Male osteoporosis-what are the causes,diagnostic challenges,and management

Osteoporosis is underrecognized and undertreated in men, even though up to 25% of fractures in patients over the age of 50 years occur in men. Men develop osteoporosis with normal aging and accumulation of comorbidities that cause bone loss. Secondary causes of bone loss may be found in up to 60% of men with osteoporosis. Mortality in men who experience major fragility fracture is greater than in women. Diagnosis of osteoporosis in men is similar to women, based on low-trauma or fragility fractures, and/or bone mineral density dual-energy X-ray absorptiometry (DXA) T-scores at or below ?2.5. Because most clinical trials with osteoporosis drugs in men were based on bone density endpoints, not fracture reduction, the antifracture efficacy of approved treatments in men is not as well documented as that in women. Men at a high risk of fracture should be offered treatment to reduce future fractures.     

Diagnosis of osteoporosis and assessment of fracture risk

The diagnosis of osteoporosis centres on the assessment of bone mineral density (BMD). Osteoporosis is defined as a BMD 2.5 SD or more below the average value for premenopausal women (T score < -2.5 SD). Severe osteoporosis denotes osteoporosis in the presence of one or more fragility fractures. The same absolute value for BMD used in women can be used in men. The recommended site for diagnosis is the proximal femur with dual energy X-ray absorptiometry (DXA). Other sites and validated techniques, however, can be used for fracture prediction. Although hip fracture prediction with BMD alone is at least as good as blood pressure readings to predict stroke, the predictive value of BMD can be enhanced by use of other factors, such as biochemical indices of bone resorption and clinical risk factors. Clinical risk factors that contribute to fracture risk independently of BMD include age, previous fragility fracture, premature menopause, a family history of hip fracture, and the use of oral corticosteroids. In the absence of validated population screening strategies, a case finding strategy is recommended based on the finding of risk factors. Treatment should be considered in individuals subsequently shown to have a high fracture risk. Because of the many techniques available for fracture risk assessment, the 10-year probability of fracture is the desirable measurement to determine intervention thresholds. Many treatments can be provided cost-effectively to men and women if hip fracture probability over 10 years ranges from 2% to 10% dependent on age.     

The role of selective estrogen receptor modulators in the prevention and treatment of osteoporosis

Osteoporosis can affect almost everyone in the population, and although clinical outcome of fracture is manifested in late life, the disease process begins in the early postmenopausal years in women. The pharmacologic agents currently available for osteoporosis prevention and treatment act by inhibiting bone resorption, and include estrogen or hormone replacement therapy (estrogen with progestin), bisphosphonates, salmon calcitonin nasal spray, and selective estrogen receptor modulators (SERMs). Raloxifene is a benzothiophene SERM that has estrogen against effects in bone and on serum lipid metabolism and estrogen antagonist effects on breast and uterine tissue. This article summarizes the effects of these antiresorptive agents, as measured by changes in bone mineral density, biochemical markers of bone turnover, and incident fractures in postmenopausal osteoporosis.     

Treatment-related osteoporosis in men with prostate cancer

Osteoporosis is an important complication of androgen-deprivation therapy (ADT) for prostate cancer. ADT by either bilateral orchiectomies or treatment with a gonadotropin-releasing hormone (GnRH) agonist decreases bone mineral density (BMD) and increases the risk of fracture. Prospective data about treatment or prevention of osteoporosis in men with prostate cancer are limited. Supplemental calcium and vitamin D are recommended. Additional therapy may be warranted for men with osteoporosis or fractures. Intravenous pamidronate prevents bone loss in the hip and spine during ADT. Intravenous zoledronic acid not only prevents bone loss but also increases BMD. Alendronate is approved to treatmen with osteoporosis although the efficacy of alendronate or other oral bisphosphonates has not been evaluated during ADT. Additional prospective studies are needed to evaluate the long-term effects of bisphosphonates and other the rapies on fracture risk and disease-related outcomes.     

