The diagnosis and treatment of male osteoporosis: Defining, assessing, and preventing skeletal fragility in men

European Journal of Internal Medicine 18 (2007) 6 – 17 www.elsevier.com/locate/ejim

Review article

The diagnosis and treatment of male osteoporosis: Defining, assessing, and preventing skeletal fragility in men Steven Boonen a,b,c,⁎, Jean-Marc Kaufman d , Stefan Goemaere d , Roger Bouillon a,b , Dirk Vanderschueren a,b a

Leuven University Center for Metabolic Bone Diseases, Katholieke Universiteit Leuven, Leuven, Belgium The Leuven University Department of Geriatric Medicine, Katholieke Universiteit Leuven, Leuven, Belgium The Leuven University Laboratory for Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium d Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, Ghent, Belgium b

c

Received 6 February 2006; received in revised form 5 September 2006; accepted 19 September 2006

Abstract Male osteoporosis is associated with a significant burden in terms of morbidity, mortality, and economic cost. Despite recent advances in the understanding of the male osteoporotic syndrome, the evaluation and treatment of men suffering from osteoporosis remains a clinical challenge. In men with osteoporosis, it remains particularly critical to exclude underlying pathological causes as these are much more likely to be present than in women. There is increasing evidence that the approaches developed to diagnose and treat the disorder in women may be equally useful in men. The available evidence suggests that the anti-fracture efficacy of treatment with alendronate, risedronate, or teriparatide is similar in both sexes. Additional research is warranted to prospectively address the usefulness of BMD measurements to predict fracture risk, to identify those men who are likely to benefit the most from therapy, and to monitor individual responses to therapy. © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Keywords: Osteoporosis; Men; Bone mineral density

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Epidemiology of male osteoporosis . . . . . . . . . . . 1.1. Incidence of osteoporotic fractures in men . . . . 1.2. Prevalence of osteopenia and osteoporosis in men The relationship between BMD and fracture risk in men 2.1. Defining osteoporosis in men . . . . . . . . . . . 2.2. Choosing the assessment site . . . . . . . . . . . 2.3. Clinical features of osteoporosis in men . . . . . 2.4. Age-associated osteoporosis. . . . . . . . . . . . 2.5. Secondary osteoporosis . . . . . . . . . . . . . . 2.6. Idiopathic osteoporosis . . . . . . . . . . . . . .

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⁎ Corresponding author. Leuven University Center for Metabolic Bone Diseases and Division of Geriatric Medicine, Universitaire Ziekenhuizen K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail address: [email protected] (S. Boonen). 0953-6205/$ - see front matter © 2006 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2006.09.005

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Diagnostic assessment of male individuals with vertebral fractures and/or low BMD . . . . . . . . . . . . . . . . . . . . . 3.1. Assessment of BMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Clinical evaluation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Biochemical assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Additional testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Pharmacological options in men with vertebral fractures and/or low BMD . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Calcium and vitamin supplementation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Androgen replacement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Teriparatide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Therapeutic approach for men with low BMD and/or vertebral fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Therapeutic approach in men with a T-score below − 2.5 below the young adult mean in men but above −2.5 compared to the female reference range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Therapeutic approach in osteoporotic men (men with existing vertebral fractures and/or a T-score below − 2.5 below the young adult mean in women) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Learning points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Epidemiology of male osteoporosis Male osteoporosis is associated with a significant burden in terms of morbidity, mortality, and economic cost [1–6]. Although less frequent than in women, osteoporosis in men is also a relatively common problem. 1.1. Incidence of osteoporotic fractures in men Of all hip fractures, some 25–30% occur in men [7,8]. The increased risk of fracture in women compared to men reflects differences in life expectancy between the two sexes [7,9] as well as differences in age-specific incidence rates [9–11]. Both in women and men, hip fracture incidence increases with age [7]. In fact, age is the main determinant of hip fracture occurrence, which typically affects old and very old men over 80 [8–10]. Because of the aging of the population, the incidence of hip fractures will increase dramatically in men. It has been estimated that, only 20 years from now, there will be as many hip fractures in men as there are today in women [7,12]. Compared to age- and sex-matched controls, male hip fracture patients have about a three-fold increase in mortality [13]. Even compared to women with recent hip fracture, mortality is almost doubled [14–16]. These differences in mortality can only partly be explained by differences in comorbidity [15–17]. Of those men who do survive the fracture, close to 50% will have to be institutionalized and less than 20% will fully recover and regain independence [17]. Vertebral fractures are associated with long-term clinical consequences as well [18]. These fractures will typically be diagnosed on X-rays taken because of acute back pain. The incidence of these symptomatic or so-called “clinical” vertebral fractures is close to the incidence of hip fractures, but they occur at younger ages. In men, vertebral fractures often result from a major trauma [19]. In addition to these

