Senile osteoporosis

Aging of men is accompanied by progressive bone loss, which persists and may even accelerate in old age. Osteoporosis in men is increasingly being recognized as a significant problem of public health. The age-specific incidence of both hip and vertebral fracture is about half that in women (Van Der Klift et al. 2002), and occurring with a delay of five to six years. One out of four patients suffering a hip fracture is a male and the prognosis of hip fracture, as well as of other major osteoporotic fractures, appears to be worse in men as compared to women in terms of both morbidity and mortality (for review Bilezikian 1999; Kaufman etal. 2000; 2001, and Orwoll and Klein 1995; see Chapter 7).

A number of recent studies and clinical observations have demonstrated that estrogens are essential for both bone acquisition and maintenance of adult skeletal integrity in men and that both androgenic and estrogenic input intervenes in the regulation of adult bone metabolism in the male (for review Riggs et al. 2002). A preponderant role of estrogen in the regulation of bone metabolism in elderly men has been elegantly demonstrated in a short-term intervention study with selective manipulation of testosterone and estradiol levels (Falahati-Nini etal. 2000). In cross-sectional studies in elderly men, associations of bone mineral status or biochemical markers of bone turnover with sex steroid levels have been rather weak, although statistically significant. In several of the latter studies (free or bio-available) estradiol was more strongly associated with bone mineral density and/or bone turnover markers than (free or bio-available) testosterone. Khosla etal. (2001) and Van Pottelbergh etal. (2003) have observed an inverse relationship in healthy elderly men between serum bio-available estradiol and prospectively assessed bone loss, without independent contribution of serum (bio-available) testosterone in the determination of this loss. In the latter study, changes in bone mineral density, personal clinical fracture history ofthe subjects and fracture history in their first-degree relatives, were all associated, independently of serum estradiol levels, with a polymorphism of the CYP19 gene that encodes for the aromatase enzyme suggesting indirectly that local aromatization of testosterone in bone tissue might play a role. Barrett-Connor et al. (2000) reported an association of vertebral fractures with low serum estradiol levels in elderly men of the Rancho Bernardo Study.

In community-dwelling men over age 70 years, we found no association of bone mineral density or bone metabolism with a CAG repeat polymorphism of the androgen receptor (Van Pottelbergh etal. 2001), whereas in another study including younger men 20 to 50 years old such an association was found (Zitzmann et al. 2001).

Profound hypogonadism in younger men (Mauras etal. 1999;Stepan etal. 1989) as well as in older men (Mittan et al. 2002; Stoch et al. 2001) has been shown to result in accelerated bone loss with high bone turnover and there is indication that testosterone replacement therapy in men with acquired hypogonadism may result in partial recovery ofbone density (Behre etal. 1997;Devogelaer etal. 1992;Finkelstein et al. 1989; Katznelson et al. 1996). Hypogonadism has also been reported to be a risk factor for hip fracture in elderly men (Boonen etal. 1997; Jackson etal. 1992;

Stanley etal. 1991), but besides low bone mass, other factors related to testosterone, such as muscle weakness maybe involved.

Currently available controlled data on the effects of testosterone treatment in elderly men is limited and not conclusive. Observed effects of androgen treatment in elderly men on biochemical indices of bone turnover have been rather inconsistent. Morley et al. (1993) observed an increase of serum levels of osteocalcin, a marker of osteoblastic activity, during androgen treatment. Tenover (1992) reported reduced hydroxyprolinuria, a marker ofbone resorption, in a small group of elderly men treated with androgen. Orwoll and Oviatt (1992) found no significant effect of androgen treatment on biochemical indices ofbone turnover in a larger group of elderly men. No change in serum osteocalcin or alkaline phosphatase was observed in a longer-term study by Sih et al. (1997). There were no clear effects on markers of bone turnover in two controlled studies of the effects in the elderly of longer duration transdermal testosterone administration (Kenny etal. 2001; Snyder etal. 1999a). Also, dehydroepiandrosterone supplementation to older men (90 mg/day for 6 months versus placebo) was without effect on bone turnover markers in men 50 to 80 years of age (Kahn and Halloran 2002). The lack of consistent effect of treatment on biochemical markers of turnover might result in part from methodological problems, as well as from the complexity of differential effects of testosterone and its aromatization product estradiol (Falahati-Nini et al. 2000; Riggs et al. 2002). Snyder etal. (1999a), in a randomized double-blind trial of transdermal administration of testosterone by scrotal patch (6 mg/day) or placebo to men with normal or low serum testosterone (n = 108), found that after three years of treatment lumbar spine bone mineral density was increased in the placebo group as well as in the active treatment group, both receiving calcium and vitamin D supplements, without significant testosterone treatment effect; there was no change in bone mineral density at the hip region in either treatment group. These negative findings for testosterone effects on bone were accompanied by significant treatment effects on fat mass and lean body mass. Kenny etal. (2001) reported prevention ofbone loss at the hip during one-year treatment with transdermal testosterone (5 mg/day by body patch) as compared to placebo in healthy elderly men aged 65 to 87 years, but differences between placebo and active treatment were rather small. Crawford etal. (2003) found a beneficial effect of 12 months administration of testosterone, but not of the only minimally aromatizable androgen nandrolone, on bone mineral density in men treated with glucocorticoids who had initially low or low normal serum testosterone levels.

These rather disappointing results, as compared to the findings for bone effects of testosterone administration in younger hypogonadal men, may be explained by the fact that many of the men included in these studies had either normal or near normal initial androgen levels and by the possible existence of a threshold effect with the testosterone and derived estrogen requirements for near maximal bone effects being situated at the lower end of the physiological range for sex steroid levels. In support of this view is a post hoc analysis of the results of the study by Snyder et al. (1999a) which indicates that only those men with initially low serum total testosterone (<300-350 ng/dl) increased their bone mineral density during treatment. For their cohort study in healthy elderly men Khosla etal. (2001) have described a threshold for serum bio-available estradiol below which these levels are negatively associated with prospectively assessed bone loss. However, Van Pottelbergh etal. (2003) did not detect such a threshold in their cohort study.

In conclusion, evidence for the involvement of (relative) hypoandrogenism in senile osteoporosis in men remains limited, additional studies being needed to clarify this clinically important point and to further evaluate the potential role of hormonal and related treatments for senile osteoporosis.

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