20
Bone Density Measurement
The clinical benefit of being able to define men with osteoporosis lies in the potential to identify those men at risk for future fracture. In 1994, the WHO established diagnostic criterion for the detection of osteoporosis. These guidelines were designed to assess the risk of fracture in postmenopausal women and were based on BMD measurements taken from white postmenopausal women.2 A BMD of greater than or equal to 2.5 SD below the mean for young healthy people (T-score < −2.5) was defined as osteoporosis. A BMD between 1 and 2.5 SD below the mean for young healthy people (−2.5 < T-score < −1) was defined as osteopenia.42 The term young healthy people refers to young white healthy women. The applicability of these criteria to men has not been accepted, largely because no official consensus has yet been reached. However, despite potential diagnostic inaccuracies, dual energy xray absorptiometry (DEXA) scans continue to be used to assess bone mass in elderly men. The National Osteoporosis Foundation currently recommends BMD measurements for all postmenopausal women between the ages of 60 and 65 years.26 No such official recommendations currently exist for men.
The hypothesis that BMD is a determinant for fracture risk is well established. A prospective study showed a strong relationship between BMD and fracture risk in men and women.2 At issue is whether possible gender differences in the BMD–fracture risk relationship necessitate different BMD guidelines for women and men. To date, several guidelines for the diagnosis of male osteoporosis have been proposed based on the WHO criteria developed for women. They include using more than 2.5 SD below the mean for young healthy men, using 3–4 SD below the mean for young healthy men, and using more than 2.5 SD below the mean for young healthy women.2 Initially it was feared that the first proposal would overestimate the number of men at risk for fracture. Proposals two and three were more restrictive definitions, but a study revealed that these later two criteria actually may underestimate the prevalence of men at risk for future fracture.2
Unfortunately, no official consensus exists on which BMD standards to use in assessing for osteoporosis in men.8,27,33 Until data suggest otherwise, it is recommended that the WHO criteria for postmenopausal women be applied to men using young healthy men as the reference range.2 It generally is recommended that BMD measurements are appropriate for men with previous low-trauma fracture history and/or medical conditions predisposing to osteoporosis, such as hypogonadism and steroid excess.33 In light of the exponential rise in hip fracture incidence after age 75 years, men older than 75 years also may warrant BMD measurement.33
A recent study by de Laet et al8 seeks to clarify the confusion regarding BMD standards for diagnosis and potential intervention of osteoporosis in men. Men and women have different BMD distributions, and the average BMD in men who sustain a hip fracture is higher than the average BMD in women. To account for this discrepancy, that is, to potentially prevent the same proportion of hip fractures in men as in women, de Laet et al proposed raising the threshold BMD in males relative to the BMD in females. A gender-specific T score would allow for this increase in the threshold BMD in males and better identify potential hip fractures in males.8 However, they noted that the overall hip fracture incidence in men is less than in women. As a result, they concluded that establishing the same absolute BMD thresholds for decisions about intervention would better address absolute overall risk of fracture in men and women.8 Establishing a consensus regarding BMD thresholds in men continues to pose a challenge.
Fracture incidence among men and women shows a bimodal distribution, with peaks occurring in youth and old age.49 In youth, fractures of long bones predominate, usually after trauma. These traumatic fractures are greater in males than in females and are not related to osteoporosis. After 35 years of age, however, the fracture incidence in women surpasses that in men. This disparity is particularly pronounced in postmenopausal women. Such postmenopausal fragility fractures occur in weakened, osteoporotic bone and predominate at the hip, spine, and distal radius. The incidence of fragility fracture in men in approximately ⅓ of that observed in females. However, approximately 30% of hip fractures occur in men, and the morbidity and mortality resulting from hip fractures is greater in men than in women.42
The incidence of hip fractures in men and women shows an exponential increase with old age.12 In women, this exponential rise occurs at approximately 65 years. In men, the increase occurs, on average, 10 years later. Therefore, the absolute incidence of hip fractures in men lags behind the incidence in women by approximately 10 years. In comparison with hip fractures, there are fewer studies assessing the patterns of vertebral fractures in men. Vertebral deformities are challenging to diagnose, and most of fractures never reach clinical attention.49 However, strong associations exist between the number of vertebral deformities and the prevalence of reported back pain and height loss.21 What is more, the functional impairment and decreased quality of life resulting from vertebral fracture is reported to be greater in men than women.28 Population-based studies suggest that the age-specific prevalence of vertebral fractures is similar in men and women.31 The EVO Study20 showed a 12% prevalence of vertebral deformity in men and women. Men younger than 65 years had a higher prevalence of vertebral deformity than women. After the age of 65, the trend reversed. The prevalence increased with age across genders, but the increase was steeper in women, particularly after age 65.31
The incidence of distal radius fractures in men is constant between 20 and 80 years.49 There is a slight increase of distal radius fractures reported in men older than 80 years. This is in contrast to women, who experience a sharp increase in incidence after menopause. In fact, approximately ½ of all distal radius fractures occur in women older than 65 years.49 Incidence rates of proximal humeral, pelvic, and tibial shaft fractures also increase with age, although women incur a greater number of these fractures than do men.49 Nevertheless, diaphyseal fractures among elderly men should raise suspicion for an osteoporosis-related fracture.