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clinical fractures, aging men may suffer from “radiological” vertebral fractures without symptoms, diagnosed at the time of radiological screening. The prevalence of these radiological fractures varies according to the criteria used [20], and even when similar criteria are applied, significant regional differences exist [21,22]. While clinical vertebral fractures are clearly more common in women than in men, the prevalence of radiologically diagnosed vertebral fractures is similar in both sexes, affecting some 10–12% of all individuals [23]. This unexpected finding may reflect an increased exposure to trauma in men and raises questions as to whether or not some of these deformities should be regarded as consequences of bone fragility [20]. Some of the incidentally discovered vertebral deformities in men are not related to metabolic bone disease and should not be interpreted as fractures. A typical example is vertebral epiphysitis (Sheuermann's disease), a cause of significant vertebral deformity in men. Nevertheless, epidemiologic data in men suggest that most vertebral fractures, regardless of their clinical expression, are related to bone density, even the majority of asymptomatic vertebral deformities [22,24]. Deformities that were not associated with acute back pain at the time of diagnosis will induce chronic back pain in many individuals [25], emphasizing the importance of all types of vertebral fractures. Aging is associated not only with an increased risk of hip and vertebral fractures, but also of a variety of non-vertebral fractures, including fractures of the humerus, pelvis, and ankle. Fractures of the distal radius (Colles' fracture) become more frequent with aging as well, but the incidence of this type of fracture remains remarkably low in men compared to women [9,12,26]. In those men who do suffer from a Colles' fracture, the risk of subsequent osteoporotic fractures is considerable. In contrast to women, Colles' fractures in men even carry a higher absolute risk for hip fracture than spinal fractures [27]. These

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findings support the concept that forearm fracture is an early and sensitive marker of male skeletal fragility. Non-vertebral fractures typically occur as a result of a fall [1,14,15,17,28]. In both sexes, fall incidence increases with age [29] and fall orientation has been identified as an independent risk factor for hip fracture [30]. A number of studies have confirmed that in men, as in women, fracture risk is increased in the context of a variety of chronic comorbidities [31], low body mass index [32,33], weight loss [31], muscle weakness [34], postural instability [34,35], or intake of psychotropic agents [36]. It is, therefore, clear that osteoporotic fractures in both sexes are the consequence of a more complex predisposition that includes both fall-related and fragility-related components. 1.2. Prevalence of osteopenia and osteoporosis in men Bone mineral density (BMD) can be measured by dualenergy X-ray absorptiometry (DXA) in men as in women. In women, a BMD greater than 2.5 standard deviations below the young normal adult mean (a T-score below − 2.5) is considered to be in the osteoporotic range [37]. This threshold is based on the predictive ability of DXA to predict future fracture risk in women; it has not yet been validated in men [1]. To date, there is no consensus as to how male osteoporosis should be defined. One of the most critical questions is whether a similar approach can be used in men, i.e., whether male osteoporosis can be defined as a T-score below − 2.5 based on a male reference range. Because peak bone densities attained in men exceed those in women, even a T-score of − 2.5 may not confer a high absolute risk of fracture. If so, defining male osteoporosis as a T-score below − 2.5 based on a male reference range might result in overdiagnosis. When using male cut-offs, the overall prevalence of osteoporosis in men over 50 is about 3–6% [38]. If, on the other hand, female reference ranges were to be used to define male osteoporosis as a T-score below − 2.5 below the young adult mean in women, only about 1–4% of older men would be considered osteoporotic. 2. The relationship between BMD and fracture risk in men As indicated, the choice of the cut-off to define osteoporosis has a very significant impact on the prevalence of osteoporosis. The diagnosis of osteoporosis should ideally reflect a similar absolute risk of fracture in both sexes. One of the problems is that the relationship between DXA-defined BMD and bone fragility may be different in men and women. In fact, DXA is a projectional method that integrates cortical and trabecular bone values and provides no direct assessment of the geometry of the bone, one of the key determinants of bone strength. Compared to women, men have increased (areal) BMD values, not because of an increase in true (volumetric) BMD, but because of differences in bone size [2]. That is partly because aging men have less endocortical