Osteoporosis in men

Osteoporosis is defined as "a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture". Approximately 40-50% of women sustain osteoporotic fractures in their lifetime; as such, it is appropriate that studies initially focused upon females. Despite an increased recognition of osteoporotic fractures in men, there continues to be neglect of this disease in males. This ongoing neglect is inappropriate as 25-33% of men in some populations will sustain osteoporotic fractures in their lifetime. Testosterone plays an important role in male skeletal health. However, recent data suggest that estrogen may in fact be the dominant hormone regulating skeletal status in both men and women. BMD measurement may be utilized for osteoporosis diagnosis and to assist with fracture risk prediction in men prior to their sustaining a fracture. Recognizing this need, the International Society for Clinical Densitometry (ISCD) recommended and recently reaffirmed use of a BMD T-score of -2.5 or below be utilized to diagnose osteoporosis in men. Androgen therapy of hypogonadal men may be considered with the caveat that data do not exist to document that this treatment reduces fracture risk. At this time, the data is inadequate to support use of androgen treatment in eugonadal men with osteoporosis. Parathyroid hormone treatment does increase BMD; existing studies have not been of adequate size or duration to document fracture reduction efficacy. Bisphosphonate therapy increases BMD, reduces vertebral fracture risk and is considered the standard of care for osteoporotic men at this point in time.     

Osteoporosis in elderly: prevention and treatment

Osteoporosis is a major clinical problem in older women and men. Almost any bone can fracture as a result of the increased bone fragility of osteoporosis. These fractures are associated with higher health care costs, physical disability, impaired quality of life, and increased mortality. Because the incidence of osteoporotic fracture increases with advancing age, measures to diagnose and prevent osteoporosis and its complications assume a major public health concern. BMD is a valuable tool to identify patients at risk for fracture, to make therapeutic decisions, and to monitor therapy. Several other modifiable and nonmodifiable risk factors for osteoporosis have also been identified. Treatment of potentially modifiable risk factors along with exercise and calcium and vitamin D supplementation forms an important adjunct to pharmacologic management of osteoporosis. Improved household safety can reduce the risk of falls. Hip protectors have been found to be effective in nursing home population. The pharmacologic options include bisphosphonates, HRT, SERMs and calcitonin. PTH had received FDA advisory committee approval. Alendronate has been approved for treatment of osteoporosis in men, and other treatments for men are under evaluation.     

Bone mineral density measurement and treatment for osteoporosis in older individuals with fractures: a gap in evidence-based practice guideline implementation

BACKGROUND: Osteoporosis evaluation and treatment guidelines state that, because of the high risk for future fractures, a fracture in an older individual warrants initiation of pharmacological treatment or bone mineral density (BMD) measurement followed by treatment according to BMD. We compared current practice with these guidelines. METHODS: We used the electronic data systems of a health maintenance organization to collect fracture, BMD measurement, and pharmacy data for women aged 50 to 89 years and men aged 65 to 89 years who sustained a study-defined fracture during 1998 or 1999. We determined those who had BMD measurement or pharmacological treatment for osteoporosis (bisphosphonate or estrogen) during the 2 years. We compared the evaluation and treatment data with evidence-based clinical guidelines (for women) or expert consensus (for men). RESULTS: Of 70 513 members in the eligible age groups, 2804 persons sustained study-defined fractures. Overall, only 4.6% of those with fractures had treatment initiated after the fracture. Women sustained 80.7% of the study-defined fractures; 8.4% had BMD measurement and 42.4% received any treatment during the 2 years. Bone mineral density measurement and treatment frequency decrease significantly with age in women. In men, 1.5% had BMD measurement and 2.8% received any treatment. Approximately 51% (51.2%) of women and 95.5% of men in our study population were not evaluated or treated in accord with guideline or expert recommendations. CONCLUSIONS: Evaluation and treatment rates for osteoporosis in older individuals with fractures fall far below national recommendations, especially for men. Intervention strategies should be developed and evaluated to prevent refracture in older individuals with fractures.     

