Osteoporosis in men

Best Practice & Research Clinical Endocrinology & Metabolism Vol. 22, No. 5, pp. 787–812, 2008 doi:10.1016/j.beem.2008.09.005 available online at http://www.sciencedirect.com

7 Osteoporosis in men Jean M. Kaufman *

MD, PhD

Professor and Doctor

Stefan Goemaere

MD

Doctor Ghent University Hospital, Department of Endocrinology, 9K12IE, De Pintelaan185, 9000 Gent, Belgium

About one in three osteoporotic fractures occur in men, and the consequences of fractures are more severe in men. However, only too few men at high risk of fracture are detected and treated. There is no consensus definition of osteoporosis in men based on bone mineral density (BMD), and therapeutic decisions should be based on absolute fracture risk as estimated from age, BMD, fracture history, and additional clinical risk factors. In men, secondary osteoporosis deserves particular attention. Genetically determined alterations of bone mass acquisition during growth are involved in idiopathic osteoporosis in the young, whereas senile osteoporosis involves progressive bone loss throughout adult life. Estradiol appears to be the predominant sex steroid involved in regulation of bone maturation and metabolism. The evidence base for the long-term efficacy and safety of therapies for osteoporosis in men, including the bone-active agents (i.e. bisphosphonates and teriparatide), is limited, so that they should be applied with discernment based on clinical judgement and careful estimation of fracture risk. Key words: osteoporosis; man; bone mineral density; secondary osteoporosis; idiopathic osteoporosis; aging; glucocorticoids; bone size; parathyroid hormone; testosterone; oestradiol; bisphosphonates; teriparatide; epidemiology.

Continuous bone loss and increased bone fragility, higher prevalence of associated morbidity, and deterioration of neuromuscular functions with increased incidence of falls, all contribute to an exponential increase in bone fracture rates seen in aging men.1–5 However, the age-specific risk of spine and hip fracture in older men is only about one third to one half that in women. Men reach the same absolute facture risk at an older age.6–8 Factors that may contribute to this lower fracture rate in men include the higher bone mass with larger bone size achieved during growth and maintained throughout adult life, * Corresponding author. Tel.: þ32 9 332 21 30; Fax: þ32 9 332 38 17. E-mail address: [email protected] (J. M. Kaufman). 1521-690X/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.

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a better preservation of trabecular structure in adult life, and a relatively lower risk of falls in the elderly. Absolute fracture numbers in older men are lower than in women because of both the lower age-specific risk and the shorter life expectancy in men.1–5 Albeit lower than in women, fracture risk in men is substantial, with one in three osteoporotic fractures after the age of 50 years occurring in men.9 Moreover, the consequences of fractures in older men, both in terms of morbidity and mortality, appear to be more severe than in women.10–13 In fact, low bone mineral density (BMD) in older men is a marker of frailty as suggested by the findings that low BMD in older men is associated with higher mortality rates.14,15 Osteoporosis thus represents a significant threat for the health and wellbeing of the aging male population and a significant problem for public health. About one third of the burden of hip fracture worldwide, expressed in disability-adjusted life years, and one third of the costs of osteoporotic fractures in Europe result from fractures in men.16 Nevertheless, at present few treatments for osteoporosis have been validated in men, and awareness amongst the public and health providers remains poor. Rates of diagnosis and treatment of osteoporosis in men who have sustained an osteoporotic fracture are worryingly low.17,18 EPIDEMIOLOGY AND BURDEN OF THE DISEASE ‘Fragility’ fractures are the primary clinical expression of osteoporosis in men. Their immediate and longer-term consequences – mitigated by factors such as age, general health status, associated morbidity and socio-economic status – are major determinants of the burden of osteoporosis in men. From adolescence through midlife, fracture incidence is higher in male than in female subjects, a trend that is reversed after midlife.19 Although relative bone fragility contributes to the occurrence of fractures in younger men, many involve high-energy trauma events related to sport and traffic accidents or in the work place. The major fracture types associated with osteoporosis in men include fractures of the hip, vertebrae, humerus and distal forearm. Other skeletal sites contributing significantly to the burden of fracture in osteoporotic men are the pelvis, ribs, clavicula, sternum and distal femora. These different types of fragility fracture tend to result from low-energy trauma; their incidence increases with age and with lower BMD, and they are predictive for the occurrence of fractures at classical sites of osteoporotic fracture, i.e., fractures of the hip and vertebrae. Because of their high incidence and severe consequences, the latter undoubtedly contribute most to human suffering and socioeconomic burden.16,20 Hip fractures Hip fractures in men, either cervical or trochanteric, occur most commonly as a consequence of a fall after the age of 75 years. Their age-specific incidence rises exponentially from age 70 years onwards. Trochanteric fractures tend to occur at a somewhat later age and are more often preceded by other fragility fractures.6,16,20 There are large geographical and ethnic differences in incidence rates and lifetime risk of hip fractures, with high incidences in northern Europe and North American Whites. The highest incidences are recorded in Sweden, whereas low incidences are recorded for Asian populations, Blacks in North America, and for some South-American populations. Although a marked age-related increase in fracture risk is seen in all populations, interestingly gender differences with markedly higher age-specific incidence in women are not seen in the populations with low hip fracture risk.16 For the population of Malmo¨ in Sweden the 10-year risk of hip fracture in men at age 50 years was estimated at

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0.8%, increasing to 5.9% and 7.6% at 75 and 80 years of age, respectively.21 The remaining lifetime risk of hip fracture at age 50 years in Sweden lies around 10%; this risk is around 5% in the UK and the Netherlands, with somewhat higher risk estimates for Australia and for Whites in the USA.16,21 The 1-year mortality after hip fracture has been estimated at around 30%. Associated morbidity plays an important role, which might explain that the relative risk of death in the year following a hip fracture has been reported to be higher at age 60 than at age 80 years. A hip fracture carries a substantial risk of loss of autonomy.2,9–12,16 Vertebral fractures Only a minority of vertebral fractures in men come to medical attention: 5–50%, depending on the considered study population and age group. Most vertebral fractures are associated with no known trauma or with low-energy trauma such as lifting, change in position, and falls. Falls, mostly from standing height or less, play a major role in the occurrence of clinical vertebral fractures in elderly men.16,22 The prevalence of radiographic vertebral deformities in younger men is higher than in women, a trend which is reversed after the age of 65 years.23 The age-standardized incidence of vertebral deformities in older men is about half that in women, and it increases less with age than in women and than is the case for hip fractures. There are geographic variations in the incidence of vertebral fractures, with highest rates reported for Sweden and low rates for African Americans and Hispanic populations, but these differences are smaller than for hip fracture rates.6,16,24 For clinical vertebral fractures in older men, incidence rate increases markedly with age.7 In the North American arm of the MrOS (Osteoporotic Fractures in Men) study clinical vertebral fracture incidence was 0.7% in the age group 65–69 years and reached up to 5% in men 85 years.22 Interestingly, whereas the highest prevalence of vertebral deformities are usually situated in the mid-thoracal spine region, incidental clinical vertebral fractures in the older subjects were mainly situated in the thoraco-lumbar transition and in the lumbar spine. In Swedish men the remaining lifetime probability of clinical vertebral fractures after the age of 50 was estimated at 8.3%.21 Vertebral fractures have been associated with excess mortality. Highest risk has been linked to clinical vertebral fractures and in cases of multiple fractures; although the risk is lower and findings are less consistent, radiographic vertebral deformities have also been linked to risk of death.10,16,25,26 Vertebral fractures predict the occurrence of subsequent vertebral fractures and other osteoporotic fractures.26–29 Whereas vertebral fractures often occur silently, they are not uncommonly accompanied by acute back pain, may require hospitalization and, especially in the case of multiple fractures, are associated with loss of height, functional impairment, and long-term adverse effects on health and quality of life.13,16,30–33 Other fractures The incidence of distal forearm fractures in men is considerably lower than in women, with a gender ratio of 1/5 or higher, and varies little during adult life, with some increase seen only after age 80 years.8 Distal forearm fractures are not associated with excess mortality.16 Notwithstanding the particular features of the epidemiology of distal forearm fractures in men, which seem to differentiate them from other classical osteoporotic fractures, men with a history of distal forearm fracture are at