bone resorption and more periosteal bone formation. In the trabecular bone compartment, thinning of individual trabeculae is observed, rather than perforation, as is the case in postmenopausal women [39–43]. DXA does not provide a direct assessment of any of these age-associated changes in cortical and trabecular bone, suggesting that similar absolute DXA-values in men and women may or may not reflect similar fracture probabilities. 2.1. Defining osteoporosis in men As in women, defining osteoporosis in men should allow one to identify those men who have the highest risk of fracture and who would benefit from medical treatment. Ultimately, this requires prospective studies on the relationship between DXA-assessed BMD and future fracture risk. Although some prospective data have been published in men, it should be emphasized that most of the available evidence is of a cross-sectional nature. Overall, these data suggest that similar absolute BMD values are associated with similar absolute fracture probabilities in both sexes [44– 46]. This concept is further supported by prospective evidence of a similar relationship between DXA-defined BMD and the risk of vertebral fractures [47] and hip fractures [48] in men and women. It would seem, therefore, that, for the time being, a conservative but reasonable approach is to define male osteoporosis as a T-score below − 2.5 below the young adult mean in women [49]. Men with prevalent vertebral fractures should also be regarded as osteoporotic, even when DXA-assessed BMD is not below this threshold. What should be emphasized, though, is that there is currently no generally accepted T-score criterion to define male osteoporosis. In the context of this paper, the use of a T-score below − 2.5 below the young adult mean in women is primarily intended to identify high-risk individuals who warrant anti-resorptive treatment. In men, as in women, there is no absolute T-score value that necessarily leads to fracture and, therefore, to the absolute need for treatment. Information about a man's BMD must be combined with other risk factors, as well as with information about the effectiveness, inconvenience, side effects, risks, and costs of the treatment considered. For a proportion of men with T-scores below a certain threshold, the risk of a fracture during their remaining lifetime could theoretically be sufficiently low that treatment would not be appropriate. Conversely, a significant proportion of men who do not reach the threshold of osteoporosis as used in this paper – a T-score below − 2.5 below the young adult mean in women – may have other risk factors and circumstances that would justify treatment. During the 2005 Position Development Conference of the International Society for Clinical Densitometry (ISCD), the ISCD updated its official positions with respect to the utilization of T- and Z-scores for BMD reporting [50]. The 2003 ISCD official positions had implied (but not explicitly stated) that Z-scores should be used in men between the

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ages of 20 and 50 years. The ISCD recommendation to use Z-scores in young adults was, in part, intended to avoid misapplication of WHO criteria, which are based upon the T-score, to inappropriate populations. According to the ISCD, a Z-score of − 2.0 or lower is defined as “below the expected range for age” and a Z-score above − 2.0 is defined as “within the expected range for age” [50]. The WHO criteria were developed for postmenopausal white females, and extrapolation to other groups (like young men) might not identify people at equivalent levels of fracture risk. In the updated 2005 ISCD official positions, an assessment of the difference between T-scores and Z-scores was reported for major manufacturers and measurement sites [50]. As expected, in (healthy) young men (ages 20–50), there are relatively small differences between the respective T-scores and Z-scores for a given BMD measurement. At age 50, in men as in women, a Z-score of − 2.0 is approximately equivalent to a T-score of − 2.5. These findings suggest that both T-scores and Z-scores may be appropriate to diagnose osteoporosis in men below the age of 50. 2.2. Choosing the assessment site BMD measurements at any site are able to predict spine and non-spine fracture risk to a similar extent [8,31,35,44]. One exception is hip BMD, which is somewhat better than other measurements for predicting hip fractures. Because lumbar spine BMD can be confounded by degenerative changes, particularly in older men, it is generally recommended to measure both the spine and the hip. 2.3. Clinical features of osteoporosis in men Most osteoporotic fractures occur in older men and result from the process of bone loss that inevitably occurs with aging. This relatively common type of male osteoporosis mainly affects men over the age of 70 and is referred to as “age-associated osteoporosis”. “Age-associated” male osteoporosis should be distinguished from “idiopathic” male osteoporosis, which is a distinct clinical entity. Idiopathic osteoporosis is less frequent and typically affects younger men between the ages of 30 and 60. Male patients should only be diagnosed as having age-associated or idiopathic osteoporosis after excluding underlying, secondary causes of bone loss. Secondary osteoporosis is much more common in men than in women. In those men who have osteoporosis but no apparent underlying causes, the osteoporotic syndrome, by convention, is referred to as “idiopathic osteoporosis” in individuals younger than 70 years of age and as “ageassociated osteoporosis” in those over 70. 2.4. Age-associated osteoporosis Age is the major determinant of osteoporotic fracture occurrence, both in women and in men [47,48], and ageassociated osteoporosis is the common type of male