Bisphosphonate treatment of osteoporosis

Bisphosphonates represent the agents of choice for most patients with osteoporosis. They are the best studied of all agents for the prevention of bone loss and reduction in fractures. They increase BMD, primarily at the lumbar spine, but also at the proximal femur. In patients who have established osteoporosis, bisphosphonates reduce the risk of vertebral fractures, and are the only agents in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures. Bisphosphonates reduce the risk of fracture quickly. The risk of radiographic vertebral deformities is reduced after 1 year of treatment with risedronate [68]. The risk of clinical vertebral fractures is reduced after 1 year of treatment with alendronate [69] and just 6 months' treatment with risedronate [157]. The antifracture effect of risedronate has been shown to continue through 5 years of treatment [158]. Alendronate and risedronate are approved by the FDA for prevention of bone loss in recently menopausal women, for treatment of postmenopausal osteoporosis, and for prevention (risedronate) and treatment (alendronate and risedronate) of glucocorticoid-induced osteoporosis. Alendronate is also approved for treatment of osteoporosis in men. Other bisphosphonates (etidronate for oral use, pamidronate and zoledronate for intravenous infusion) are also available and can be used off label for patients who cannot tolerate approved agents. Although bisphosphonates combined with estrogen or raloxifene produce greater gains in bone mass compared with single-agent treatment, the use of two antiresorptive agents in combination cannot be recommended because the benefit on fracture risk has not been demonstrated and because of increased cost and side effects.     

The role of rank-ligand inhibition in the treatment of postmenopausal osteoporosis

Osteoporosis is a skeletal disease affecting millions of people worldwide in which a decreased bone mass and a microarchitectural deterioration compromise bone strength leading to bone fragility and increased susceptibility to fracture. Bone turnover increases at menopause, with osteoclast-mediated bone resorption exceeding bone formation. Recent discoveries in bone biology have demonstrated that RANKL, a cytokine member of the tumor necrosis factor superfamily, is an essential mediator of osteoclast formation, function and survival. Denosumab is a fully human monoclonal antibody with a high affinity and specificity for human RANKL. By binding to its target, denosumab prevents the interaction of RANKL with its receptor RANK on osteoclasts and their precursors and inhibits osteoclast-mediated bone resorption. Administered as a subcutaneous injection every six months, denosumab has been shown to decrease bone turnover and to increase bone mineral density in postmenopausal women with low bone mass and osteoporosis. In these patients denosumab significantly reduced the risk of vertebral fractures, hip fractures and nonvertebral fractures. In all clinical trials published to date, denosumab was well tolerated with an incidence of adverse events, including infections and malignancy, generally similar to subjects receiving placebo or alendronate. The denosumab therapeutic regimen consisting in a subcutaneous injection every 6 months may increase patient compliance and persistence with a further benefit from treatment. By providing a new molecular target for osteoporosis treatment, denosumab is a promising drug for the treatment of postmenopausal osteoporosis and the prevention of fragility fractures.     

Evaluation of bone mineral density, hormones, biochemical markers of bone metabolism, and osteoprotegerin serum levels in patients with ankylosing spondylitis

OBJECTIVE: To evaluate bone metabolism in patients with ankylosing spondylitis (AS) and test the hypothesis that osteoprotegerin (OPG) serum concentrations are correlated with the severity of bone loss as assessed by bone mineral density (BMD) and biochemical markers of bone turnover. Osteoporosis occurs frequently in patients with AS and OPG represents a soluble decoy receptor that neutralizes receptor activator of nuclear factor-kB ligand (RANKL), an essential cytokine for osteoclast function. METHODS: Clinical data, radiographs of the spine, BMD of lumbar spine and the femur, biochemical markers of bone turnover, and serum levels of OPG were evaluated in 264 patients with AS (72% men) and 240 age-matched healthy controls (76% men). RESULTS: OPG serum levels were significantly lower in patients with AS compared to controls (1.84 +/- 1.15 vs 3.54 +/- 2.18 pmol/l, p < 0.001), and in contrast to controls, were not positively correlated with age. In addition, BMD of the hip and the femoral neck were significantly lower in patients with AS than in controls. There were positive correlations in patients with AS between BMD of the femoral neck and free testosterone serum levels in men and free estradiol serum levels in women, respectively. Patients with AS and osteoporosis had higher biochemical markers of bone resorption and inflammatory activity. CONCLUSION: Bone loss in patients with AS is associated with low sex steroid hormone serum levels, high biochemical markers of bone resorption and inflammatory activity, low OPG serum levels, and lack of compensatory age-related increase of OPG serum levels.     