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increased risk for vertebral and hip fracture. In fact, Colles’ fractures were shown to be a sensitive marker of skeletal fragility in White men; the remaining lifetime risk for hip fracture in men with history of Colles’ fracture was 8% compared to 6% in men with previous spine fracture and 3% in men of the general population.34,35 Other osteoporotic fractures, including fractures of the pelvis, ribs, humeral shaft, proximal humerus, clavicula, scapula and sternum, show increasing incidence rates with age in older men. The clinical consequences are far from negligible, and some – e.g. the proximal humerus fractures – have been associated with excess mortality.10,16 The cumulated burden and related medical costs of these various fracture types are substantial. Various studies have estimated cumulated lifetime risks for different fracture types. In 50-year-old North American white men, the remaining lifetime risk of experiencing a fracture of a hip, vertebra (clinical) or wrist was estimated at 13%. In 50-year-old Swedish men remaining lifetime risk for hip, distal forearm, clinical spine or proximal humerus fracture was 22.4%. In the Australian Dubbo Osteoporosis Epidemiology Study the mortality-adjusted residual lifetime risk of any osteoporotic fracture in 60-year-old men was 25%.16,21,36 SKELETAL CHANGES WITH AGE As assessed by dual-energy x-ray absorptiometry (DXA), a two-dimensional projection technique, young adult men have a higher peak bone mass than women. More detailed analysis reveals that this is explained by larger bone dimensions in men, whereas both trabecular and cortical volumetric BMD evaluated by quantitative computed tomography (QCT) techniques appear to be somewhat higher in women. As to trabecular bone structure, young men have similar numbers of trabeculae and trabecular separation as women but greater trabecular thickness and ratio of trabecular bone volume over tissue volume.37–41 Cross-sectional data39,42 confirmed by longitudinal observations43 indicate that trabecular bone loss begins before midlife, continues throughout life, and accelerates in older subjects at critical bone sites, i.e., at the spine and femoral neck. At the distal radius and distal tibia, trabecular bone loss tends rather to slow down in the elderly. In men, decrease of the ratio of trabecular bone volume to tissue volume results primarily from trabecular thinning, with preservation of trabecular numbers and trabecular separation.40,41 Periostal bone apposition is a continuous process throughout adult life. Cortical bone loss occurs mainly after the age of 60 years, when this periostal apposition no longer compensates for increased endosteal bone resorption. Consequently, in elderly men, compared to the young, the total cross-sectional area of long bones is increased whereas cortical thickness is decreased, and there is little change in volumetric cortical BMD with age. The adverse biomechanical consequences of decreased cortical mass and thickness in elderly men are compensated in part by a more favourable geometric distribution of cortical bone, further out from the neutral axis of the long bones.2,38,39,42,43 Data from longitudinal studies have consistently shown that the rate of cortical bone loss in older men may be considerably more rapid (0.5–1% a year) than estimated from cross-sectional studies (0.1–0.3% a year).44 The increased rate of trabecular and cortical bone loss in older men is accompanied by a usually modest to moderate increase in the levels of biochemical markers of bone turnover, which becomes evident only after age 60–70 years; the increase of resorption markers is somewhat larger than for those of bone formation. In older men values for both resorption and formation markers are inversely correlated with BMD, suggesting that increased bone turnover underlies the accelerated bone loss in the elderly.45,46

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SEX STEROIDS AND THE REGULATION OF BONE MASS There is evidence that the gender-specific skeletal aspects and possibly also the lower propensity to fall, which underlie the lower fracture rate in elderly men compared to women, are related in part to differences in sex steroid hormone exposure and action. Peak bone mass and size Pubertal exposure to rising blood concentrations of sex steroids, partly in concert with transiently increased activity of the somatotropic axis, is instrumental in a pubertal acceleration of bone growth and acquisition of bone mass, followed by growth inhibition and closure of the epiphyseal cartilages in late puberty. Quantitative, qualitative, and temporal differences in sex steroid action in the peripubertal period play an important role in establishing skeletal gender dimorphism.2,47 Oestrogens are essential for skeletal maturation with closure of epiphyseal cartilages and for adequate acquisition of bone mass in men. This is illustrated by observations of a low bone mass and failure of growth plate fusion in men with lack of functional oestrogen receptor a (ERa) or with aromatase deficiency, which in the latter case can be reversed by oestrogen treatment.48 The gender dimorphism in skeletal maturation with greater periosteal expansion and radial bone growth in men has traditionally been attributed to opposite actions of sex steroids on periosteal bone apposition with androgen-driven stimulation in males and oestrogen-mediated inhibition in females. However, evidence from animal studies and observations in the human indicate that oestrogens play an important role in the stimulation of periosteal apposition and radial bone growth.49–51 There is also ample evidence for an androgen-receptor-mediated role of androgens in the determination of adult bone dimensions in men.50,51 The greater periosteal expansion in men may then result from combined effects of androgens, i.e. testosterone (T) and its 5a-reduced active metabolite dihydrotestosterone, mediated by the androgen receptor (AR) and oestradiol (E2), the main aromatization product of T, mediated by ERa, whereas inhibitory actions of E2 in women might possibly be mediated by ERb. The biphasic oestrogen actions on bone might be mediated in part by changes in growth hormone and/or insulin-like growth factor 1 (IGF-1) levels and through modulation of the sensitivity of periosteal bone to mechanical stimuli.51 It should also be noted that there have been data suggesting that E2 can also inhibit radial bone growth in pubertal boys.52 Preservation of adult bone mass Acquired, profound hypogonadism results in a state of high bone turnover with accelerated bone loss.53–55 Although AR-mediated androgen effects in the adult male skeleton help prevent osteoporosis by preservation of cancellous bone and stimulation of periosteal cortical bone apposition, there is ample direct and indirect evidence in experimental animals and humans indicating a major role for aromatization of T to E2 in the regulation of bone homeostasis in adult men. Oestrogens are required for effective restraining of bone turnover, and it has been suggested that threshold concentrations of (free or bioavailable) E2 may be required to limit agerelated bone loss.47–49

