Osteoporosis is also a male disease






Jean-Marc KAUFMAN
MD, PhD
Stefan GOEMAERE,MD
Unit for Osteoporosis and Metabolic Bone Diseases
Ghent University hospital
Ghent, BELGIUM

Osteoporosis is also a male disease


by J. M. Kaufman and
S. Goemaere,
Belgium



One in three osteoporotic fractures occur in men; and the consequences of a fracture in men tend to be more severe than in women. Yet, only a small minority of men at high risk of fracture are identified and treated. Although there are sex differences in the pathophysiology of osteoporosis— such as in the pattern of bone loss—similarities predominate, which is also the case for clinical risk factors. According to more traditional diagnostic criteria, osteoporosis in men can be defined as a femoral neck T-score of –2.5 or less, calculated using the bone mineral density of women aged 20-29 years from the database of NHANES III (Third National Health And Nutrition Examination Survey) as a reference. Calculation of the 10-year probability of osteoporotic fracture using the FRAX® algorithm (Fracture Risk Assessment tool) is a useful approach to identify men at high risk of osteoporotic fracture and those who are thus most likely to benefit from treatment. Currently approved drugs for the treatment of osteoporosis in men include the antiresorptive drugs bisphosphonates and denosumab (only in men receiving androgen deprivation therapy for prostate cancer), the bone-forming agent teriparatide, and strontium ranelate, a drug with opposite effects on bone resorption and formation. Although the evidence for the efficacy and safety of these drugs in men is still relatively limited, available data indicate that treatment effects in men are very similar to those observed in the treatment of postmenopausal osteoporosis.

Medicographia. 2014;36:176-183 (see French abstract on page 183)



Osteoporosis in men carries a significant burden in terms of morbidity for patients and economic cost for society. Although osteoporosis is clearly more prevalent in women, it has been estimated that up to one-third or more new osteoporotic fractures occur in men.1 Nevertheless, although awareness of male osteoporosis is increasing, osteoporosis remains a disease commonly considered to be a disease of women. Male osteoporosis is largely underdiagnosed and undertreated, even in those men with a history of fracture, who are at high risk of new fractures.2-4

Epidemiology and burden of male osteoporosis

From adolescence through midlife, the fracture incidence is higher in men than in women, a trend that is reversed in older age.5 Indeed, although relative bone fragility contributes to the occurrence of fractures in younger men, many fractures result from high-energy trauma related to sports, traffic accidents, or the workplace.

Progressive bone loss and deterioration of bone biomechanical properties, increased prevalence of comorbidities, and regression of neuromuscular function with an increased propensity to fall, all contribute to an exponential increase in the incidence of fractures in elderly men, as is the case in elderly women. However, the age-specific fracture risk in men over the age of 50 years is lower than in women, and osteoporotic fractures tend to occur on average 5 to 10 years later than in women, depending on the type of fracture. Men thus have a similar absolute fracture risk at an older age. Estimates of the lifetime risk of fracture after age 50 years in men range between 13% and 25%. This is substantially lower than estimates in women, who have a lifetime risk of fracture of up to 50%. This can be explained by both a lower age-specific fracture incidence and shorter life expectancy in men.6-8

The major fractures associated with osteoporosis in men are fractures of the vertebrae, hip, proximal humerus, and distal forearm. Other fractures contributing to the burden of osteoporosis in men include fractures of the ribs, sternum, clavicle, pelvis, and distal femur.6-9 The incidence of hip fractures increases exponentially with advancing age,6 but there are differences in reported fracture incidences between countries.10 In Europe, estimates of the 10-year probability of a hip fracture at age 50 range between 0.1% and 0.6% in men as compared with 0.2% to 1.1% in women. The fracture probability increases with advancing age in men and women, although the longer term 10-year probability ultimately decreases in the oldest old because of limited life expectancy. Hip fractures typically occur as a consequence of a fall after age 75 years. Compared with cervical hip fractures, trochanteric fractures tend to occur in somewhat older men and more often in men with a history of other fragility fractures.9,10