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osteoporosis. Although there is no male equivalent of the menopause, endocrine deficiencies are likely to contribute to age-associated bone loss in men [51–59]. Current evidence suggests that a changing exposure to sex steroids, growth hormone-insulin-like growth factor-I (GH-IGF-I), and vitamin D-parathyroid hormone (25(OH)D-PTH) may be more or less involved. Yet, the extent to which alterations in these endocrine axes increases fracture risk in men independently of aging remains to be clarified. Most studies in aging men have addressed the potential impact of hormonal changes on BMD (as a surrogate marker for fracture risk) and have used a cross-sectional design. These studies have reported either the presence or absence of an association between selected potential endocrine determinants (using different assays) and measurements of BMD (using different methodologies and sites), mostly in a small number of subjects with a wide variation of age ranges. This heterogeneity, both in terms of methodology and study population, and the inconsistent results make it difficult to interpret the findings of these studies. Moreover, some investigations failed to adjust for concomitant changes in body mass index or age and, thus, do not allow one to establish independent associations between hormonal changes and bone loss. Even more importantly, most studies do not take into account the complex interactions that exist between testosterone, estradiol, IGFI, sex hormone-binding globulin, and/or PTH, and which may significantly confound reported associations. It has generally been held that estrogen and testosterone are the major sex steroids regulating bone metabolism in women and men, respectively. However, compelling evidence has emerged in recent years, which has led to a reconsideration of this notion. The extreme delay in skeletal maturation in men suffering from estrogen deficiency as the result of a mutation in either the estrogen receptor [60] or the aromatase enzyme [61] suggests that part of the androgen action on the male skeleton is mediated by estrogen [62]. In line with this concept, administration of estrogens has been shown to increase bone mass in an aromatase-deficient man [63]. More recently, observations of low-dose estrogen treatment of an adolescent male with aromatase deficiency provided evidence that exposure to estrogens is essential for the process of pubertal periosteal bone expansion typically associated with the male bone phenotype [64]. Androgens alone are insufficient to drive the expansion of bone associated with male growth. Estrogens may also be critically important in determining the rate of bone loss with aging and, by implication, the risk of osteoporotic fracture in older men. Due to peripheral conversion of testosterone by the aromatase enzyme, circulating levels of estradiol in men are similar to those in postmenopausal women [55,56]. In older women, exposure to these (relatively low) levels of estradiol affects BMD, bone loss, and even fracture risk. It is tempting to speculate that the ageassociated decline in circulating estradiol – partly resulting from an age-related increase in serum SHBG – may play a central role in male osteoporosis and osteoporotic fracture

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occurrence [58]. Support for this concept comes from observational studies that have related BMD to sex steroids in aging men. Overall, correlations between testosterone, the major gonadal androgen, or DHEAS, the major adrenal androgen, and BMD are weak or absent [52–54]. These findings contrast with those from studies on the levels of estrogens in aging men, which report stronger positive associations between BMD and serum estradiol, especially bioavailable estradiol (the fraction of estradiol that is not bound to sex hormone-binding globulin) [55–57]. Further evidence that estrogen plays a major role in regulating bone metabolism in older men comes from prospective and interventional data. In a prospective study, low levels of estradiol were associated with fracture occurrence in old men [65]. An interventional study assessed the relative contributions of testosterone versus estrogen in preventing changes in bone turnover markers during pharmacologically induced hypogonadism and aromatase inhibition in normal elderly men [66]. This trial established that estrogen is the dominant sex steroid regulating bone resorption in elderly men and that both estrogen and testosterone contribute to the regulation of bone formation. 2.5. Secondary osteoporosis In our experience, underlying causes can be identified in 30–70% of men with fragility fractures and/or low BMD (unpublished observations). These observations are in line with a number of series reported in the literature [67–70]. The main causes of secondary osteoporosis are glucocorticoid excess (either endogenous, i.e., Cushing's syndrome, or, more commonly, chronic glucocorticoid therapy), alcohol abuse, and hypogonadism [3]. Other etiologies, listed in Table 1, are less frequent but should be excluded before the diagnosis of idiopathic osteoporosis can be applied. Glucocorticoid excess, found in 16–18% of cases, is probably the major cause of secondary osteoporosis in men [67,68,71]. Osteoblast insufficiency is considered to be the main mechanism in this type of osteoporosis [72], but glucocorticoids may also induce muscular atrophy, secondary hyperparathyroidism, and secondary hypogonadism [6]. Androgen deficiency is another frequent cause of male osteoporosis. An increase in bone loss and osteoporotic fracture incidence has been reported following surgical or chemical castration in men suffering from prostatic carcinoma [73–76], supporting the view that skeletal homeostasis in men is partly mediated by exposure to androgens. In line with this concept, male hypogonadism is associated with reduced BMD [45], especially when present before puberty [77–79]. Hypogonadism (either primary or secondary) is reported in 15–20% of cases with spinal osteoporosis [67,71]. In case-control studies of male hip fracture patients, high prevalences of hypogonadism have been reported as well, especially when considering free or bioavailable testosterone concentrations [51,80]. However, the use of different and insufficiently validated thresholds for both total

Table 1 Secondary osteoporosis in men Endocrine disorders Hypogonadism Cushing's syndrome Hyperthyroidism Hyperparathyroidism Medication-related osteoporosis Corticosteroid therapy Anticonvulsants Chemotherapy Genetic diseases Osteogenesis imperfecta Homocystinuria Gastrointestinal diseases Malabsorption syndromes Primary biliary cirrhosis Systemic illnesses Mastocytosis Rheumatoid arthritis Multiple myeloma Other causes Alcohol abuse Hypercalciuria Immobilization Renal insufficiency