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Senile bone loss Aging in men is accompanied by a progressive decline in T production with a moderate decrease in serum total T levels. A marked age-related increase of sex hormone binding globulin (SHBG) results in a more substantial decrease of the non-SHBG-bound fractions that are readily available to the tissues for biological action, i.e., free T (FT) and bioavailable T (bioT). Notwithstanding the decreased levels of the T precursor, serum concentration of total E2 is maintained with aging as a result of increased aromatization capacity. Nevertheless, the increase in SHBG levels results in a moderate age-related decrease in non-SHBG bound fractions of serum E2, i.e. free E2 and bioavailable E2 (bioE2).56 This raises the question of the potential relevance of these age-related hormonal changes as to senile bone loss and osteoporosis in men. Cross-sectional studies, in which age and body mass index (BMI) or weight are major confounders, have yielded inconsistent results as to the association of serum T levels with prevalent BMD assessed by DXA in elderly men. Multivariate analyses more consistently indicated that free E2 or bioE2 is a better predictor of prevalent BMD in elderly men than FT or bioT (reviewed by Kaufman and Vermeulen).56 Serum bioE2 has also been associated with volumetric BMD, geometric variables and trabecular structure of bone as assessed by QCT.57,58 Furthermore, high values for markers of bone resorption are more consistently associated with low serum E2 than with serum T levels.45,57,59,60 Osteoprotegerin levels have been reported to be positively associated with E2 levels and negatively correlated with markers of bone resorption.61 A role for aromatization of T to E2 in the regulation of bone turnover in elderly men and its possible mediation through modulation of RANK-ligand production has also elegantly been demonstrated during short-term controlled manipulation of sex steroid levels.62,63 Finally, longitudinal studies have confirmed that serum (bioavailable) E2 rather than serum (bioavailable) T is a determinant of bone loss in elderly men.60,64,65 Moreover, bone loss has been associated with a TTTA repeat polymorphism of the CYP19 aromatase gene65,66, possibly also independently of circulating E2 levels, thus suggesting a role for local aromatization of T in bone.65 The findings of some60,64 but not all65 studies suggested the existence of a threshold bioavailable E2 level below which bone loss increases. OTHER HORMONAL FACTORS IN THE REGULATION OF BONE MASS The acquisition of optimal peak bone mass – and in particular bone size – during growth requires adequate activity of the somatotropic axis and probably also appropriate timing of peripubertal exposure to growth hormone (GH) and IGF-1 together with sex steroids.47,67,68 Aging in men is accompanied by a marked decline in GH and IGF-1 serum levels, and it is plausible that these changes might affect senile bone homeostasis. Moreover, there are undoubtedly relevant functional links with regard to regulation of bone homeostasis between the sex steroids and the somatotropic axis in elderly men, but at present information on this important area for research is scarce.47,56,67 In this context it has been hypothesized that the decreased activity of the somatotropic axis might play a role in the age-related increase in serum SHBG.56 Aging in men is also accompanied by a substantial (up to 80%) decline in the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA-sulphate between the ages of 20 and 70 years. However, there is little indication that the reduced secretion of these steroids (which are precursors for T and oestrogens) plays a significant role in the

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regulation of bone metabolism in elderly men with still substantial, albeit diminished, circulating T concentrations.56 Vitamin D insufficiency is not uncommon in elderly men, in particular in those who are house-bound or residing in nursing homes. Aging in men is accompanied by a modest increase in mean serum parathyroid hormone (PTH) levels and in the prevalence of secondary hyperparathyroidism37, but there are few data on the contribution of the latter to senile bone loss in men. Observed positive associations of serum PTH with the levels of biochemical markers of bone turnover and inverse associations with BMD are rather weak.45,69 BONE MASS AND FRACTURE RISK In men, fracture risk is inversely correlated to prevalent BMD, with both low BMD and older age contributing to some extent independently to fracture risk. The relationship between prevalent BMD and fracture risk is complex and depends on the measurement technique and site, as well as on the type of considered fracture, in addition to variables such as age and population characteristics. Limited data suggest that also more rapid bone loss is associated with increased fracture risk, independently of prevalent BMD.4,8,16,44,70 Risk of both hip fracture8 and spine fracture70 have been reported to be similar in men and women with the same absolute areal BMD (g/cm2) as assessed by DXA, although for the latter this was true for BMD measured at the spine or the hip trochanter, but not at the femoral neck. Others found that fracture risk remains greater in men also after adjustment for BMD, although this was mainly the case in the younger (65–69 years old) and less in the older (80 years) subjects.71 Anyhow, the finding of a similar fracture risk for a same absolute areal BMD by the bi-dimensional DXA technique is likely to be largely coincidental, whereby the same areal BMD may in fact result from a different constellation of bone size and true volumetric BMD according to gender. Importantly, in a meta-analysis of cohorts followed prospectively for fracture incidence which included close to 10,000 men and 30,000 women (a total of 168,000 person-years)72, femoral neck BMD by DXA was an equally strong predictor of hip fracture in men and women; at age 65 years relative risk (RR) was 2.94 (95% CI: 2.02–4.27) in men and 2.88 (2.31–3.59) in women for each 1 SD decrease in BMD; risk gradient per 1 SD decrease in BMD was greater in subjects at age 50 compared to 80 years, and tended to increase with lower prevalent BMD. Risk gradient per 1 SD decrease in femoral neck BMD for prediction of any fracture or any osteoporotic fracture was also similar for men and women, but was smaller than for hip fracture: at age 65years, RR of 1.41 (1.33–1.51) for any osteoporotic fracture in men; in contrast with hip fracture RR increases with higher age as well as with lower prevalent BMD. In the same study, data on a smaller number of subjects for BMD at peripheral sites and measurements by quantitative ultrasound techniques showed somewhat smaller risk gradients for fracture prediction.72 Although both quantitative ultrasound techniques for bone assessment and biochemical markers of bone turnover are potentially useful tools for fracture risk evaluation, data on fracture prediction in men by either quantitative ultrasound or biochemical turnover markers are sparse.26,46 The QCT techniques allow for highly informative bone evaluation, but they are neither widely accessible for this purpose nor validated for clinical fracture risk assessment in men. It can thus be concluded that, besides older age, low BMD as assessed by DXA is a well validated and clinically an extremely useful tool for fracture risk assessment in men.

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CLINICAL PRESENTATION OF OSTEOPOROSIS IN MEN Osteoporosis in men, with its clinical expression of bone fragility, may be ‘primary’ or ‘secondary’, depending on whether the underlying generalized qualitative and quantitative skeletal defects result from characteristics or changes inherent in the affected individual or rather are an epiphenomenon of another disease or its treatment (Table 1). Primary osteoporosis includes senile osteoporosis, osteoporosis linked to a specific (mono)genic disease (e.g. osteogenesis imperfecta, osteoporosis pseudoglioma syndrome) and ‘idiopathic’ osteoporosis in younger men. However, the boundaries

Table 1. Causes of osteoporosis.