The incidence of vertebral fracture in men also increases with age, although less steeply than in women.6,7 Similarly, in men fracture rates for other fractures resulting from low-energy trauma, such as fractures of the proximal humerus, rib, or pelvis, also increase with advancing age. The epidemiology of distal forearm fractures in men differs more markedly from that in women. Whereas in women the incidence of this type of fracture increases substantially between age 45 and 60 years, with a plateau (or a limited increase) thereafter, in men the frequency of forearm fracture remains low with hardly any age-related increase. Nevertheless, distal forearm fractures in men appear to be associated with a considerable risk for the occurrence of other osteoporotic fractures, in particular hip fractures.11

Temporal changes in the age-specific incidence of fractures have been reported—particularly for hip fracture rates—and there is geographical heterogeneity in these changes. While the rate of hip fractures in Western populations—which was increasing at the end of the past century—seems to have stabilized and may even have decreased, incidence rates appear to be rising in other populations, in particular in Asian countries and Latin America. However, the hip fracture rate is lower in both women and men in Asian and Latin American populations than in Western populations, and sex differences are also less marked.7,12-14

Although the fracture rate is lower in men, the consequences of a fracture tend to be more severe in men than in women, in terms of both morbidity and mortality, which is explained only in part by a higher prevalence of comorbidities in men.9,15,16 As much as one-third of the burden of hip fractures worldwide, expressed in disability-adjusted life years, and onethird of the cost of osteoporotic fractures in Europe result from fractures in men.17

Relationship of fracture incidence to BMD and diagnosis of osteoporosis

The operational definition of osteoporosis relies on quantitative assessment of bone mineral density (BMD), usually by dual energy x-ray absorptiometry (DXA). As initially proposed by a working party of the WHO (World Health Organization) for postmenopausal women, osteoporosis is defined as a BMD that is 2.5 standard deviation or more below the mean BMD of young women at age of peak bone mass, ie, a T-score equal to or below –2.5. Since the T-score value is dependent on the skeletal measurement site and the reference population considered, osteoporosis is now more precisely defined as a T-score of –2.5 or less at the femoral neck as measured by DXA, using the average BMD measured in women aged 20-29 years from the NHANES III database (the Third National Health and Nutrition Examination Survey; USA) as a reference.18 This approach was later broadened to also include men.7,8,19

The relationship between femoral neck BMD—as assessed by DXA—and fracture risk appears similar in women and men, with a consistent increase in the relative risk of fracture for each standard deviation decrease in BMD. In both men and women this gradient of risk is steeper for the risk of hip fracture than for the risk of all osteoporotic fractures and is similarly dependent on age.20 Thus, women and men of the same age and with a same absolute BMD, have a similar risk of fracture. Available studies suggest that this is the case for both hip and vertebral fractures.7 These findings constitute the rationale supporting the use in men of the same operational definition as in women, ie, a T-score of –2.5 or less, calculated using the mean BMD of the women aged 20-29 years in NHANES III as a reference.19




Pathophysiology of low bone mass

Adult bone mass is the resultant of the peak bone mass acquired during growth and maturation and the subsequent bone loss in adulthood. Peak bone mass is largely genetically determined and its optimal acquisition is dependent on the absence of interfering disease and on optimal exposure to growth hormone and to estrogens and androgens during puberty.21-23 Trabecular bone loss begins before midlife, continues throughout life, and tends to accelerate in older men at critical bone sites, ie, at the lumbar spine and femoral neck, whereas it slows down at other sites such as the distal radius and tibia. In men, trabecular bone loss results primarily from trabecular thinning, with a relatively better preservation of trabecular numbers and connectivity than in women.24-26

Periosteal bone apposition is a continuous process throughout life. Cortical bone loss occurs mainly after age 60 years, when periosteal apposition no longer compensates for increased endocortical bone resorption. Thus, with aging, the cross-sectional area of bones tends to increase, while the cortex becomes thinner as a result of endosteal bone resorption, which is characterized by a process of trabecularization of the endosteal envelope of long bones. Data from longitudinal studies have consistently shown that the rates of cortical bone loss in elderly men may be considerably more rapid (0.5% to 1% per year) than previous estimates from crosssectional studies (0.1% to 0.3% per year).7,24,26,27

In elderly men, increased trabecular and cortical bone loss is accompanied by a modest-to-moderate increase in levels of the biochemical markers of bone turnover, mostly evident after the age of 60 to 70 years.28 Acquired profound hypogonadism in men results in high bone turnover and accelerated bone loss.29,30 Androgen effects, mediated through activation of the androgen receptor, play an important role in the maintenance of adult bone health in men by preserving cancellous bone and stimulating periosteal bone apposition.