Differences Between Bone in Men and Women
Two main factors contribute to fracture occurrence in an individual: bone strength and the amount of force applied to the bone.2 A force large enough in magnitude can fracture bone regardless of its strength. However, if the bone tissue deteriorates, as in osteoporosis, small forces may become adequate to fracture the bone.2 Therefore, the composition of bone determines its ultimate strength.
Bone mass, bone size, geometry, and microarchitecture all are factors that influence bone strength.2 Many of these structural differences between men and women arise during pubertal development. The pubertal growth spurt in males is greater than the growth spurt in females and lasts longer. In addition, the onset of male puberty begins, on average, 2 years later than in females. These additional 2 years of prepubertal growth additionally contribute to the longer femur length seen in boys.40 During puberty, young men achieve a greater bone size than females. In men, the periosteum expands with little change in endocortical (medullary) diameter. Increased cortical thickness and cortical diameter result.40 During puberty in women, periosteal expansion ceases while endocortical bone formation continues, producing a thickened cortex at the expense of a decreased cortical diameter.40 The larger cortical diameter and the greater limb length are responsible for the greater peak bone mass and BMD achieved after puberty. This larger peak bone mass and greater bone size provides men with a stronger bone than women.2
Men and women experience a gradual decline in BMD with age. Termed involutional osteoporosis, this gradual decline in bone density likely is related to declining levels of sex hormones and IGF-1. In addition to this involutional loss of bone, women also experience a rapid, high turnover bone loss soon after menopause. This rapid, postmenopausal bone loss is unique to women and marked by accelerated endocortical bone resorption. Trabecular dropout and cortical porosity result. With time, men also experience bone resorption. In fact, the total endocortical bone loss in men is comparable with that in women. However, because men lack the rapid, high turnover component of menopause, endocortical bone resorption in men is less disruptive to skeletal architecture than in women. Men experience trabecular thinning, whereas women have a loss of trabecular connectivity with time.2
Another process that contributes to overall bone composition is the periosteal deposition of new bone. This periosteal apposition occurs in men and women, offsetting endocortical bone loss.40,41 Gender differences do, however, emerge. Periosteal apposition is more robust in men than women. As a result, aging men experience less net bone loss than do aging women.41 Less bone loss coupled with a more organized trabecular network and cortical composition provide the aging male with a stronger bone.40 Because of an increased periosteal apposition, aging men also have a greater area of bony surface. Consequently, the stress on bone, defined as force per unit area, decreases more in men than in women.41 A stronger bone undergoing less stress correlates to a decreased stress to strength ratio and a biomechanical advantage. Accordingly, men experience fewer fragility fractures than women.41
Treatment of osteoporosis in men involves prevention and intervention. General prevention strategies aim to maximize peak bone mass by the third decade and minimize bone loss in old age. Boys should receive the recommended daily calcium intake and engage in regular physical activity. Gonadal sex hormone deficiencies, if identified, should be corrected early to allow for normal skeletal development. In men, preventive measures include adequate calcium and vitamin D intake, smoking cessation, regular exercise, fall prevention, and limiting the amount of alcohol consumed to < 60 g per day (approximately four cans of beer or 2 ounces of liquor).42 The National Institutes of Health (NIH) recommends a calcium intake of 1500 mg per day for men older than 65 years and a vitamin D intake of 600 IU for all adults older than 70 years.42 Calcium and vitamin D are best absorbed with food and ideally, dosage should be attained through diet. Hip padding may prevent fractures in those predisposed to falling.2,42 Men diagnosed with osteoporosis should have a complete evaluation for secondary causes.