Bilateral tibial stress fracture in a young man due to hypercalciuric osteoporosis: a case report

Osteoporosis is commonly thought of as a disease of postmenopausal women, and older men have a lower risk of fracture than women. A stress fracture is an overuse injury and an important cause of disability in the athletic population. Presented here is a 30-year-old healthy man with pain on the anterior surface of the bilateral tibia. He did not communicate any trauma or overuse activity. The neurologic and locomotor system examinations were normal. Radiological examinations revealed tibial stress fractures in both left and right tibia and he had low bone mineral density. Routine hematological tests, bone resorption and formation markers were normal, except for hypercalciuria. After analyzing the results of these tests, the patient was diagnosed with bilateral tibial stress fractures due to hypercalciuric secondary osteoporosis. Osteoporosis should be considered in the differential diagnosis of atraumatic insufficiency fractures, especially in young healthy adults.     

Osteoporosis: gender differences and similarities.

Although osteoporosis has traditionally been considered a disease of women, men also incur substantial bone loss with aging, and elderly men have age-specific hip fracture incidence rates and vertebral fracture prevalence rates that are at least half those in women. Early postmenopausal bone loss (which results in the syndrome of type I osteoporosis) is due to the direct skeletal consequences of estrogen deficiency, manifested by an increase in bone resorption without an adequate increase in bone formation. Recent evidence indicates that even late postmenopausal bone loss (type II or 'smile' osteoporosis) in women may be due to estrogen deficiency. In particular, the late consequences of estrogen deficiency in elderly women result in abnormalities in calcium homeostasis and increases in parathyroid hormone secretion, leading to increased bone resorption and bone loss. The etiology of bone loss in aging men has remained relatively unclear. Recent evidence from a male deficient in estrogen receptor-alpha and in two males with aromatase deficiency indicate that estrogen may play a significant role in bone metabolism in men. Moreover, several large epidemiologic studies have found that bone mineral density correlates better with serum estrogen than testosterone in aging men. Thus estrogen deficiency may lead to bone loss in men.     

Idiopathic or Hypogonadal Osteoporosis in Men

Osteoporosis is being recognized increasingly in men, and represents a substantial public health problem. As the male population ages and lives longer, the incidence of osteoporotic fractures is expected to increase. The current lifetime risk for a fragility fracture is approximately 27% in men aged 50 years or more, and will increase further over the next 20 years. A major problem with osteoporosis in men is that it continues to be unrecognized, and the majority of men with fragility fractures due to osteoporosis are not being treated. A higher level of awareness is required amongst both general practitioners and the general public that osteoporosis is a treatable condition that can affect men. Secondary causes for osteoporosis are more common in men than in women, and require rigorous exclusion and treatment. Undiagnosed clinical hypogonadism is a common cause of osteoporosis in men, and is readily treatable. The cause of primary osteoporosis in men is unknown, but it results in an osteoblast defect. Genetic factors are likely to be important. In some but not all men, relative estrogen deficiency contributes to rapid rates of age-related bone loss and fractures. An adequate calcium intake, regular weight-bearing exercise, and normal vitamin D status are all very important, particularly with increasing age. The role of testosterone in treating eugonadal men with osteoporosis is currently unclear, and larger prospective studies will be required to carefully evaluate the benefits and risks of therapy. First-line treatment of osteoporosis in hypogonadal or eugonadal men is with bisphosphonates. Alendronate increases bone density and reduces vertebral fractures measured using a semiquantitative method in eugonadal or hypogonadal men with osteoporosis. In the near future, it is likely that subcutaneous human parathyroid hormone (1-34) or teriparatide will also be available as an important new anabolic treatment for men with osteoporosis. Teriparatide treatment also increases bone density in men. Selective estrogen receptor modulating drugs require further evaluation in men, but would appear to theoretically benefit men, especially those with low estradiol levels. In the future, selective androgen receptor modulating drugs may be useful in the prevention and treatment of osteoporosis, and in increasing lean body mass in men, without having adverse effects on prostate and breast tissue.     