There is, however, ample direct and indirect evidence in both experimental animals and humans that aromatization of testosterone to estradiol plays a major role in the regulation of bone homeostasis in males. Estrogen effects, mediated through activation of estrogen receptor alpha, are required to effectively restrain bone turnover, and there is evidence that threshold levels of (free or bioavailable) estradiol might be required to limit age-related bone loss in men.22,23,31,32

Other hormonal factors likely to contribute to senile bone loss are decreased activity of the somatotropic axis, with possible adverse effects on osteoblastic function, and secondary hyperparathyroidism.9,21,33 The latter increases bone resorption and cortical porosity and is the consequence of the combined effects of highly prevalent vitamin D insufficiency, age-related decrease in the efficiency of intestinal calcium absorption, and low dietary calcium intake in the elderly.

Clinical risk factors

Major risk factors for fracture in men include older age, a history of prior fracture after age 50 years, and a low BMD, with further independent contribution provided by additional risk factors. Many factors are related to impaired bone strength, whether they directly contribute to bone fragility (eg, excess glucocorticoids) or merely reflect existing bone fragility (eg, history of prior low-energy trauma fracture). Other risk factors contribute to increased exposure of the skeleton to excessive biomechanical stresses (ie, primarily risk factors for falls). Obviously, some factors may be related to both bone fragility and the risk of falls (eg, excessive alcohol consumption).


Table I
Table I. Some clinical risk factors for fracture in men as identified
in epidemiological studies. *See Table II.

Adapted from reference 9: Kaufman and Goemaere. Best Pract Res Clin Endocrinol
Metab. 2008;22:787-812. © 2008, Elsevier Ltd.



Epidemiological studies have identified a large number of risk factors for fracture (Table I), although there is considerable heterogeneity in reported risk factors among studies. A limited number of clinical risk factors have been validated in meta-analyses involving large numbers of subjects and shown to contribute to fracture risk estimates independently of BMD. These include age, history of previous fragility fracture, current glucocorticoid use, current smoking, excessive alcohol consumption (≥3 units/day), parental history of hip fracture, low BMI (≤19 kg/m2), and secondary causes of osteoporosis, in particular rheumatoid arthritis.17

FRAXR®(Fracture Risk Assessment tool), a computer-based algorithm, combines these risk factors and patient characteristics (sex, age, height, weight) with or without femoral neck BMD to calculate the 10-year probability of a hip fracture and of a major osteoporotic fracture.17

Clinical presentation

Osteoporosis in men may be “primary,” which includes senile osteoporosis, osteoporosis linked to a specific monogenic syndrome (eg, osteoporosis-pseudoglioma syndrome), and “idiopathic” osteoporosis in young men. Osteoporosis may also be “secondary,” ie, the consequence and epiphenomenon of another disease or its treatment (Table II). Some of the more common secondary causes of osteoporosis in men include glucocorticoid treatment, alcohol abuse, obstructive pulmonary disease, hypogonadism, post-transplantation, and androgen ablation therapy in prostate cancer.7,9,33 The distinction between primary and secondary osteoporosis is not absolute. Indeed, it is not always clear whether an adverse environmental factor can be seen as a mere risk factor modulating the expression of primary (senile) osteoporosis or rather one that plays a decisive role in its pathogenesis and should thus be considered as a secondary cause of osteoporosis.