Primary: Genetic Idiopathic Aging

Secondary: Immobilization Alcoholism Endocrine disorders Hypogonadism Cushing’s syndrome Hyperparathyroidism Hyperthyroidism Diabetes mellitus (type 1) Gastrointestinal diseases Post-gastrectomy Coeliac disease Post-bariatric surgery Malabsorption syndromes (other) Inflammatory bowel disease Primary biliary cirrhosis Chronic obstructive pulmonary disease Post-transplantation Rheumatoid arthritis Pernicious anaemia Hyperhomocysteinaemia Neoplastic diseases Systemic mastocytosis Cystic fibrosis Homocystinuria Hypercalciuria Haemochromatosis Renal insufficiency Medication-related Glucocorticoids Anticonvulsants Chemotherapy Glitazones GnRH-analogues

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between primary and secondary osteoporosis are not absolute, as it is not always clear whether a particular environmental factor can be seen as a mere risk factor that modulates the expression of primary osteoporosis or rather plays a decisive role in the pathogenesis and should thus be considered a secondary cause of osteoporosis. It is often suggested that compared to the presentation of osteoporosis in women, a greater proportion of cases in men are secondary osteoporosis.1 However, this has not been formally established, and it is plausible that this is a biased view resulting from the fact that in men fewer cases of primary osteoporosis come to medical attention. Indeed, even men having sustained a fracture are infrequently subjected to bone densitometry outside the context of suspected secondary osteoporosis. Also, the evaluation in men is complicated by lack of a consensus on an operational definition of osteoporosis, in particular of a bone densitometry-based operational definition.1,16,44 Secondary osteoporosis Secondary causes of osteoporosis are listed (non-exhaustively) in Table 1. The occurrence of osteoporosis may be directly linked to the physiopathology of a disease, such as in hyperthyroidism, primary hyperparathyroidism, or Cushing’s disease, with direct deleterious bone effects of excess thyroid hormone, parathyroid hormone (PTH) and glucocorticoids, respectively. Osteoporosis may also be an epiphenomenon indirectly linked to a disease, such as in neurological disease with consequent immobilization, or in malabsorption syndromes with ensuing secondary hyperparathyroidism. Finally, osteoporosis may result from disease treatment such as in glucocorticoid-induced osteoporosis or treatment of prostate cancer with gonadotropin-releasing hormone (GnRH) analogues. Rather commonly, several mechanisms are contributing, such as is typically the case in chronic obstructive pulmonary disease (COPD) or in posttransplantation osteoporosis. In prepubertal causes of hypogonadism, with failure of timely and full pubertal development (e.g. Kallmann’s syndrome and other causes of hypogonadotropic hypogonadism), osteoporosis results from deficient accretion of bone mass and size. This is the consequence of combined androgen and oestrogen deficiency.47–51 Potential for reversibility is dependent on the stage of skeletal maturation. Also men with a history of delayed puberty may have a low bone mass with mainly reduced bone size37, as is the case in men with history of childhood-onset GH deficiency.68 Acquired profound hypogonadism in adult men induces high bone turnover and accelerated bone loss, as is typically the case during androgen-deprivation treatment of men with prostate cancer, which results in low bone mass and increased fracture risk.49,54,55 Systemic use of glucocorticoids is a common secondary cause of osteoporosis in men, resulting primarily from decreased osteoblast genesis and survival, as well as diminished calcium absorption and increased calcium excretion with secondary hyperparathyroidism, decreased muscle mass and strength, and frequent relative hypogonadism.73,74 Osteoporosis in men with advanced COPD has a multifactorial origin with, beside the use of systemic and inhaled glucocorticoids and relative hypogonadism75, a role for low BMI, vitamin D deficiency, smoking, and sedentary lifestyle.76 Recipients of solid-organ and bone-marrow transplantation are at increased risk of fracture.77 The contributing factors may include pre-transplantation bone disease, use of glucocorticoids and other immunosuppressive drugs, hypogonadism, vitamin D deficiency, secondary hyperparathyroidism, and sedentary lifestyle. Alcohol abuse, but not low to moderate alcohol intake of 2 units/day, may be associated with osteoporosis and fracture risk.78 Mechanisms involved in osteoporosis

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associated with alcohol abuse may include direct toxic actions of alcohol on bone cells, vitamin D deficiency, malnutrition, and hypogonadism. The prevalence of hypercalciuria in men with osteoporosis has not been reliably ascertained, as most reports concern selected groups of patients. Hypercalciuria may play a causal role in some cases or may merely be a marker of altered mineral metabolism in others. Currently, the role of hypercalciuria in the pathogenesis of osteoporosis in men remains poorly understood.79 Idiopathic osteoporosis in young men In clinical practice, in up to half the men under the age of 65 years presenting with osteoporosis a thorough search for known causes of osteoporosis fails to reveal a clear-cut aetiology.1,44,79 These men are usually considered as having ‘idiopathic osteoporosis’. Whereas the latter can be defined as osteoporosis without any known cause, it remains a rather loosely defined clinical entity with several grey zones as to the diagnostic criteria. Even though osteoporosis in older men might not uncommonly result from senile bone loss superimposed on a pre-existing low bone mass at younger age, an upper age limit of 65 or 70 is usually set for the diagnosis of idiopathic osteoporosis.1,79 A distinction should be made between idiopathic osteoporosis in mature young adult men with low peak bone mass and situations with delayed and incomplete skeletal maturation. Men with idiopathic osteoporosis are often symptomatic at presentation with vertebral fracture or back pain.1,79 In men with idiopathic osteoporosis, BMD is usually markedly low, below the expected distribution for age, i.e. with a Z score below 2 (often a T score below 3 using a male reference range). Although the patients have generalized low bone mass, the deficit tends to be more prominent at the axial skeleton. Generally, findings for histomorphometry and for biochemical markers of bone turnover have indicated that a majority of men with idiopathic osteoporosis, including a substantial proportion of men with low bone mass and prevalent vertebral fracture, present with a low bone turnover state79,80, although other studies have suggested the occurrence of increased turnover81 which may reflect aetiological heterogeneity among young men with low BMD. There is a convergence of clinical evidence to indicate that idiopathic low bone mass in men with or without prevalent fracture is most commonly the result of deficient acquisition of bone mass, rather than being the consequence of premature bone loss. Indeed, there is a strong familial component80,82, with as many as 50% of young adult sons of the patients being also affected. Recent studies provided further evidence for a role of genetic factors and for gene–environment interaction.83,84 Moreover, there is no relationship between BMD and age among affected men, and biochemical markers do not indicate increased turnover. At the spine, the patients as well as their affected relatives have both a low volumetric BMD and smaller vertebral dimensions.80 Finally, when following untreated men with idiopathic low bone mass we did not observe accelerated bone loss. Aetiological considerations are per definition only speculative, but there are interesting clues that offer directions for further research. The relative skeletal site and gender specificity observed in family studies and in genetic studies in mice and men suggest the possibility of alteration in bone acquisition during specific phases of pubertal development. There have been reports of altered IGF-1 levels as well as sex steroids and SHBG levels.79,85 These limited data do not allow for any firm conclusion, but they do warrant further research in this area. The search for aetiological clues

