University of Newcastle upon Tyne, Musculoskeletal Unit, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK.
Osteoporosis is characterized by a reduction in bone density, associated with skeletal fragility and an increased risk of fracture after minimal trauma. Although osteoporosis is widely considered to be a condition predominantly affecting women, up to 20% of symptomatic vertebral fractures and 30% of hip fractures occur in men [1]. The number of men presenting with these fractures is rising, because of increasing life expectancy and a doubling of the age-specific incidence of fractures over the past three decades.
Osteoporotic fractures are associated with substantial morbidity in both men and women. There is considerable disability after hip fracture in men; only 21% are living independently in the community a year later, whereas 26% are receiving home care and 53% are living in an institution [2]. Men with symptomatic vertebral fractures commonly complain of back pain, loss of height and kyphosis, but also have significantly less energy, poorer sleep, more emotional problems and impaired mobility compared with age-matched control subjects [3].
There is increased mortality of about 20% after hip fracture, much of the excess mortality occurring in the first year. A number of studies show a higher mortality rate after hip fracture in men than in women, but the reason for this remains uncertain. Vertebral crush fractures are also associated with excess mortality of about 18% at 5 yr, due mainly to coexisting conditions associated with osteoporosis rather than the fracture itself. The annual cost of osteoporotic fractures in the UK has been estimated at £942 million, of which 23% is due to fractures in men [4].
The risk of fracture is determined by a number of factors, including bone mass, bone turnover, trabecular connectivity, skeletal geometry and the frequency and severity of trauma applied to the skeleton. Bone mass at any age is determined by the peak bone mass, the age at which bone loss starts and the rate at which it proceeds. Genetic factors account for up to 80% of the variance in peak bone mass in both sexes. Men with a family history of osteoporosis have a bone mineral density (BMD) that is lower than expected and an increased risk of vertebral fractures, but the major genes determining bone density and the risk of fracture in men remain uncertain. Other determinants of peak bone mass in men include dietary calcium intake, exercise during childhood and age at puberty [5].
Bone loss starts between the ages of 35 and 50 yr in men and women and continues into old age in both sexes. The age-related decrease in circulating concentrations of free testosterone, adrenal androgens, growth hormone and insulin-like growth factor 1 may contribute to the observed reduction in bone formation and continuing bone loss with age in men. It is now apparent that the actions of testosterone on the male skeleton may be mediated in part by aromatization to oestradiol, such that oestrogen deficiency may contribute to age-related bone loss in men [6]. Case reports have described osteoporosis in men with mutations in the oestrogen receptor or aromatase genes. There is also a positive correlation between bone density and serum oestradiol in healthy older men, but only a weak, inverse relationship with circulating testosterone. A number of other factors have been implicated in bone loss in men, including physical inactivity, tobacco and alcohol consumption, poor dietary calcium intake, vitamin D insufficiency and secondary hyperparathyroidism [5].
The development of osteoporosis may be accelerated by underlying secondary causes of bone loss, which are found in over 50% of men presenting with symptomatic vertebral crush fractures [7]. The major secondary causes of osteoporosis in men with vertebral fractures are hypogonadism, oral steroid therapy and alcohol abuse. A recent casecontrol study from Newcastle showed a significantly increased risk of symptomatic vertebral fractures in men with oral steroid therapy, anticonvulsant use, smoking, alcohol consumption and a low free androgen index [3].
Casecontrol studies of hip fractures in men have shown an increased risk of fracture for disorders associated with secondary osteoporosis, such as thyroidectomy, gastric surgery and hypogonadism [8, 9]. There is also a greater risk of hip fracture for conditions related to an increased risk of falling, such as hemiparesis, Parkinson's disease, dementia, vertigo, alcoholism and blindness [8]. A prospective study from Australia showed a higher risk of hip fracture in men with low hip bone density, quadriceps weakness, increased body sway, falls in the past year, previous fractures, low body weight and short stature [10].
Until recently, the diagnosis of osteoporosis in men was based on the development of fractures after minimal trauma. The introduction of dual-energy X-ray absorptiometry for the measurement of bone density has stimulated interest in the diagnosis of osteoporosis before fractures occur. The World Health Organization (WHO) has defined osteoporosis as a BMD 2.5 standard deviations or more below the mean value for young adults (T score less than -2.5), but this has been established only for women. Studies show a similar relationship between absolute bone density measurements and the risk of fracture in both sexes [11]. Furthermore, work from the USA demonstrates that the prevalence of a T score less than -2.5 at the hip, spine or forearm in men over the age of 50 yr is broadly similar to the lifetime risk of fractures at these sites [12]. This suggests that the WHO criteria may be applicable to the diagnosis of osteoporosis in men and women.