It has been suggested that in men a larger proportion of patients present with secondary osteoporosis, than is the case in women.34 Although this may well be the case in clinical practice— eg, in the practice of an endocrinologist or a rheumatologist— this has never been formally established in population based epidemiological studies. It is possible that the impression that there is a larger proportion of secondary osteoporosis cases in men is biased by the fact that in current clinical practice the rate of referral for bone densitometry is much lower in asymptomatic men than in asymptomatic women.

In young men with idiopathic osteoporosis, genetically determined deficiency in the acquisition of peak bone mass and size appears to be the dominant pathogenic presentation— although increased cortical porosity in those presenting with vertebral fracture has been reported.35-37 Deficient acquisition of peak bone mass may also be a predominant presenting feature in cases of secondary causes of osteoporosis already present during childhood and adolescence.37 Bone loss with its attendant deterioration of bone microarchitecture usually plays a predominant role in secondary and senile osteoporosis. In terms of bone turnover, the picture in male osteoporosis is rather heterogeneous, but levels of the biochemical markers of bone turnover are often less markedly increased than in postmenopausal osteoporosis.

Management of osteoporosis in men

Strategies
Presently only a small proportion of men at high risk of fracture are being treated. As is the case in women, there is no generally accepted algorithm for the management of osteoporosis in men and no validated strategy for systematic osteoporosis screening. Active case-finding (opportunistic screening) should thus be encouraged, and focus primarily on the detection and treatment of those men at high risk of fracture. Whereas treatment decisions in men have largely been based on BMD Tscores and/or occurrence of a prior fragility fracture, it is now widely accepted that identification of those men most likely to benefit from treatment can be refined by taking into account additional clinical risk factors.17 Using a stepwise approach, clinical risk factors can also be used to select men for referral for bone densitometry.7 In this context, integration of fracture risk probability calculation with the validated FRAXR algorithm can represent a step forward toward a rational approach to case-finding and treatment decisions.7,17 Nevertheless, it should be noted that taking into account age, history of fracture, and BMD will capture a substantial part of the fracture risk in men and that the risk of falls is not considered in FRAXR. As for the latter, there is presently no generally accepted and applied measure of the propensity to fall.19


Table II
Table II. Some causes of osteoporosis in men.

Adapted from reference 9: Kaufman and Goemaere. Best Pract Res Clin Endocrinol
Metab. 2008;22:787-812. © 2008, Elsevier Ltd.



General measures
Men at moderately increased risk of fracture should be given lifestyle advice. A balanced diet and daily intake of 1200 mg calcium, moderate sun exposure, and safe weight-bearing exercise should be encouraged. Excessive alcohol consumption and smoking should be discouraged. All necessary measures to reduce the risk of falls should be taken in elderly and frail men. This includes a reappraisal of the indications for psychotropic and cardiovascular medication.

Evidence from available randomized trials does not support systematic supplementation with calcium and/or vitamin D in elderly men to reduce the fracture risk.38 Nevertheless, supplementation with 500 to 1000 mg calcium (depending on dietary intake) and 800 to 1000 IU vitamin D (or higher in case of intestinal malabsorption) should be considered in men with deficiencies or at risk of deficiencies (eg, men who are house- bound or residing in a home for the elderly, men avoiding milk products, men on glucocorticoid treatment, men with secondary hyperparathyroidism…). Calcium supplementation, usually with vitamin D, is an obligatory complement to other specific pharmacological treatments of osteoporosis, because these supplements were an inherent part of the treatment regimens validated in clinical trials.

Before initiating a pharmacological treatment for osteoporosis, patients should be evaluated for secondary causes of osteoporosis as secondary osteoporosis might require a disease specific treatment (eg, surgery in primary hyperparathyroidism) instead of, or in addition to, osteoporosis medication.