and free testosterone makes it difficult to compare different studies, and the degree of hypogonadism in patients with male osteoporosis has varied significantly across studies. These discrepancies emphasize the need to establish cut-offs to define hypogonadism based on the impact of different degrees of androgen deficiency on the musculoskeletal or other systems [53]. Alcohol abuse can be demonstrated in about 15–20% of osteoporotic men [67,68,71] and is probably an underestimated cause of skeletal fragility in men. Bone loss has been shown to be increased in men with alcohol intake above the median, and recent findings indicate that alcohol abuse may even be associated with an increase in the relative risk of hip fracture [81]. Some studies could not find an association between femoral bone loss and alcohol intake [82,83], whereas other studies even reported a protective effect of moderate alcohol intake against hip fracture [35], suggesting that bone loss and fracture risk will only be significantly increase in men with alcohol abuse and not in the context of moderate alcohol consumption. A particular secondary cause of osteoporosis in men is idiopathic hypercalciuria [84,85]. Hypercalciuria (N 0.1 mmol/ kg per day or 4 mg/kg per day), if present, may be due in part to increased intestinal absorption of calcium resulting from alterations in vitamin D metabolism [65]. If, or to what extent, hypercalciuria reflects increased bone resorption or decreased renal reabsorption of calcium remains to be established [56]. According to data from the Mayo Clinic, hypercalciuria may

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be observed in 8% of male patients presenting with osteoporosis [85]. Our own experience suggests that the prevalence of hypercalciuria in this population may be even higher, amounting to up to 15% (unpublished observations). 2.6. Idiopathic osteoporosis Idiopathic osteoporosis can be defined as osteoporosis that occurs without any known cause. The prevalence of idiopathic osteoporosis in series of osteoporotic men varies considerably [65,67,86], probably as a result of the use of different criteria to exclude secondary causes. Experience from our own centers, as well as from series reported in the literature, suggests prevalence ranges between 30% and 50%. According to the Mayo Clinic data, the incidence of idiopathic osteoporosis in the general population aged 20– 44 years is only 4 new cases/100,000 persons/year [67]. Most patients will present between the ages of 35 and 65 [67,86]. In line with other authors [3,87], we would suggest that the diagnosis of idiopathic osteoporosis be applied only to men under the age of 70 years. By that stage of life, one would expect the poorly understood process of age-related bone loss to have inevitably occurred, a phenomenon quite distinct from the unexpected appearance of osteoporosis in younger men. Moreover, in older men with osteoporosis, it is more likely that the disease is at least partly the result of the cumulative effects of factors that affected skeletal health earlier in life (e.g., failure to achieve adequate peak bone mass, calcium undernutrition, inadequate exercise, and declines in gonadal hormones) but that are no longer identifiable. The overwhelming majority of patients with idiopathic osteoporosis is symptomatic and presents with fractures [87]. Fractures are most frequently in cancellous bone, most often at the vertebrae [86,88], although cortical fractures may occur as well, including stress fractures of the lower extremities or hip fractures. The predominant presenting symptom is back pain [3,65,89]. Bone mass measurements in these men reveal markedly reduced BMD. Typically, lumbar spine density T-scores are below − 2.5 SD [68]. In our experience, the mean T-score is even below − 3.0. Fewer studies have reported femoral neck density values, but available data [83] – and our own experience – suggest a similar decrease in areal BMD at this site. By definition, biochemical screening shows no abnormalities in serum calcium, phosphorus, creatinine, liver function, 25(OH)D, PTH, TSH, testosterone, or 24-h urinary excretion of cortisol [3,87]. In idiopathic osteoporosis, the average urinary calcium excretion is normal. Biochemical parameters of bone turnover are also normal [3,86]. Likewise, histomorphometric indices of bone resorption, such as eroded surfaces, are not increased in most studies [67,88,89]. However, some histologic data (in small numbers of men) suggest osteoblastic insufficiency, as evaluated by wall thickness, without alterations in activation frequency, resulting in a negative calcium balance at the level of the

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individual remodelling unit [86,90]. There is no evidence of osteomalacia in idiopathic osteoporosis. The natural course of idiopathic osteoporosis is not well documented. Available data [67] suggest that, even with conservative measures, bone loss is not accelerated, suggesting that most of these middle-aged osteoporotic men have low bone mass in part because they failed to reach normal peak BMD. As indicated, there is histological evidence to suggest osteoblast insufficiency in patients suffering from idiopathic osteoporosis. However, the pathogenesis of idiopathic osteoporosis is unknown. A lack of exposure to endogenous IGF-I and (partial) androgen deficiency have been suggested as potential determinants, but it should be emphasized that these etiological considerations are hypotheses. By no means have they been established as causes. In men with idiopathic osteoporosis, serum concentrations of IGF-I – and its predominant binding protein IGFBP-3 – have been shown to be in the low normal ranges, and statistically significant associations have been observed between these concentrations and BMD [87,91] or osteoblastic surface [92]. Relative growth hormone deficiency may be responsible for this relatively lower secretion of IGF-I [91,93,94]. Partial androgen deficiency has been implied as another cause of idiopathic osteoporosis [95]. Although, by definition, men with idiopathic osteoporosis have (sub)normal testosterone concentrations, the possibility cannot be excluded that skeletal homeostasis in these men may be affected by slight differences in exposure to sex steroids, either by differences in the aromatization of testosterone, or by differences in the synthesis of the sex hormone-binding globulin, or even in estrogen or androgen receptor activity [62]. In men suffering from idiopathic osteoporosis, a reduced ratio of estradiol to sex hormone-binding globulin has been reported [91], consistent with the hypothesis that male idiopathic osteoporosis may reflect partial estrogen deficiency. 3. Diagnostic assessment of male individuals with vertebral fractures and/or low BMD Several recommendations for the investigation of men presenting with low BMD and/or fragility fractures have been published [1,3–5,87,96]. However, it should be emphasized that the most appropriate approach to the evaluation of osteoporosis in men has not been systematically developed or tested. 3.1. Assessment of BMD BMD measurement with DXA should be performed in all men who present with low-trauma fractures. As indicated, there is some ongoing controversy as to whether or not gender-specific T-scores should be used. Most data support the use of absolute BMD rather than gender-specific diagnostic criteria. The implication is that, in the absence of fragility fractures, male osteoporosis may have to be