Studies1,34 have identified alendronate as an effective treatment of male osteoporosis. Alendronate is a potent bisphosphonate that inhibits osteoclast-mediated resorption at doses that do not impair bone mineralization. The efficacy of bisphosphonates have been shown previously for the treatment of postmenopausal women with osteoporosis.9,32 A 2-year randomized double-blind study of 241 men showed that 10 mg alendronate significantly increased lumbar spine, hip, and total body BMD.34 Alendronate also showed antifracture efficacy, significantly reducing the number of incident vertebral deformities. No significant reductions in nonvertebral fractures were seen.34 This is in contrast to a previous study in postmenopausal women, which showed the effectiveness of alendronate in significantly reducing the incidence of hip fractures.32 Limitations of this alendronate study in men are few but important to consider. The efficacy of alendronate at doses other than 10 mg is unknown, as is the response to treatment after the 2-year period.34 In addition, most men enrolled were white, and the effects of alendronate on other racial groups are as yet unknown. Alendronate has, however, been shown effective for the treatment of postmenopausal black women.34
Another important treatment of osteoporosis in men is intermittent PTH, the first bone-forming agent approved for the treatment of osteoporosis. Parathyroid hormone has dual site-specific actions on bone, anabolic and catabolic.3 Low, intermittent doses of PTH stimulate osteoblasts within cancellous bone. Higher, continuous doses of the hormone stimulate osteoclasts at cortical surfaces.3 A previously published study documented significant reductions in vertebral fracture incidence in a large group of postmenopausal women treated with intermittent PTH.29 A randomized controlled double-blind study on 23 men with primary, idiopathic osteoporosis suggested that intermittent PTH (teriparatide) also might be effective in men. Twenty-three men, with a mean age of 50 years and T-scores less than −2.5, were assigned to placebo and treatment arms.3 All subjects received either a daily injection of PTH (400 IU) or a solution of citrate and mannitol. In men treated with PTH, lumbar spine and femoral neck BMD increased significantly after 18 months.
Histomorphometric analyses on a subset of those treated revealed improvements in cancellous connectivity without increases in cortical porosity. Impressive gains also were evident on endocortical surfaces.3 The implication is that PTH may improve skeletal structure in ways different from antiresorptives, such as alendronate. The absence of cortical porosity also eases concerns that PTH may have detrimental effects on cortical bone. A larger trial of 437 men with osteoporosis confirmed that intermittent PTH increases BMD in men.35 After 11 months, lumbar spine BMD increased 5.9% (20 ug) and 9% (40 ug), compared with a 0.5% increase with placebo. Femoral neck BMD increased 1.5% (20 ug) and 3% (40 ug), compared with a 0.3% increase with placebo.35 Disadvantages include the need for daily injections and the potential for high cost.3 Nevertheless, future studies need to address fracture incidence in a large, multicenter trial, as accomplished previously for alendronate.
Another anabolic agent that deserves mention is fluoride. Although this drug was not shown to be of benefit in the past, a more recent study suggested the use of fluoride with antiresorptive agents may prove useful for treating osteoporosis.38 In a small study of 33 men with severe osteoporosis (BMD T-score < −3.6 SD and mean number of vertebral fractures 4.3), the combined administration of etidronate and fluoride resulted in significant increases in lumbar spine, total hip, and femoral neck BMD compared with etidronate alone.38 It remains unknown whether this will translate into a decrease in osteoporotic fractures.
Intranasal calcitonin has shown efficacy in increasing BMD in the treatment of men with osteoporosis. A recent 12-month randomized, double-blind, placebo-controlled trial investigated 28 men with primary osteoporosis (mean age 52 years).48 The increase in lumbar spine BMD was significantly greater but no significant changes at the femoral neck or trochanter were observed. Fracture incidence was not a primary end point. Based on this small study, calcitonin is not thought to be as effective as alendronate.48 Calcitonin is prescribed for the treatment of osteoporosis in men, but it is characterized best as a second line agent for men who do not tolerate bisphosphonates.48 Calcitonin also is considered a weaker agent for the treatment of osteoporosis in women.
Diminished IGF-1 levels have been shown to be associated with idiopathic osteoporosis in men.25 In a small, randomized, controlled study of 29 men, 2 years of intermittent or continuous treatment with recombinant human growth hormone resulted in gains in BMD and bone mineral content (BMC).18 These BMD and BMC increases also were sustained for at least 1 year after treatment. This study lacked a placebo-treated control group and had a small sample size.18 In addition, the results attained are not as impressive as those reported with antiresorptive agents. Larger double-blind placebo control trials are needed to adequately assess the role of growth hormone in the treatment of idiopathic osteoporosis in men.18 The alternative anabolic agent is PTH.