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should not be limited to the pubertal period since individual determination of bone mass is already evident long before puberty. RISK FACTORS FOR FRACTURE IN MEN Many risk factors for fracture are related to impaired bone strength, whereby they may either directly contribute to bone fragility (e.g. glucocorticoid treatment) or rather reveal existing impairment of bone strength (e.g. prior low-energy fracture). Other factors are related to increased risk of exposure of the skeleton to excessive stresses (i.e. primarily to risk for falls). Obviously some risk factors, such as old age or alcoholism, may be related to both bone fragility and increased risk for falls. A large series of potential clinical risk factors for fracture in men have been identified in epidemiological studies (Table 2), although for many of these the findings across studies have not been consistent. Such a broad list of risk factors may help identify men who should be considered for osteoporosis assessment, whereas a more limited number of risk factors has been thoroughly validated in meta-analyses involving large numbers of subjects, and can contribute to refine fracture risk assessment in men and thus help to identify those men most likely to benefit from interventions aimed at reducing fracture risk.16 As discussed earlier, lower BMD and older age, independently from BMD, are strong determinants of fracture risk. Measurement of BMD by DXA does not fully account for the effect of bone size, geometry, or other variables of bone strength Table 2. Some clinical risk factors for fracture in men as identified by epidemiological studies. Family history of fracture (parents; sibling) Prior fracture after age 50 years Fall-related: Older age Increased incidence of falls Fall in the past year Blindness Pre-morbid dysfunction lower limbs Recent vertigo Dementia; poor mental score Decreased quadriceps muscle strength Increased body sway Parkinsonism Hemiplegia Secondary osteoporosisa Medication-relateda Anthropometrics and lifestyle-related Low body weight, low BMI <10% loss body weight Decreased body height Decreased skinfold thickness Alcohol abuse Smoking Low level of physical activity Low intake of dairy products Low sun exposure a

See Table 1.

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such as bone micro-architecture and material properties. This probably explains part of the BMD-independent effect of age and most likely why a history of fragility fracture is a strong predictor of fracture risk after adjustment for BMD. A history of a prior fracture in men increases the risk of any future fracture by a factor of 2 with little change with age or after adjustment for BMD; RR for hip fracture at age 50 years was 5 and 3.9 with and without BMD adjustment, respectively; these RRs decreased to 1.9 and 1.4 at age 80 years.86 A parental history of fracture is associated with an RR of 2 for hip fracture and 1.2 for any osteoporotic fracture; RR is somewhat greater for parental history of hip fracture and tends to be greater in younger subjects.87 Low BMI is associated with increased fracture risk: as compared to a BMI of 25 kg/m2, in subjects with BMI of 20 and 15 kg/m2 RR for hip fracture is estimated at 2 and 4.5, respectively; RR after adjustment for BMD is 1.4 and 2.2.88 After adjustment for the effect of age, BMI and BMD, risk of hip fracture is increased by a factor of 1.5 in smokers.89 Fracture risk is increased, independently from BMD, in men consuming more than 2 units of alcohol/day: in men using 4 units/day RR is 1.8 and 2.8 for any osteoporotic and hip fracture, respectively.78 Compared to the population risk, subjects with history of ever use of glucocorticoids had a risk of any fracture increased by 1.5 and of hip fracture by 2, with a somewhat higher risk gradient in younger subjects.90 For most causes of secondary osteoporosis, low numbers of documented cases in cohort studies do not allow for a precise evaluation of the associated fracture risk. An increased risk, independent of BMD and glucocorticoid use, has been documented for rheumatoid arthritis.16 Bone mass and skeletal characteristics such as size and geometry are highly heritable. Despite existence of rare monogenic diseases and evidence for a major gene in some family studies, osteoporosis is generally considered as a complex polygenic trait resulting from the interaction of numerous genes and environmental factors. The list of candidate genes for the regulation of bone mass and structure in men, and a fortiori for fracture risk, is close to unlimited. A host of associations between polymorphisms in candidate genes and low bone mass and/or fracture risk have been documented, and at least part of them also in men. However, effect size is generally small, and for many associations reproducibility in different populations has been problematic. Although genetic factors are an important area for research in male osteoporosis, currently no genetic marker can be considered as validated for clinical use in fracture risk assessment. DIAGNOSIS OF OSTEOPOROSIS AND FRACTURE RISK ASSESSMENT IN MEN A low BMD can be defined as a Z score lower than 2, i.e., a BMD >2 standard deviations (SD) below the gender- and age-specific population mean. The commonly used BMD-based operational definition of osteoporosis as originally proposed by a working party of the WHO – i.e. a BMD >2.5 SD below the mean for the young adult population (i.e. below a T score of 2.5) – has been validated for white postmenopausal women only. There is no consensus BMD-based definition of osteoporosis in men, and the BMD threshold to be applied in the clinic to identify men at ‘unacceptably high’ risk of fracture remains an area of controversy.2,44 The data already discussed indicating a similar fracture risk in elderly men and women with a same absolute level of BMD by DXA8,70 imply that the use of a cut-off BMD corresponding to a T score of 2.5 according to the female reference range will select men with comparable fracture risk to women. This approach ensures a comparable specificity of DXA to predict

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fracture risk independently of gender. The problem, however, is that DXA has a low sensitivity to detect men who will fracture. Indeed, even when using a gender-specific reference range, more than 80% of fractures occur in men with BMD greater than the (gender-specific) T score of –2.5.91,92 Thus, use of the female reference range T score, albeit identifying men truly at high risk and most likely to benefit from treatment, will leave undetected the vast majority of men who will experience a fracture. Currently it remains rather common to evaluate BMD in men in relation to the gender-specific reference range, which some consider a compromise between still reasonable specificity and at least minimal sensitivity to detect men at risk. Nevertheless, this is likely to imply departure from the principle that intervention thresholds are set at the same level of absolute fracture risk independently of gender. The truth is that the controversy surrounding the BMD definition of osteoporosis in men illustrates the great limitation of decision-making concerning intervention aimed at reducing fracture risk in men if based solely on BMD. Obviously, decision to intervene should preferably be based on some estimate of absolute fracture risk, to which end the use of validated clinical risk factors can greatly contribute. In this regard, age and history of fragility fracture, besides situational elements such as prevalent cause of secondary osteoporosis, are essential risk determinants that clinicians are expected to integrate, at least intuitively, when interpreting BMD results. Recently a WHO scientific group16 has proposed a more systematic and quantitative approach to absolute fracture risk assessment using the different validated risk factors discussed in the previous section. Algorithms combining risk factors for estimation of the 10-year probability of fracture have been developed, as well as a user-friendly calculation tool accessible on the web (available at http:// www.shef.ac.uk/FRAX/).16 EVALUATION OF MEN SUSPECTED OF OSTEOPOROSIS Clinical, bone densitometry, radiographic, and/or laboratory evaluation of men with osteoporosis is aimed at: (1) confirmation of diagnosis and differential diagnosis with diseases that can mimic skeletal symptoms and/or bone densitometry findings in osteoporosis; (2) screening for secondary causes of osteoporosis that may require specific therapeutic measures; and (3) estimation of fracture risk, which is an important element of therapeutic decision-making. Who should be evaluated? Only a small proportion of osteoporotic men at high risk of fracture is being detected and treated.18 At present there is no validated strategy for a systematic osteoporosis screening in men. Active case-finding (opportunistic screening) focusing primarily on the detection of men at high risk for fracture should thus be encouraged. In this approach men presenting with major risk factors or who accumulate several minor risk factors are selected for further evaluation, usually BMD assessment by DXA. Assessment of BMD BMD measurement by DXA should be performed in men with clinical evidence for high fracture risk, but there is no generally accepted or validated guideline on who should be tested. Men to be considered for BMD assessment certainly include those