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defined as a BMD measurement value greater than 2.5 SD below the young female reference range. A measurement value greater than 2.5 SD below the young male reference may not be associated with a sufficiently high absolute risk of fracture to justify the diagnosis of osteoporosis and, by implication, may not warrant anti-resorptive treatment. However, even a T-score below − 2.5 by male standards warrants further investigation to exclude secondary causes of bone loss. This evaluation should include not only a thorough history and physical examination, but also a set of biochemical tests. In addition, it seems reasonable to make general recommendations regarding lifestyle measures and appropriate dietary intake of calcium in these individuals and to perform a follow-up assessment of BMD after 2 years. 3.2. Clinical evaluation The medical history should include a family and a fracture history and should address calcium intake, medications, alcohol intake, and tobacco use. The clinical examination should focus on signs of hypogonadism (especially testicular atrophy and span length for early hypogonadism), alcohol abuse, and glucocorticoid excess. Length should be monitored as a marker of osteoporosis. Dorsal kyphosis may indicate severe vertebral deformities. Low body mass index should be considered as a risk factor. 3.3. Biochemical assessment To distinguish between secondary osteoporosis and idiopathic or age-associated osteoporosis, male individuals with low BMD and/or vertebral fractures should be screened by biochemical measures (Table 2). This biochemical evaluation should include a complete blood count and serum calcium, phosphate, alkaline phosphatase, albumin, creatinine, 25(OH)D, liver function tests, ferritin (to detect hemochromatosis and alcoholic liver disease), and serum protein electrophoresis (to exclude multiple myeloma, in particular in older individuals). Intact PTH should be measured to exclude primary or secondary hyperparathyroidism in men with abnormal serum values of calcium, phosphorus, or 25(OH)D. In all patients, we would recommend measurement of serum testosterone and TSH to exclude hypogonadism and hyperthyroidism, especially in older individuals [5]. A 24-h urine calcium and creatinine Table 2 Biochemical screening in men with low BMD and/or vertebral fractures Complete blood count and serum protein electrophoresis Serum calcium and 24-h calciuria, serum phosphorus, albumin, creatinine, alkaline phosphatase, gamma-GT and cortisol Serum TSH Serum 25-hydroxyvitamin D and PTH Serum testosterone and SHBG LH and prolactin (unless testosterone is normal)

excretion is needed to exclude hypercalciuria (N300 mg). Hypocalciuria (b 100 mg) should raise the suspicion of markedly reduced dietary calcium absorption (due to vitamin D deficiency, bowel disease, or malnutrition). Serum levels of cortisol (or a 24-h excretion of cortisol) may be indicated whenever there is clinical suspicion of Cushing's syndrome. Total testosterone should be measured in a morning sample because testosterone concentrations fluctuate according to a circadian pattern. Some controversy remains as to whether free testosterone, bioavailable testosterone, or sex hormonebinding globulin should be assessed in all patients [96]. Some authors even advocate the routine measurement of estradiol [3]. In men with androgen deficiency, serum levels of luteinizing hormone (LH) and prolactin should be measured to allow differentiation between primary and secondary hypogonadism and to detect a potential prolactinoma. Specialized centers use biochemical markers of bone turnover, such as serum osteocalcin or bone-specific alkaline phosphatase as indices of bone formation or urinary collagen crosslinks as indices of bone resorption, but the added value of these markers in the clinical management of osteoporotic men remains to be demonstrated [1,3,5]. 3.4. Additional testing In men who present with a severe degree of osteoporosis without apparent cause, additional testing may be required. These tests should only be considered in specialized centers. One example is a bone biopsy procedure to exclude rare cases of systemic mastocytosis or osteomalacia [1,3]. 4. Pharmacological options in men with vertebral fractures and/or low BMD Pharmacological therapy is the cornerstone to reduce fragility fractures in both women and men. However, pharmacological strategies have to be complemented with lifestyle measures and dietary recommendations, whenever appropriate. Adequate exercise should be recommended and excessive alcohol intake or smoking discouraged. Medications that potentially increase the risk of falling, such as psychotropic drugs, should be reconsidered, particularly in frail, elderly men. 4.1. Calcium and vitamin supplementation Dietary supplementation with calcium and vitamin D reduces the rate of bone loss in elderly men with low calcium intake and may even have an effect on (non-vertebral) fracture incidence [97,98], at least in individuals with vitamin D insufficiency (levels b 50 nmol/l). In line with the recommendations of the National Institutes of Health and the Food and Nutrition Board, dietary calcium intake should be at least 1200 mg/day. In the context of calcium and vitamin D insufficiency, calcium supplements of at least 500–1000 mg and vitamin supplements of 600–800 IU daily are required.