Secondary causes of osteoporosis should be sought in men presenting with fragility fractures and/or low BMD by careful history-taking, physical examination and appropriate investigation. Investigations should include full blood count, erythrocyte sedimentation rate, biochemical profile, thyroid function tests, serum testosterone, sex hormone-binding globulin and gonadotrophins, together with serum and urine electrophoresis in men with vertebral fractures [7]. Prostate-specific antigen should also be measured in men with vertebral fractures and symptoms of prostatism or evidence of sclerosis on X-rays. In elderly men with osteoporosis, serum 25-hydroxyvitamin D and intact parathyroid hormone measurements may exclude vitamin D insufficiency and secondary hyperparathyroidism, but these are probably unnecessary if calcium and vitamin D supplementation is planned.
All men with osteoporosis should be given advice on lifestyle measures to decrease bone loss. Where there is a history of falls, attempts should be made to identify and modify the underlying intrinsic and extrinsic causes, in the hope that these may be modified and the risk of further falls and fractures decreased. There is also growing interest in the use of hip protectors, which are available in appropriate sizes for men and women, which may decrease the risk of femoral neck fractures in frail elderly patients with recurrent falls.
Any underlying secondary cause of osteoporosis should be treated if possible, as specific treatment of underlying conditions such as hyperthyroidism, hypogonadism and hyperparathyroidism may increase bone density by 1020%. There is as yet no well-established treatment for idiopathic osteoporosis in men, but therapeutic options include bisphosphonates, testosterone, anabolic steroids, fluoride salts, and calcium and vitamin D.
Observational studies in men with idiopathic and secondary osteoporosis suggest that intermittent cyclical etidronate therapy increases bone density at the lumbar spine by 510%, with smaller increases at the hip [13]. It would therefore appear that cyclical etidronate has similar effects on bone density in men and women, but the effect on the incidence of fracture in men remains uncertain. A recent randomized controlled trial (RCT) in 241 men with osteoporosis aged between 31 and 87 yr, 36% of whom were hypogonadal, showed that alendronate increased bone density at the lumbar spine by 5.3% and femoral neck by 2.6% compared with the control group [14]. There was also a trend for reduction in vertebral fractures and a significant decrease in height loss with alendronate.
In addition to improving bone density in men with hypogonadism, testosterone also appears to increase spine bone density in eugonadal men with vertebral fractures. An observational study of testosterone treatment in 14 eugonadal men with vertebral fractures showed an increase in bone density of the spine of 6.1% after 3 yr of treatment [15]. A subsequent uncontrolled study in 21 eugonadal men with vertebral osteoporosis showed a significant increase in bone density of the spine of 5% after 6 months of treatment with testosterone, but no change in hip bone density was seen [16]. Analysis of the biochemical markers of bone turnover in this study showed a reduction in bone resorption with testosterone, possibly mediated by its conversion to oestradiol [16]. A multicentre RCT is due to start shortly in the UK, to assess the safety and efficacy of testosterone supplementation in eugonadal men with osteoporosis.
An RCT of the anabolic steroid nandrolone in 21 men with idiopathic osteoporosis showed an increase in bone density after 3 months of treatment, which decreased to basal levels after 1 yr of treatment [17]. The apparent lack of benefit with nandrolone may be related to suppression of endogenous testosterone production and the inability to aromatize anabolic steroids such as nandrolone to oestradiol.
An RCT in Germany in 64 men (mean age 53 years) with osteoporosis showed that low-dose intermittent monofluorophosphate and calcium increased bone density and decreased the risk of vertebral fractures [18]. Nevertheless, this treatment is not widely available and the therapeutic window is likely to be narrow.
The role of calcium and vitamin D supplementation in the management of osteoporosis in men remains unclear. In an RCT in 86 normal men aged 3087 yr, supplementation with 1000 mg calcium and 1000 iu of vitamin D daily had no effect on bone loss from the forearm or spine [19]. In contrast, an American RCT in 389 older men and women (mean age 70 yr) living at home demonstrated that 700 iu vitamin D3 and 500 mg elemental calcium daily had a modest beneficial effect on bone density and decreased the incidence of non-vertebral fractures [20].
Osteoporotic fractures are a major public health problem in men and women. Further work is required to clarify the pathogenesis of osteoporosis and fractures in men and to develop diagnostic criteria for osteoporosis in men. Further studies are needed to establish the most effective treatment for osteoporosis in men. Meanwhile, testosterone replacement should be considered in men with hypogonadism, whereas bisphosphonates are probably the treatment of choice in other men with osteoporosis. Calcium and vitamin D supplements may be useful in frail, elderly men with osteoporosis, who are likely to have vitamin D deficiency and secondary hyperparathyroidism.
References
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