Osteoporosis in the elderly man

Elderly men are at substantial risk for fracture. Morbidity after osteoporotic fractures appears to be more serious and mortality more common in men than in women. Risk factors for osteoporotic fractures in men appear to be qualitatively similar to those in women. Low bone mineral density (BMD) is an important risk factor for fracture in men; however, further clarification of the relationship between BMD, bone geometry and fracture risk is needed. Our understanding of the mechanisms underlying senile bone loss and the pathogenesis of senile osteoporosis in men remains fragmentary with, in particular, the need for further clarification regarding the precise impact of hormonal status in elderly men on skeletal homeostasis. Nevertheless, the available evidence indicates a role for both testosterone and estrogens in the regulation of bone metabolism in elderly men. Recommendations concerning prevention and treatment of senile osteoporosis in men should focus on the minimization of known risk factors for bone loss and falls. Testosterone treatment may be useful only in those men with initially low serum testosterone. As to other pharmacological treatment modalities, prospective trials specifically in elderly men, and preferably with fracture incidence as the primary clinical endpoint, are required.     

Antiresorptive Therapy for the Prevention of Postmenopausal Osteoporosis

Osteoporosis is a condition associated with decreased bone strength and an increased fracture risk. It may be defined based on bone mineral density (BMD) with a T-score at the hip or spine of less than -2.5 standard deviations in young healthy individuals or from an osteoporotic fracture (i.e. a fracture occurring after low-energy trauma or no apparent trauma). Risk factors predisposing to fractures include: increasing age; female gender; low BMD; a prior fragility fracture; a family history of fragility fractures; low bodyweight; lack of estrogen in women (i.e. post menopause); corticosteroid use; smoking; a number of diseases; deficiency in calcium and vitamin D; an increased risk of falls (i.e. impaired vision); immobilization; and Caucasian race. The more risk factors that are present the higher the risk of fractures over the following 10 years. The need to initiate preventive therapy with anti-osteoporotic treatment increases steeply with the absolute fracture risk. Indications for referral for dual energy x-ray absorptiometry measurement of BMD include: age >65 years; age <65 years in postmenopausal women with any of the risk factors already mentioned; premature menopause (<45 years); prolonged amenorrhea (>1 year) in younger women; fragility fractures; and diseases or conditions known to lead to osteoporosis.Anti-resorptive therapies include calcium plus vitamin D, bisphosphonates (alendronate, etidronate, risedronate, ibandronate), selective estrogen receptor modulators (raloxifene), hormone replacement therapy, and calcitonin. Guidelines from several countries on when to initiate anti-resorptive therapy state that therapy may be started in patients with a prior fragility fracture (some guidelines state that in this situation no BMD measurements are necessary) or in patients with a T-score of less than -2.5 (some guidelines state that additional risk factors need to be present in this situation). Some guidelines state that anti-resorptive therapy may be initiated in patients with a T-score in the osteopenic range (from -1 to -2.5, i.e. not frank osteoporosis) in the presence of other risk factors. The cost effectiveness of anti-resorptive therapy increases with the absolute fracture risk. In some scenarios, treatment with bisphosphonates may be cost effective in a 50-year-old woman with an absolute hip fracture risk of >or=1.1% over the next 10 years.     

Osteoporosis in men

With the aging of the population, there is a growing recognition that osteoporosis and fractures in men are a significant public health problem, and both hip and vertebral fractures are associated with increased morbidity and mortality in men. Osteoporosis in men is a heterogeneous clinical entity: whereas most men experience bone loss with aging, some men develop osteoporosis at a relatively young age, often for unexplained reasons (idiopathic osteoporosis). Declining sex steroid levels and other hormonal changes likely contribute to age-related bone loss, as do impairments in osteoblast number and/or activity. Secondary causes of osteoporosis also play a significant role in pathogenesis. Although there is ongoing controversy regarding whether osteoporosis in men should be diagnosed based on female- or male-specific reference ranges (because some evidence indicates that the risk of fracture is similar in women and men for a given level of bone mineral density), a diagnosis of osteoporosis in men is generally made based on male-specific reference ranges. Treatment consists both of nonpharmacological (lifestyle factors, calcium and vitamin D supplementation) and pharmacological (most commonly bisphosphonates or PTH) approaches, with efficacy similar to that seen in women. Increasing awareness of osteoporosis in men among physicians and the lay public is critical for the prevention of fractures in our aging male population.     