As discussed previously, testosterone replacement increases lumbar spine BMD in men with hypogonadism.14,23,46 How testosterone treatment impacts BMD of the hip and fracture incidence is unclear.14 In men with primary idiopathic hypogonadotropic hypogonadism, long-term androgen replacement therapy for at least 2 years did not normalize BMD or bone turnover markers.19 Although there is some evidence to suggest that testosterone treatment in men with eugonadal osteoporosis may improve lumbar spine BMD, larger studies are needed.14 The safety of testosterone replacement therapy also is a concern. Testosterone treatment may accelerate clinically significant disease in men with benign prostatic hypertrophy or clinically silent prostate cancer. These complications have been reported in men receiving treatment for hypogonadism.14 Additional studies are indicated to establish the safety and effectiveness of testosterone treatment in men with osteoporosis and hypogonadism or eugonadism.14
It is evident that osteoporosis is an important disease in men and women. The increased morbidity and mortality associated with osteoporosis in men demands that increased attention be given to the development of appropriate screening, prevention, and treatment strategies in men at risk for low bone mass. Although men do not experience the rapid high-turnover bone loss seen in postmenopausal women, they do experience a gradual, but considerable loss of bone with age. This most likely is mediated by decreased free testosterone and thereby free estrogen levels, and diminished IGF-1 levels.
A secondary cause of osteoporosis is observed in as many as ⅔ of men with this disease, with hypogonadism, steroid excess, and alcoholism being the most common. Although there are no clear guidelines for screening men with osteoporosis, men with these conditions and those who have sustained low trauma fractures should have BMD testing. It also may be argued that screening is warranted in men older than 75 years.
Establishing a consensus regarding BMD thresholds in men continues to pose a challenge. At issue is whether gender differences in the BMD-fracture risk relationship necessitate different BMD guidelines for women and men. Given that the overall hip fracture incidence in men is less than in women, establishing the same absolute BMD thresholds for decisions about intervention would better address overall risk of fracture in men and women.8
Clinical trials have included male patients and there is sufficient evidence to suggest that treatment with bisphosphonates is effective in men. Specifically, it was shown that alendronate significantly increases lumbar spine, hip, and total body BMD in a randomized, double-blind study of 241 men during a 2-year period.34 This study also showed an antifracture efficacy of alendronate, but only as it pertained to reducing the incidence of vertebral deformities.34 Additional investigation is necessary to show if alendronate can reduce the incidence of nonvertebral fractures, particularly hip fractures, as has been shown in women.32
Intermittent PTH (teriparatide) seems to be another potent anabolic agent in men. Future studies need to address the antifracture efficacy of intermittent PTH in a large, multicenter, randomized, controlled trial. In light of the important role of estrogen in the male skeleton, future treatments may be directed at developing selective estrogen receptor modulators that can be used in men.
1. Adami S, Prizzi R, Colapietro F. Alendronate for the treatment of osteoporosis in men. Calcif Tissue Int
2. Amin S, Felson DT. Osteoporosis in men. Rheum Dis Clin North Am
3. Bilezikian JP, Kurland ES. Therapy of male osteoporosis with parathyroid hormone. Calcif Tissue Int
4. Bilezikian JP, Morishima A, Bell J, et al. Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med
5. Cohen-Solal ME, Baudoin C, Omouri M, et al. Bone mass in middle aged osteoporotic men and their relatives: Familial effect. J Bone Miner Res
6. Compston J. Secondary causes of osteoporosis in men. Calcif Tissue Int
7. Consensus Development Conference V. 1993: Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 90:646–650, 1994.
8. de Laet CE, van der Klift M, Hofman A, et al. Osteoporosis in men and women: A story about bone mineral density thresholds and hip fracture risk. J Bone Miner Res
9. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3 year randomized clinical trial. Multiple Outcomes of Raloxifene Investigation (MORE). JAMA
10. Evans RA, Marel GM, Lancaster EK, et al. Bone mass is low in relatives of osteoporotic patients. Ann Intern Med
11. Falahati-Nini A, Riggs BL, Atkinson EJ, et al. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest
12. Farmer ME, White LR, Brody JA, et al. Race and sex differences in hip fracture incidence. Am J Public Health
13. Finkelstein JS, Klibanski A, Neer RM, et al. Osteoporosis in men with idiopathic hypogonadotrophic hypogonadism. Ann Intern Med
14. Francis RM. Androgen replacement in aging men. Calcif Tissue Int
15. Gennari L, Becherini L, Falchetti A, et al. Genetics of osteoporosis: Role of steroid hormone receptor gene polymorphisms. J Steroid Biochem Mol Biol
16. Gennari L, Brandi ML. Genetics of male osteoporosis. Calcif Tissue Int
17. Gennari C, Seeman E. The First International Conference on Osteoporosis in Men, Siena, Italy, February 2001. 69:177–178, 2001.
