JRSM >
Volume 94, Number 12 >
Pp. 620-623
Department of Medicine, Royal Free & University College Medical School, London, UK
Correspondence to: Dr G M Prelevic, Cobbold Laboratories, Middlesex Hospital, Mortimer Street, London W1N 8AA, UK E-mail: G.Prelevic{at}ucl.ac.uk
 | INTRODUCTION |
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 TOP INTRODUCTION CAUSES OF OSTEOPOROSIS IN...SEX STEROIDS AND BONE...MANAGEMENT OF OSTEOPOROSIS IN...REFERENCES |
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Epidemiological studies suggest that, in the USA, about 1.5 million men over 65 years of age have osteoporosis and another 8-13 million have osteopenia1. The calculated lifetime risk of fracture for men is 13.5% at the age of 50 years and 25.6% at the age of 601.
The prevalence in men of fractures of the spine or hip is about one-third that in women2. There seems to be a lag period such that an exponential increase in fracture incidence begins 10 years later in men than in women3, coinciding with the phase of accelerated bone loss after the age of 704.
Although women have a higher overall prevalence of fracture, the increase in fracture risk for each standard deviation decrease in bone mineral density (BMD) seems to be higher in men. Moreover, mortality associated with hip fracture is two to three times higher in men than in women5,6,7,8. Strict criteria for the diagnosis of osteoporosis in men are still lacking: the World Health Organization definition, based on a T score greater than -2.5, relates to Caucasian women. The underlying mechanisms, risk factors and natural history of osteoporosis in men are now attracting much research attention.
| CAUSES OF OSTEOPOROSIS IN MEN |
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TOPINTRODUCTIONCAUSES OF OSTEOPOROSIS IN...SEX STEROIDS AND BONE...MANAGEMENT OF OSTEOPOROSIS IN...REFERENCES |
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Causes of osteoporosis can be identified in some 40-60% of men with osteoporotic fractures11,12. The most common are hypogonadism and glucocorticoid therapy. In addition, gastrointestinal disease, vitamin D deficiency, excessive alcohol intake or chronic anticonvulsant use are present in a substantial proportion. Lately, transplantation has emerged as an important cause of osteoporosis in both men and women13.
Overt hypogonadism has long been recognized as a cause of osteopenia or osteoporosis. Using dual energy X-ray absorptiometry (DEXA) Finkelstein et al.14,15 found that men with a history of delayed puberty had a significantly lower spinal bone density than age-matched healthy controls. Although there was extensive overlap with normal men, many of those with delayed puberty had osteopenia or osteoporosis. Pubertal delay also results in a reduced anteroposterior diameter of vertebral bodies, causing an apparent reduction in bone density (g/cm2), whereas volumetric bone density (g/cm2) may be normal16. This observation is disputed17; in any case, reduced vertebral size itself seems to be associated with increased fracture risk. A history of delayed puberty is elicited in some 2-3% of men with so-called idiopathic osteoporosis. These findings indicate that timing of puberty is an important determinant of peak bone mass, which in turn is a major determinant of bone density in later life (as it is in women).
The observation that young men with hypogonadotropic hypogonadism have osteoporosis even before epiphyseal closure suggests that the problem lies in defective bone accretion18. When hypogonadism is acquired during adult life, osteoporosis seems to result largely from accelerated bone loss14.
In addition to inducing bone loss directly, corticosteroids may act indirectly by causing hypogonadism. A dose-dependent decrease in serum testosterone19 is thought to result from both suppression of hypothalamic gonadotropin-releasing hormone secretion and direct effects on testicular testosterone production.
Whereas moderate alcohol consumption seems to be associated with raised BMD, excessive alcohol is associated with osteopenia/osteoporosis and osteoporotic fractures11. Why excessive alcohol should adversely affect BMD is not known but a possible mechanism is decreased bone formation via a direct effect on osteoblast function20. Additional factors are vitamin D insufficiency/deficiency and the low serum testosterone often found in alcoholics.
When all possible causes are excluded a considerable proportion of men with osteoporosis (almost 50%) come into the category idiopathic. Some studies have pointed to diminished osteoblastic function21 in this group. Increased bone resorption has also been suggested but the data are not convincing. Insulin-like growth factor-1 (IGF-1) concentration was found to correlate positively with BMD in men but not in women22, and low IGF-1 and IGFBP-3 have been reported in men with idiopathic osteoporosis23. Neither the clinical relevance nor the mechanism of this observation is clear. Relative or partial oestrogen deficiency has also been suggested as a possible mechanism in idiopathic osteoporosis. Another hypothesis is that, in some men with idiopathic osteoporosis, bone cells respond poorly to normal oestrogen levels because of defective oestrogen receptor expression24.
| SEX STEROIDS AND BONE METABOLISM IN MEN |
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TOPINTRODUCTIONCAUSES OF OSTEOPOROSIS IN...SEX STEROIDS AND BONE...MANAGEMENT OF OSTEOPOROSIS IN...REFERENCES |
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In contrast to data showing no correlation between testosterone
concentration and BMD, oestradiol concentrations were positively associated
with BMD independent of androgen
concentration29,30.