Bisphosphonates

Osteoporosis is the result of bone loss due to an imbalance in bone turnover such that bone resorption exceeds bone formation. Bisphosphonates are potent inhibitors of osteoclast activity that reduce bone turnover and re-establish the balance between bone resorption and formation. In clinical studies, several bisphosphonates prevent bone loss, preserve bone structure, improve bone strength and, in patients with osteoporosis, substantially reduce fracture risk. They are effective in multiple clinical settings including postmenopausal osteoporosis, low bone mass in men and drug-induced bone loss. Intermittent oral dosing and intravenous administration are more convenient than the original daily dosing regimen. These drugs are generally well tolerated and have an excellent safety profile in that serious side effects are uncommon. Potent bisphosphonates are generally the preferred treatment option for most patients with or at risk for osteoporosis.     

Geriatrics grand rounds: Eve's rib, or a revisionist view of osteoporosis in men

It is widely accepted that estrogen withdrawal following menopause predisposes women to accelerated bone loss and increased risk of developing osteoporosis. Although osteoporosis is a significant public health problem for aging men as well as women, the cause of osteoporosis in men remains largely unknown. A substantial number of men with osteoporosis present with bone loss secondary to conditions associated with reduced gonadal steroid hormone levels. Although hypogonadism is related to bone loss in men, and androgen levels decline with age in men, it is not at all clear that reduced androgen levels are related to bone loss in older men. What, then, is the role of gonadal steroids in osteoporosis in men? This review focuses on recent research--including clinical investigations of men with genetic disorders of estrogen action, basic biomedical studies of estrogen receptor "knockout" mice, and population-based comparisons of bone density with gonadal steroids in older men--leading to the surprising conclusion that estrogen plays a vital role in maintenance of bone in men as well as in women. Possible mechanisms whereby reduced estrogen levels might result in bone loss in both sexes are also reviewed, as are potential therapeutic implications of a role for estrogen in osteoporosis in men.     

Miscellaneous hormone therapies for osteoporosis

Miscellaneous hormones, such as oral contraceptives (OCs) and tibolone, have not been evaluated as extensively as other hormonal therapies, but remain an option for the prevention and management of osteoporosis. OCs have been conside red for osteoporosis treatment since the 1970s and have demonstrated significant bone mineral density (BMD) increases with high doses that contained 50 μg of ethinyl estradiol. As OCs have evolved with lower doses of ethinyl estradiol (25–40 μg), the literature continues to report improved or maintained BMD in older women. Data are more controversial about OC fracture prevention abilities, the most clinically important end point in osteoporosis trials. Tibolone has not been approved for use in the United States, but it has been used in Europe for almost two decades for the management of osteoporosis. It has unique tissue-specific effects, including estrogen effects on bone and vaginal tissue, progestational effects on the endometrial tissue, and androgenic effects on the brain and liver tissue. Although fracture data are lacking, patients receiving 1.25 to 2.5 mg of tibolone have shown significant improvements in BMD. Tibolone can be regarded as an alternative to conventional hormone therapy for the prevention of postmenopausal bone loss based on similar BMD efficacy and minimal side effects, but its effects would still be less than bisphosphonates. Data supporting the use of oral contraceptives and tibolone for osteoporosis prevention and management will be discussed in this article.     

Drug insight: Existing and emerging therapies for osteoporosis

Osteoporosis is a major public health problem that is characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures. Currently, many women and men affected with this disease are not diagnosed or treated. As osteoporosis is often clinically silent, risk-factor assessment and measurement of BMD are needed to identify those who may benefit from osteoporosis therapy. Although adequate daily intake of calcium and vitamin D, and regular weight-bearing exercise are important for skeletal health, they are not adequate treatments for individuals with osteoporosis. Therapies approved for treatment and/or prevention of osteoporosis in the United States include oral bisphosphonates (alendronate, ibandronate and risedronate), calcitonin, estrogens, teriparatide (parathyroid hormone fragment [1-34]), and raloxifene. For most patients, oral bisphosphonates are the treatment of choice, given the large-scale randomized-trial data demonstrating efficacy in fracture reduction, although bisphosphonates that reduce spine and nonspine fractures (e.g. alendronate and risedronate) are preferred. For high-risk patients (those with very low bone density, or with fractures), teriparatide therapy for 2 years should be considered. The treatment paradigm for osteoporosis will evolve further as promising new treatments progress through clinical development.