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with a previous fragility fracture. Another important category is men presenting with diseases or treatments associated with high risk for secondary osteoporosis: e.g. exposed to endogenous or exogenous glucocorticoid excess, with primary hyperparathyroidism, with longstanding hypogonadism or malabsorption, with alcoholism and liver disease, after organ transplantation, etc. Men over the age of 65 years with suspicion of low bone mass should also be considered for BMD assessment: e.g. men with osteopenic aspect of bones on radiography, with loss of body height and/or marked thoracal spine kyphosis, with markedly low BMI, or more generally those who accumulate more than one known clinical risk factor for osteoporosis and fracture, such as listed non-exhaustively in Table 2. The finding of a BMD value lower than a Z score of 2.0 confirms the presence of a low bone mass. Together with the clinical elements that have motivated the BMD assessment, in particular in men with previous fragility fracture, this allows the diagnosis of osteoporosis to be made, i.e., the existence of a high fracture risk that warrants intervention. Generally speaking, the same holds true when considering as alternative to the Z score a BMD lower than the gender-specific T score of 2.5. It should, however, be kept in mind that the vast majority of men who present with a ‘low-energy’ fracture do so at a BMD level above the 2.5 T score.70,92 Therefore, men with strong clinical evidence for bone fragility (e.g. with multiple prevalent vertebral fractures) should be diagnosed as having osteoporosis even though they might have a BMD greater than the gender-specific 2.5 T score (e.g. with a T score between 1.0 and 2.5). On the other hand, in the absence of independent risk factors, the absolute fracture risk in men with BMD below the gender-specific 2.5 T score may be insufficient to warrant a diagnosis of osteoporosis and therapeutic intervention, in particular before the age of 80 years1; in this case a threshold for diagnosis corresponding to the 2.5 T score according to the female reference range might be more appropriate in view of the rather comparable fracture risk in men and women having the same absolute level of BMD.1,8,70 Besides helping to confirm the diagnosis of osteoporosis, a second important contribution of BMD assessment is to help define the severity of the disease, i.e., to estimate the magnitude of the fracture risk. For this purpose information gained from BMD measurement should be integrated with that derived from the clinical risk profile of the patient; as already mentioned, this can be done ‘intuitively’, but also in a more quantitative approach with use of appropriately validated algorithms such as the recently proposed FRAXTM for estimation of the 10-year probability of fracture.16 In this context, BMD measurement, albeit a clinically extremely valuable tool, is only one of several elements contributing to the risk assessment, and in some patients a high 10-year probability of fracture indicating the need to consider treatment is apparent even without information on BMD (e.g. a man older than 65 years, with parental history of hip fracture, prevalent vertebral deformity, and history of systemic glucocorticoid use, or an 85-year-old men with a recent history of hip fracture). As to the measurement site, hip BMD predicts hip fractures better than BMD at other sites, but for prediction of the probability of other fractures the different classical measurement sites perform rather equally. Often measurements both at the spine and the hip are performed. In elderly men, the hip is the preferred measurement site because of the better prediction of hip fracture and the frequent artefacts interfering with the measurements at the spine (e.g. osteoarthritis lesions, vertebral deformities, and aorta calcifications). Assessment of BMD by DXA does not differentiate between osteoporosis and osteomalacia as causes of low BMD.

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Clinical assessment A thorough clinical assessment is needed for differential diagnosis between osteoporosis and other diseases, to detect possible underlying disease as cause of secondary osteoporosis, to gather information needed for estimation of future fracture risk, and to evaluate the already prevalent consequences of the osteoporosis for the health and well-being of the patient. The medical history should address the family and fracture history, past diseases and present symptoms, with special attention being paid to common secondary forms of osteoporosis and differential diagnostic pitfalls (e.g. osteomalacia and multiple myeloma), use of medication, lifestyle-related factors including calcium intake, exercise, use of alcohol and tobacco, history of and risk factors for falls, as well as the possible consequences of osteoporosis (e.g. loss of body height, backaches). In the clinical examination attention should be paid to the anthropometrics (body height and proportions, BMI), to possible signs of inherited syndromes, to signs suggestive for causes of secondary osteoporosis, to possible consequences of osteoporosis (e.g. thoracal spine kyphosis). Clinical assessment should allow for an evaluation of the general health status, the presence of associated morbidity, and the degree of frailty. Radiographic assessment In many instances spine x-ray is needed to complement clinical evaluation, for objective documentation of a history of clinical vertebral fracture, for differential diagnosis of back pain (which often is the reason for consultation), and for detection of ‘silent’ vertebral deformities. As to the latter, it is important to differentiate vertebral factures from other deformities not related to osteoporosis, such as vertebral epiphysitis (Sheuermann’s disease). Laboratory assessment Laboratory assessment can contribute to differential diagnosis with multiple myeloma and osteomalacia, and to evaluation for secondary osteoporosis. Initial laboratory evaluation should include a complete blood count, a marker for inflammatory diseases (e.g. C-reactive protein), blood glucose, serum protein electrophoresis, serum ferritin, and renal and liver function tests. Tests of the calciotropic axis should include serum calcium (corrected for serum albumin), phosphate, alkaline phosphatase (total or bone-specific), 25-hydroxyvitamin D, and PTH. Assessment of 24-hour urinary calcium (and creatinine) excretion can reveal hypercalciuria (>300 mg/24 h) or rather low calcium excretion (<100 mg/24 h) as indication for low calcium intake or absorption (if no use of calcium-sparing diuretics). Additional tests should include serum total testosterone (before 10 a.m.; if borderline, to be repeated on a separate occasion together with SHBG to calculate free/bioavailable testosterone)56, serum thyrotropin, serum cortisol (additional testing such as 24-hour urinary cortisol or evening salivary cortisol if high serum value or clinical suspicion of Cushing’s syndrome). Although serum oestradiol is an important regulator of skeletal homeostasis in men, because of technical issues and too-limited normative data, its measurement currently offers little added value for clinical management in individual men.

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Biochemical markers of bone turnover are extremely useful tools for research purposes as surrogate markers in drug trials, and may have a role in monitoring of treatment. However, stringent requirements for sample collection, problems of (inter-laboratory and between-tests) standardization, a variety of possible interfering clinical factors such as associated morbidity and medication, and above all the limited data for men concerning their ability to predict rapid bone loss and fractures46 limits the usefulness in clinical practice of urinary and serum markers of bone formation and resorption. Obviously the medical history, the clinical findings, or the initial laboratory findings might indicate the need for additional laboratory tests. A bone biopsy is rarely needed in men with severe osteoporosis and no evident cause, e.g., for exclusion of systemic mastocytosis or associated osteomalacia. MANAGEMENT OF OSTEOPOROSIS IN MEN General measures and prevention of osteoporosis Men with moderately increased fracture risk should be advised about lifestyle and dietary recommendations. Safe weight-bearing exercise, a balanced diet and daily calcium intake of 1200–1500 mg, as well as moderate sun exposure should be encouraged. Excessive alcohol intake and smoking should be discouraged. Particularly in frail, elderly men, measures to reduce the risk of falls should receive much attention, including a critical reappraisal of indications for psychotropic and cardiovascular drugs. The available prospective, randomized trials do not yet allow the conclusion that systematic calcium and vitamin D supplementation to elderly men is beneficial in terms of fracture reduction or even for preservation of BMD.1,93 Nevertheless, daily supplementation with 500–1000 mg (depending on the intake in the diet) elemental calcium and 800 IU vitamin D should be considered in men with or at high risk for deficiencies (e.g. men avoiding milk products, with low serum 25-hydroxyvitamin D and/or secondary hyperparathyroidism); higher dosages might be indicated in men with intestinal malabsorption. House-bound men and those residing in homes for the elderly should be considered at risk for deficiencies. Calcium supplementation, usually with vitamin D, is an obligatory complement to other specific pharmacological treatments of osteoporosis, because these supplements have always been an inherent part of the therapies evaluated in clinical trials. Pharmacological intervention to prevent rapid bone loss and deterioration of bone micro-architecture by administration of a bisphosphonate as well as calcium and vitamin D supplements should be considered in men at initiation of treatment with high-dose systemic glucocorticoids expected to last for several months94 or with GnRH analogues (and anti-androgens) to induce chemical castration in prostate cancer95, in particular in men with low pre-treatment BMD or with other risk factors for fracture. In view of a variety of desired clinical androgen effects, younger men with marked hypogonadism should receive substitutive T treatment unless such treatment is specifically contraindicated. Although for obvious reasons there have not been controlled trials assessing the long-term bone effects of T substitution in these men, observational data generally suggest beneficial effects on BMD.49,93 There are no data on