Specific pharmacological interventions
It is only recently that the pharmacological armamentarium for the treatment of osteoporosis in men has expanded considerably.7 All drugs registered for the treatment of osteoporosis in men have previously been shown to effectively reduce vertebral fracture risk in postmenopausal women, and some of them have also been shown to reduce the risk of nonvertebral fractures. The approval of these drugs for use in men was generally granted on the basis of so-called “bridging” studies, which assessed the effects of these treatments on a surrogate end point in men, ie, BMD changes; the data based on the effect of these treatments on fracture rate in men is very limited.7 The approval of these drugs for osteoporosis treatment in men is based on the assumption that the fact that they have a similar effect on BMD in men than in postmenopausal women will also lead to a reduction in fracture risk similar to that previously documented in postmenopausal women. Although some of the premises on which this assumption is based could be argued, for a wide range of drugs the effects on BMD in men were found to be remarkably similar to their effects in postmenopausal women.7 Moreover, a recent study in osteoporotic men, with fractures as the primary end point, appears to confirm that the similarity of effects between men and postmenopausal women also applies to the reduction of fracture risk.39

Antiresorptive treatment with a bisphosphonate is the most widely applied pharmacological treatment for osteoporosis in men. Alendronate 10 mg/day was the first drug to be formally validated for use in men with osteoporosis in a dedicated randomized trial.40 Alendronate-treated men showed an increase in BMD similar to that previously observed in postmenopausal women. The radiographic vertebral, clinical vertebral, and nonvertebral fracture risks were numerically reduced, without achieving statistical significance in this study, which was not powered to assess antifracture efficacy. Risedronate 35 mg/day was also shown to significantly increase BMD in men with osteoporosis in a dedicated randomized trial.41 Approval of zoledronic acid for the treatment of osteoporosis in men was granted on the basis of the findings of the HORIZON Recurrent Fracture Trial (Health Outcomes and Reduced Incidence with Zoledronic Acid ONce yearly Recurrent Fracture Trial) in subjects with recent low-trauma hip fracture, of which about one-third were men. In this study, an annual infusion of 5 mg zoledronic acid reduced the risk of clinical fractures by 35% in the overall population compared with placebo, and there was no significant treatment-by-sex interaction.42 In a subgroup analysis, the BMD increase in men was statistically similar to that in women with hip fracture.43 Recently, in a trial in which reduction of vertebral fracture risk was the primary efficacy criterion, annual infusion of 5 mg zoledronic acid was shown to significantly reduce the incidence of vertebral fracture in men with osteoporosis.39 The observed fracture reduction was of similar magnitude to that previously reported for the treatment of postmenopausal osteoporosis with zoledronic acid.

Bone-forming treatment with daily subcutaneous injection of teriparatide was approved for the treatment of osteoporosis in men based on a bridging study in men with low BMD in which changes in vertebral BMD was the primary efficacy criterion.44 Both the pattern of changes in biochemical markers of bone turnover and the substantial increases in BMD following daily subcutaneous injection of 20 μg teriparatide compared with placebo were very similar to those observed with this treatment in postmenopausal osteoporosis. A follow-up study of 18 months including the majority of the patients from the initial trial—which was terminated early (11 months of total treatment exposure)—showed that treatment withdrawal resulted in rapid bone loss and that point estimates for the reduction in vertebral fracture rates for the overall treatment and post-treatment follow-up were similar to those observed in postmenopausal women in the larger core trial.45 Given the rapid decrease in BMD after termination of treatment with teriparatide, it seems advisable that treatment with teriparatide should be followed by subsequent administration of an antiresorptive treatment so that the achieved BMD gains can be maintained.45 However, concomitant treatment with alendronate and teriparatide was found to be less effective at increasing BMD than teriparatide alone.46

Strontium ranelate has opposite effects on bone resorption and bone formation and thus a mode of action that differs from that of both bisphosphonates and teriparatide. It was granted an indication for use in men with severe osteoporosis based on a bridging study with changes in BMD as the primary efficacy criterion.47 This study showed that the effect on BMD of daily oral administration of 2 g strontium ranelate in men with osteoporosis is similar to the effect of this treatment on BMD in postmenopausal osteoporotic women, in whom strontium ranelate treatment was shown to significantly reduce the risk of vertebral and nonvertebral fractures.