Therefore, age-related bone loss could be due to inefficiency in the
conversion of testosterone into
oestrogen31,32.
In a recent study, age-related decrease in bioavailable oestradiol correlated
with bone loss in elderly
men33. The role of
oestradiol in men is probably best illustrated by examples of gross
osteoporosis in men with oestrogen resistance due to loss-of-function
mutations in the ER
gene and in the aromatase
gene35. By
contrast, women with complete androgen insensitivity have low bone density
despite normal serum testosterone
concentrations36,37.
The detection and functional characterization of androgen receptors in bone cells has implicated bone tissue as a potential target tissue for androgens. These receptors are expressed in osteoblasts (the bone-forming cells)38 and functional androgen receptors have also been detected on osteoclasts39. Androgens directly regulate various aspects of osteoblastic lineage cells including proliferation, differentiation, mineralization and gene expression40. Therefore testosterone might stimulate bone formation directly. In addition to the effect on bone mass, androgens have beneficial effects on muscle mass and muscle strength—which is important for fracture prevention.
Some of the effects of androgen on bone may be mediated by regulation of autocrine and paracrine factors in bone such as transforming growth factor beta, IGF-1 (and differential regulation of IGF-binding proteins) and interleukin-640,41. The mediation of the skeletal effects of androgens is therefore still unclear. It may be directly via androgen receptors or indirectly via oestrogen receptors after aromatization to oestrogen. Probably both pathways are important for bone health. Indeed, a recent study which investigated bone turnover markers in elderly men being given oestrogen alone, androgen alone or both after suppression of their endogenous sex steroids with a gonadotropin-releasing hormone agonist, provided some important information42. It seems that oestradiol is essential in regulation of bone resorption whereas both oestradiol and testosterone are important in maintaining bone formation42.
Another working hypothesis is that direct androgen binding to androgen receptors in bone is most important in early skeletal development whereas bone remodelling, crucial to maintenance of healthy bones throughout life, is primarily stimulated by oestrogen.
| MANAGEMENT OF OSTEOPOROSIS IN MEN |
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TOPINTRODUCTIONCAUSES OF OSTEOPOROSIS IN...SEX STEROIDS AND BONE...MANAGEMENT OF OSTEOPOROSIS IN...REFERENCES |
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Although testosterone therapy increases BMD in hypogonadal men irrespective of age43, their response to testosterone replacement in terms of change in BMD is variable. Previously untreated men with the lowest BMD, particularly those with open epiphyses, have been noted to benefit the most43,44. Timing of the start of testosterone replacement in men with hypogonadotropic hypogonadism seems to be crucial for bone mineral accretion. If androgen replacement is initiated after the age of 20 neither cortical nor trabecular bone reaches the normal range. The degree of osteopenia/osteoporosis is proportionate to the delay in initiation of androgen replacement45.
Of older men with low testosterone, only those who had pretreatment testosterone less than 6.9 nmol/L had a significant increase in BMD with testosterone replacement46. In eugonadal men some modest improvement in spine BMD has been achieved with testosterone therapy47,48 but in this group the potential risks of such therapy demand extreme caution.
Bisphosphonates
Orwoll and colleagues have reported excellent results with alendronate,
given for 2 years to men with
osteoporosis49.
Those who received the drug showed not only a 7.1% increase of spine BMD but
also a lower incidence of vertebral fracture. The response to alendronate
seemed unrelated to baseline free testosterone or oestradiol
concentrations—that is to say, those with low serum testosterone
benefited to the same extent as those with normal testosterone and oestradiol.
Bisphosphonate therefore appears to be the treatment of choice for eugonadal
men and for men with hypogonadism in whom testosterone therapy is
contraindicated.
Future therapies
One promising strategy is to give parathyroid hormone intermittently.
Kurland et al. have reported an impressive increase in spine BMD over
18 months with this
treatment50.
Since low IGF-1 concentrations have been implicated in the pathogenesis of idiopathic osteoporosis in men, treatment with IGF-1 might also beneficial. In vitro and animal studies indicate a clear role for IGF-1 in bone metabolism and maintenance51,52. The usefulness of growth hormone is controversial. A small study in elderly men who had been recruited for growth hormone treatment on the basis of low IGF-1 concentration showed very modest increase in spine BMD of 1.6% over 6 months. Existing data offer no justification for treatment of osteoporosis with growth hormone unless the person is growth hormone deficient.
A particular need is for a selective androgen receptor modulator that acts on bone and muscle tissue while avoiding adverse effects on the prostate and lipids—ideally with a companion oestrogen receptor modulator with its oestrogen agonist effects confined to bone.
| Acknowledgments |
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| REFERENCES |
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