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the dose–effect relationship for T action on bone that would justify departure from the usual clinical practice which aims at achieving serum T levels in the mid-physiological range for young men. The preferred route of administration is intramuscular injection of T esters or transdermal T administration with use of a gel or patch.From what we know of the major role of oestradiol as well as androgens in the regulation of bone homeostasis in men, the use for substitution of T, which can be aromatized to oestradiol, seems the most physiological and the preferred choice of molecule. Elderly men with late-onset hypogonadism present with a more limited and progressive age-related decrease in serum (free or bioavailable) T, and of free E2 and bioE2. In this population, reports of beneficial effects on BMD of testosterone treatment were mainly restricted to those studies or patient subgroups including men with clearly low baseline serum T.56 In these elderly men, T supplementation can have additional beneficial effects, such as increase in muscle mass and strength, which can help reduce fracture risk through indirect effects on bone and a reduced propensity to fall. Nevertheless, the effect of testosterone treatment on fracture risk in elderly men is unknown, as is the long-term benefit-to-risk ratio of such a treatment.56 Therefore, testosterone treatment in the elderly should be reserved for men with frankly low serum (free) testosterone and clear signs and symptoms of hypogonadism. Currently, low BMD and high fracture risk should not be regarded as an indication for T treatment in the elderly. In fact, in view of the uncertainty as to the effects of T on fracture risk and the better documented effects of alternative specific osteoporosis treatments, such as bisphosphonates and PTH (teriparatide), these specific osteoporosis therapies should probably be considered in elderly men at high risk for fracture, whether or not they are also treated with T. Treatment of established osteoporosis Few prospective, randomized trials of osteoporosis therapies have been performed specifically in men. Moreover, they have mostly included rather modest numbers of subjects and addressed changes in BMD as primary endpoint, so that they were not powered to assess fracture risk reduction. Nevertheless, for bisphosphonates and teriparatide, the available data from controlled trials on BMD effects and safety profile, complemented by limited information on fracture reduction trends, suggest that treatment effects in men are rather comparable to those previously shown to substantially reduce fracture risk in postmenopausal women. In the absence of robust demonstration of anti-fracture efficacy of anti-resorptive and anabolic therapies of osteoporosis in men, their use is a pragmatic approach based on reasoned assumptions rather than robustly evidence-based. In men with low BMD (n ¼ 241, 31–87 years, gender-specific T score 2.0, with or without prevalent fracture) 10 mg/day oral alendronate together with calcium supplementation had a positive effect on BMD that is of magnitude comparable to the effects observed in postmenopausal women. This effect was observed independently of several baseline characteristics, including baseline serum T. Moreover, the observed trends in this modestly sized study suggest that treatment reduced vertebral fracture incidence.96 In a similarly designed study, weekly administration of 35 mg risedronate orally with calcium supplementation increased BMD independently of baseline serum T and prevalent fracture97, and for risedronate (5 mg daily with calcium and vitamin D supplements) there has also been a suggestion of reduced vertebral fracture risk in a randomized open-label study in men with primary and secondary osteoporosis.98 Reduction in hip fracture incidence was reported for a small study with risedronate

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in men after stroke.99 Currently, the available evidence for efficacy in men of zoledronic acid (5 mg intravenously once a year) is from a study showing reduced fracture rates in a population of patients treated after surgical repair of hip fracture, which included about a quarter male subjects100, and from placebo-controlled studies showing a favourable effect of zoledronic acid intravenously (4 mg every 3 months101 or 4 mg once yearly)102 on BMD in men receiving androgen deprivation therapy for prostate cancer. Studies with zoledronate and ibandronate specifically in men with osteoporosis are ongoing. Favourable effects of bisphosphonates on BMD in men with secondary osteoporosis have been reported, in particular for alendronate and risedronate in men treated with systemic glucocorticoids93,94 and for pamidronate and zoledronate in men with prostate cancer and androgen deprivation therapy with GnRH analogues.95 Although there is evidence from observational studies for beneficial effects of thiazides on bone mass and fracture risk, evidence from controlled prospective trials is not available. Similarly, suggestions of reduced bone turnover and increase of BMD with nasal calcitonin lacks confirmation from well-designed controlled trials.93 Therapy with PTH, as daily subcutaneous injection of a recombinant aminoterminal fragment (i.e. teriparatide, rhPTH1–34) at a dose of 20 or 40 mg/day with daily supplements calcium and vitamin D (1000 mg and 400–1200 IU, respectively), dose-dependently activated bone remodelling and increased BMD in men with idiopathic or hypogonadal osteoporosis. The data from this modestly sized study provided some indication of reduction in vertebral fracture risk and seem to indicate effects and a safety profile similar to those observed in the larger trials with teriparatide that have demonstrated beneficial treatment effects on the rates of vertebral and non-vertebral fractures in women with postmenopausal osteoporosis. The dose proposed for clinical use is 20 mg/day subcutaneously.103,104 Strontium ranelate (2 g/day orally with calcium and vitamin D supplementation) increases bone mass and reduces vertebral and non-vertebral fracture risk in women with postmenopausal osteoporosis through an uncoupling action on bone metabolism, with mild stimulation of bone formation combined with a mild anti-resorptive effect105; studies in men with osteoporosis are currently ongoing. Practical approach to therapy Osteoporosis can seriously compromise the quality of life and autonomy of elderly and frail men as well as that of younger men with severe idiopathic or secondary forms of the disease. Moreover, there is an associated excess mortality, and the size of the problem at the population level makes it a significant public health issue. Therefore, men at high risk of fracture should be treated, and where possible this should be anticipated by measures aimed at preventing the development of osteoporosis. However, the evidence base for the long-term efficacy and safety of both non-pharmacological and pharmacological prevention and treatment of osteoporosis is as yet only small, so that it would not seem justified to propose rigid guidelines. Rather, one should opt for a reasoned pragmatic approach that needs to be appropriately conservative and individualized, based on clinical judgement and careful estimation of the fracture risk. Some general principles are summarized in Table 3.