Hypogonadism and role of testosterone treatment
Hypogonadal men have a combined androgen and estrogen deficiency and adult men with acquired profound hypogonadism have accelerated bone loss and are at increased fracture risk. As discussed above, it is now well documented that estrogens are important for preservation of bone health in adult men. In aging men, increased bone loss and fracture risk may be more closely related to relative estrogen deficiency than to the age-related decline in androgen levels.31,48

The beneficial effect on BMD of the pharmacological treatments of osteoporosis in men discussed above has been shown to be largely independent of the prevailing serum (free) testosterone levels. Moreover, it has been shown that bisphosphonates and the selective estrogen receptor modulator raloxifene can prevent bone loss in severe hypogonadism induced by androgen deprivation therapy for prostate cancer.49 More recently, it has also been shown that treatment with the antiresorptive drug denosumab, a monoclonal antibody that binds and neutralizes receptor activator of nuclear factor kB ligand (RANKL) activity, increases BMD and reduces fracture risk in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.50

For obvious reasons there have been no randomized controlled trials assessing the long-term effects on the skeleton of testosterone substitution treatment in frankly hypogonadal younger men, but available observational data suggest favorable effects on BMD.22,23 Nevertheless, the effect of testosterone treatment on fracture risk is unknown and the longterm risk-benefit ratio of prolonged treatment in elderly men has not been established. In this context, hypogonadism in elderly men requires a conservative approach. Testosterone treatment in the elderly should be considered only if serum testosterone—measured in the morning with a well validated method—is found to be really low and the patient presents with unequivocal signs and symptoms of hypogonadism.

Osteoporosis is neither a sufficient nor a specific indication for testosterone treatment. In hypogonadal men with a high fracture risk, one of the several validated treatments of osteoporosis in men should be initiated, and use of such a treatment should be considered even in those men with a high fracture risk who are also treated with testosterone for symptomatic hypogonadism.19

Conclusions

One in three fragility fractures occur in men, and osteoporotic fractures in men represent a significant burden for public health, both in terms of personal suffering and societal cost. Because fractures in men tend to occur at an older age than in women, and because older men are more subject to comorbidity, fractures in men often affect frail individuals with potentially dramatic consequences.

Although awareness of osteoporosis in men among health professionals has improved, only a small minority of men at high risk of fracture are being treated. Therefore, active case finding with a stepwise approach based on assessment of clinical risk factors complemented with bone densitometry when appropriate should be encouraged. The FRAX® algorithm, which is used to assess the 10-year probability of osteoporotic fracture, is a useful tool for case-finding and identification of those men most likely to benefit from treatment. Men at high risk of fracture should be investigated for possible secondary causes of osteoporosis, even though, contrary to common belief, it has not been established that, compared with women, a larger proportion of osteoporosis cases in men are secondary. Although there are sex differences in some aspects of the pathophysiology of osteoporosis, such as in the pattern of age-related bone loss, similarities between men and women tend to predominate overall. In this regard, the major role of estrogens for maintenance of skeletal health in men deserves to be mentioned. Also, the major clinical risk factors for fracture are the same in men and in women.

In men at high risk of fracture, general preventive measures— including the prevention of falls—should be given the necessary attention. Calcium and vitamin D supplements are an integral part of all pharmacological treatment regimens aimed at reducing fracture risk. The current level of evidence regarding the efficacy and safety of osteoporosis treatments in men is lower than for the treatment of postmenopausal osteoporosis, with the evidence mainly based on BMD changes as a surrogate clinical efficacy criterion and little data on fracture reduction in men. Nevertheless, there are now several drugs registered for use in men, ranging from antiresorptive treatment with bisphosphonates, bone-forming treatment with teriparatide, and strontium ranelate with its opposite effects on bone resorption and formation. Antiresorptive treatment with denosumab is indicated for treatment in men receiving androgen deprivation therapy treatment for prostate cancer. The data available on the effects of this broad range of drugs indicate that treatment responses in men are very similar to the treatment effects previously described in postmenopausal women. Testosterone treatment should be reserved to symptomatic hypogonadal men with really low serum testosterone: osteoporosis is neither a sufficient nor a specific indication for testosterone treatment.

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Keywords: bone mineral density; epidemiology; fracture risk; male; osteoporosis; risk factor; therapy