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While several randomized, placebo-controlled trials found positive effects of calcium and vitamin D supplementation on fracture risk, some trials in community-dwelling people (including the RECORD trial performed in the UK and, most recently, the WHI clinical trial in the US) did not find a significant reduction in fracture risk during calcium and vitamin D supplementation [99–101]. The inconsistent results of the anti-fracture trials of calcium and vitamin D in individuals without documented osteoporosis suggest that there are additional considerations in ensuring the clinical efficacy of calcium and vitamin D in this setting. These include the dose of vitamin D, the addition of calcium to vitamin D, the targeting of the supplementation to those with insufficiencies, and the need for good compliance [102]. Overall, the available evidence suggests that calcium and vitamin D supplementation is most effective when targeted to those to men who are receiving anti-resorptive or anabolic osteoporosis therapy, to those who are being treated with glucocorticoids, and to men who are likely to be calcium- or vitamin D-deficient, when 800 IU/day vitamin D is complemented with a dose of 1000–1200 mg/day elemental calcium and when compliance and persistence with calcium and vitamin D are ensured [Ref. [102] and references therein]. 4.2. Androgen replacement Androgen replacement prevents bone loss and may even increase bone mass in hypogonadal men, at least at trabecular sites [48,103]. Whether androgen replacement is beneficial in normal elderly men with partial androgen deficiency and low BMD remains to be clarified. In a randomized trial, no significant gain in lumbar BMD was observed in men over the age of 65 with borderline low serum testosterone concentrations and low BMD when compared to calcium supplementation alone [104]. In elderly men with lower mean serum testosterone concentrations, on the other hand, lumbar and femoral BMD were found to improve significantly following androgen replacement [105], suggesting that the latter may be beneficial, but only in elderly men with very low serum testosterone. In addition to the lack of convincing data on the benefits of androgen replacement in normal elderly men, there is an urgent need for data regarding the long-term safety (e.g., the risk of prostate cancer or cardiovascular complications) of this type of therapy. Moreover, it is still unclear whether androgen action is related to direct stimulation of the androgen receptor or to stimulation of the estrogen receptor following aromatization [62]. This issue is of critical importance in view of the potential usefulness of selective estrogen or androgen modulators as drugs in male osteoporosis.

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deposition of mineral into existing bone matrix. The concept of a bone anabolic agent is based upon stimulation of bone formation, a physiologic process opposite that of inhibiting bone resorption. Inherent to this concept is the ability of an anabolic agent such as teriparatide to restore bone microarchitecture. In women with postmenopausal osteoporosis, teriparatide 20 μg/day reduced the incidence of vertebral and non-vertebral fragility fracture by 65% and 53% versus placebo, with an acceptable safety profile [106]. More recently, teriparatide was found to induce similar increases in BMD in men with osteoporosis and to potentially reduce the risk of fracture [107]. Even 18 months after discontinuation of therapy, the risk of vertebral fracture continued to be lower in those previously assigned to teriparatide than in those previously treated with placebo, but the numbers were small and the risk reduction did not achieve the level of statistical significance. Overall, the data support the notion that teriparatide is effective in treating osteoporosis and reducing the risk of fracture regardless of gender. 4.4. Bisphosphonates In postmenopausal osteoporosis, bisphosphonates have become first-line agents [108]. In men suffering from glucocorticoid osteoporosis, bisphosponate therapy is associated with increases in BMD similar to those in women [109]. However, there have been few trials of bisphosphonates performed exclusively in men. Nevertheless, there is no conceptual barrier to the use of bisphosphonates in men, and initial reports describe positive results. In the most comprehensive study to date, Orwol et al. reported a randomized, placebo-controlled trial with alendronate that showed significant improvements in both lumbar and femoral BMD in osteoporotic men with or without hypogonadism [110]. Over a 2-year treatment period, alendronate induced increases in lumbar spine BMD and femoral neck BMD of about 7% and 2.5%, respectively. These increases are in line with those previously observed in alendronate-treated postmenopausal women and were independent of age or androgen status. In the alendronate-treated men, the number of vertebral fractures was lower, although the study was not designed to show anti-fracture efficacy and the difference was not statistically significant. Positive results from a similarly designed study with risedronate in men with idiopathic osteoporosis are about to be reported (S. Boonen, personal communication). In male patients on corticosteroid therapy, risedronate increased lumbar spine and hip BMD, along with a statistically significant reduction in the incidence of vertebral fractures [111].