18. Gillberg P, Mallmin H, Petren-Mallmin M, et al. Two years of treatment with recombinant human growth hormone increases bone mineral density in men with idiopathic osteoporosis. J Clin Endocrinol Metab
19. Guo CY, Jones TH, Eastell R. Treatment of isolated hypogonadotropic hypogonadism effect on bone mineral density and bone turnover. J Clin Endocrinol Metab
20. Ismail AA, O’Neill TW, Cooper C, et al. Risk factors for vertebral deformities in men: relationship to number of vertebral deformities. J Bone Miner Res
21. Ismail AA, Cooper C, Felsenberg D, et al. Number and type of vertebral deformities: epidemiological characteristics and relation to back pain and height loss. Osteoporos Int
22. Kanis J, Johnell O, Gullberg B, et al. Risk factors for hip fracture in men from Southern Europe: The MEDOS Study. Osteoporos Int
23. Katznelson L, Finkelstein JS, Schoenfeld DA, et al. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab
24. Khosla S, Melton LJ III, Atkinson EJ, et al. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: A key role for bioavailable estrogen. J Clin Endocrinol Metab
25. Kurland ES, Rosen CJ, Cosman F, et al. Insulin-like growth factor-I in men with idiopathic osteoporosis. J Clin Endocrinol Metab
26. Lindsay R, Cosman F. Osteoporosis. In Braunwald E, Fauci AS, Kasper DL, et al (eds). Harrison’s Principles of Internal Medicine. Ed 15. New York, Mcgraw-Hill 2226–2237, 2001.
27. Lombardi A, Ross PD. The assessment of bone mass in men. Calcif Tissue Int
28. Matthis C, Weber U, O’Neil TW, et al. Health impact associated with vertebral deformities: Results from the European Vertebral Osteoporosis Study (EVOS). Osteoporos Int
29. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med
30. Nguyen TV, Eisman JA, Kelly PJ, et al. Risk factors for osteoporotic fractures in elderly men. Am J Epidemiol
31. O’Neill TW, Felsenberg D, Varlow J, et al. The prevalence of vertebral deformity in European men and women: The European Vertebral Osteoporosis Study. J Bone Miner Res
32. Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo-controlled, randomized trial of the effect of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: Results of the FOSIT study. Fosamax International Trial Study Group. Osteoporos Int
33. Orwoll E. Assessing bone density in men. J Bone Miner Res
34. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med
35. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res
36. Poor G, Atkinson EJ, O’Fallon WM, et al. Predictors of hip fractures in elderly men. J Bone Miner Res
37. Ralston SH. Genetic control of susceptibility to osteoporosis. J Clin Endocrinol Metab
38. Ringe JD, Rovati LC. Treatment of osteoporosis in men with fluoride alone or in combination with bisphosphonates. Calcif Tissue Int
39. Scane AC, Francis RM. Risk factors for osteoporosis in men. Clin Endocrinol
40. Seeman E. The structural basis of bone fragility in men. Bone
41. Seeman E. During aging, men lose less bone than woman. Calcif Tissue Int
42. Siddiqui NA, Shetty KR. Osteoporosis in older men: Discovering when and how to treat it. Geriatrics
43. Slemenda CW, Longcope C, Zhou L, et al. Sex steroids and bone mass in older men: Positive associations with serum estrogens and negative associations with androgens. J Clin Invest
44. Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med
45. Smith MR. Diagnosis and management of treatment-related osteoporosis in men with prostate carcinoma. Cancer
46. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab
47. Szulc P, Munoz F, Claustrat B, et al. Bioavailable estradiol may be an important determinant of osteoporosis in men: The MINOS study. J Clin Endocrinol Metab
48. Trovas GP, Lyritis GP, Galanos A, et al. A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: Effects on bone mineral density and bone markers. J Bone Miner Res
49. Walker-Bone K, Dennison E, Cooper C. Epidemiology of Osteoporosis. Rheum Dis Clin of North Am
50. Zitzmann M, Brune M, Kornmann B, et al. The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males. Clin Endocrinol (Oxf)
51. Zmuda MJ, Cauley JA, Kuller LH, et al: Androgen receptor CAG repeat length is associated with increased hip bone loss and vertebral fracture risk among older men. J Bone Miner Res 15:s491, (abstract M141) 2000.