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Table 3. Suggestions for a practical approach to prevention and treatment of osteoporosis in men. In all men, attention to possible causes of secondary osteoporosis and early initiation of specific treatment where possible

Encourage lifestyle measures (see text):  In men with idiopathic moderate low BMD: i.e. BMD Z score <2 and >female range T score 2.5; no major clinical risk factors  In men with osteopenia (Z score < 1) and minor clinical risk factors  In men with normal BMD (Z score > 1) with one major or two minor clinical risk factors  In all men presenting with causes of secondary osteoporosis  In all men with more severe risk profile than above

Calcium (usually 1000 mg) and vitamin D (usually around 800 IU) supplements:  In all men as above if suspicion of deficiencies and no contraindications  Consider systematic administration in case of frailty, if house-bound or resident in nursing home  In all men treated with a biphosphonate or teriparatide

Treatment with testosterone:  In young men with documented hypogonadism  Should be considered in elderly men with frankly low serum (free or bioavailable) T and hypogonadism-related complaints  Low BMD or increased fracture risk is in itself not an indication for T treatment

Treatment with bisphosphonates:  Consider in men with BMD below Z score of 1 and high risk causes of secondary osteoporosis (e.g. prolonged high-dose glucocorticoids; post-transplantation; androgen deprivation therapy)  Consider in men with prior clinical fragility fracture, with one major or multiple vertebral deformities even if only moderately low BMD (BMD < gender-specific T score 1)  Consider if isolated very low BMD (at least
Treament with teriparatide:  Consider in severe osteoporosis: e.g. very low BMD with prevalent fractures or in men with multiple symptomatic vertebral fractures  Consider if incident fracture during (at least 1 year) bisphosphonate treatment, after having interrupted the bisphosphonate treatment

SUMMARY AND CONCLUSIONS In recent years the knowledge base on osteoporosis in men has broadened, but a considerable gap remains compared to the extensively studied postmenopausal osteoporosis. Moreover, although osteoporotic fractures represent a significant threat to health and quality of life of older (and some younger) men, at present too few men with high fracture risk are being detected and treated. Epidemiology of fragility fractures in men is now well described and shows that the age-specific incidence of the major osteoporotic fractures is about one third to one half that in women, and that the same absolute fracture risk in men is reached at an older age. Consequently, men with osteoporotic fractures are often old and frail, which evidently has negative implications as to outcome.

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Although valuable information has been gained from prospective cohort studies on the relationship between prevalent BMD and fracture risk in men, unresolved issues remain that are due to the limitations of the DXA technique, which cannot fully account for the important gender-specific aspects of bone size, geometry and structure. This has been an obstacle to achievement of a consensus as to a BMD-based operational definition of osteoporosis in men. However, controversies on whether osteoporosis in men should be based on a gender-specific T score or rather a T score calculated relative to the female reference range seem of limited relevancy if one opts for a preferable approach of therapeutic decision-making based on estimation of the absolute fracture risk (e.g. the 10-year probability of fracture) by integrating information gained by BMD measurement with that from assessment of validated clinical risk factors. In this regard, age and history of prior fragility fracture are factors of obvious importance for risk assessment. Idiopathic osteoporosis in young men appears in most cases to be the consequence of some defect in acquisition of bone mass and size during growth, with a strong genetic component. Sex steroid hormone deficiencies might be involved to some extent in both idiopathic osteoporosis in young men and senile osteoporosis, as well as in several forms of secondary osteoporosis. Marked progress has been made in our understanding of the role of such deficiencies in the regulation of bone homeostasis in men, with ample evidence gathered for an important, if not predominant, role of E2 as the most salient new insight. However, the relative roles of T and E2 in the different aspects of bone regulation is yet to be fully unravelled, and currently the clinical implications of the progress in our understanding of the physiology remain rather modest. The aim of intervention in men with osteoporosis is to reduce fracture risk to an acceptable level. In this perspective one can only acknowledge that for no treatment of osteoporosis in men has the ability to reduce fracture risk been properly assessed in adequately powered prospective randomized trials. In this context, therapeutic strategies should be adequately conservative, targeting men at high absolute risk for fracture, and should leave ample space for clinical judgement. General lifestyle-related advice should receive sufficient attention, and calcium with vitamin D supplementation should be considered in men with or at high risk for deficiencies. Possibly because only a minority of men with primary (idiopathic or senile) osteoporosis come to medical attention, a substantial proportion of patients who consult for osteoporosis have secondary osteoporosis. It is important to react alertly in these patients, initiating a specific causal therapy if possible and considering pharmacological prevention of skeletal deterioration when appropriate. Therapy with testosterone is indicated in a broader context in men with confirmed hypogonadism for various reasons, including protection of skeletal integrity. However, as such osteoporosis is not an indication for initiation of androgen treatment. As to treatment of men at high fracture risk, anti-resorptive therapies with bisphosphonates and anabolic treatment with teriparatide have been released for use in men on the assumption that their effect and safety profile in men is similar to that in women with postmenopausal osteoporosis in whom they reduce fracture risk. For bisphosphonates and teriparatide, available data from randomized trials in men with surrogate endpoints (i.e. mostly effects on BMD and biochemical markers of bone turnover) appear so far to support the assumption of similar effects in men and postmenopausal women. On this basis, treatment with these drugs seems justified and should probably be encouraged in men with high fracture risk, but large-scale systematic application to men with only moderate risk is not warranted at present. In any case, there is obviously a need for more and larger randomized therapeutic trials in men with osteoporosis, preferably with fractures as endpoint.

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Overall it can be concluded that significant progress has been made in several areas of our understanding of osteoporosis in men and its management, but that there still is a long way to go before closing, even only partially, the gap with the large knowledge base on postmenopausal osteoporosis and the substantial evidence base in support of a variety of therapeutic options in these patients.

Practice points  osteoporosis is a serious threat to the health and wellbeing of affected men, but is largely under-diagnosed and under-treated  detection and appropriate management (causal treatment, bone loss prevention) of causes of secondary osteoporosis deserve particular attention  therapeutic decisions should be based on a careful assessment of fracture risk (e.g. 10-year probability of fracture) and not on isolated BMD measurements  age, fracture history and prevalent BMD are the cornerstones of fracture risk assessment, which can be further refined by assessment of additional clinical risk factors  calcium and vitamin D supplements should be prescribed in cases of deficiencies or high risk thereof, and are a necessary component of therapies with bone-active drugs  in view of the only limited validation in men of therapies for osteoporosis, including all agents commonly used for osteoporosis in women, these therapies should be used in men with clinical discernment, targeting men with substantial absolute fracture risk

Research agenda  clarification of the relationship between prevalent BMD and fracture risk in men versus women  how to explain large geographic/ethnic differences in fracture rates?  validation of algorithms for calculation of 10-year probability of fracture according to specific geographic and national contexts  further clarification of the relative roles of T versus E2 in bone homeostasis, of whether there are critical thresholds for serum levels of T and E2 for maintenance of bone integrity, and of the interaction of sex steroids with the somatotropic axis in the regulation of bone homeostasis  to gain further insight into the physiopathology of idiopathic osteoporosis in men  to gain further insight into the genetic components of osteoporosis in men  there is a need for further clarification of the role of calcium and vitamin D supplementation in the management of osteoporosis in men  there is a need for more controlled trials to evaluate the efficacy and safety of therapies with bone-active drugs aimed at reducing fracture risk in osteoporotic men, preferably with fractures as endpoint

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