4.3. Teriparatide

5. Therapeutic approach for men with low BMD and/or vertebral fractures

Anti-resorptives act primarily by inhibiting osteoclastmediated bone loss and may be associated with an increase in BMD by filling in of resorption cavities and increased

The ultimate goal of long-term, pharmacologic treatment of osteoporosis is to reduce the risk of fracture and, in turn, reduce the risk of fracture-related morbidity, loss of quality

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Table 3 Indications for anti-resorptive (bisphosphonate) therapy in men T-score below − 2.5 below the young adult mean in men but above −2.5 compared to the female reference range when associated with —a low-trauma fracture (like a Colles' fracture or hip fracture) or —non-modifiable risk factors for rapid bone loss (e.g., glucocorticoid treatment) or —rapid bone loss documented on consecutive DXA measurements Osteoporosis defined as prevalent vertebral fractures and/or a T-score below −2.5 below the young adult mean in women

of life, and even mortality. Unfortunately, fracture endpoint trials have not been performed in men. If, and to what extent, anti-resorptive or anabolic treatment reduces fracture risk in men is not known. In fact, fracture endpoint trials may never become available in men because they would require large sample sizes to adjust for the relatively low absolute risk of fracture. Thus, the question is whether the results from intervention trials in women with postmenopausal osteoporosis can be applied to men. Because of increasing evidence that the pathophysiology of osteoporosis and the BMD fracture risk relationship are similar in men and women, most experts agree that BMD and bone turnover endpoint studies can and should substitute for fracture endpoint studies. The implication is that osteoporotic men should have access to anti-resorptive agents with documented anti-fracture efficacy in osteoporotic women, provided the effects on BMD and bone turnover, as well as the safety profile, are similar in both sexes. Alendronate and, more recently, risedronate meet these requirements. The final part of this review includes practical recommendations to reduce fracture risk in men. In the absence of large-scale fracture endpoint trials, it should be noted that these recommendations in osteoporotic men are based on untested, but reasoned, assumptions. 5.1. Therapeutic approach in men with a T-score below − 2.5 below the young adult mean in men but above −2.5 compared to the female reference range As indicated, a measurement value greater than 2.5 SD below the young male reference may not justify the diagnosis of osteoporosis. However, even a T-score below − 2.5 by male standards warrants further investigation to exclude and potentially modify secondary causes of bone loss. In the context of calcium and vitamin D insufficiency, calcium supplements of 500–1000 mg and vitamin supplements of 600–800 IU daily are required. BMD should be remeasured after 18–24 months to detect accelerated bone loss. A measurement value greater than 2.5 SD below the young male reference may not warrant anti-resorptive treatment. In some men, however, anti-resorptive therapy with alendronate or risedronate should be considered in addition to calcium and vitamin D because of a sufficiently high absolute risk of fracture (Table 3). This is particularly

true for men with a low-trauma fracture (like a Colles' fracture or hip fracture) because these fragility fractures increase the risk of fracture recurrence independently of BMD. Similarly, bisphosphonate therapy is justified in men with non-modifiable risk factors for rapid bone loss, even if their current BMD is still above the female threshold. A typical example is a male individual with a T-score below − 2.5 (below the young adult mean in men) who will receive glucocorticoid treatment. Bisphosphonates should also be considered in the context of documented rapid bone loss on consecutive DXA measurements. 5.2. Therapeutic approach in osteoporotic men (men with existing vertebral fractures and/or a T-score below − 2.5 below the young adult mean in women) In men with documented osteoporosis (prevalent vertebral fractures and/or T-score b− 2.5 compared to the female reference range), management should include a thorough search for secondary causes, risk factor modification, supplementation with calcium and vitamin D, and anti-resorptive treatment. In these men, the absolute risk of fracture is similar to the risk in women with documented postmenopausal osteoporosis and justifies the use of alendronate or risedronate. 6. Conclusion Despite recent advances in the understanding of the male osteoporotic syndrome, the evaluation and treatment of men suffering from osteoporosis remains a clinical challenge. In men with osteoporosis, it remains particularly critical to exclude the underlying pathological causes as these are much more likely to be present than in women. There is increasing evidence that the approaches developed to diagnose and treat the disorder in women may be equally useful in men. The available evidence suggests that the anti-fracture efficacy of bisphosphonate treatment with alendronate or risedronate is similar in both sexes. Additional research is warranted to prospectively address the usefulness of BMD measurements to predict fracture risk, to identify those men who are likely to benefit the most from therapy, and to monitor individual responses to therapy. 7. Learning points ▸ Underlying pathological causes are much more likely to be present in men than in women and should be excluded in men with low BMD and/or fractures. ▸ There is increasing evidence that similar absolute BMD values are associated with similar absolute fracture probabilities in both sexes. ▸ The available evidence suggests that, in men, bisphosphonate treatment (with alendronate or risedronate) or anabolic treatment (with teriparatide) reduces fracture risk to a similar degree as in women.

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