Bone tissue

Polymorphisms of the estrogen receptor (ER) have repeatedly been demonstrated to modulate quantity and quality of bone tissue in healthy men (e.g. Sapir-Koren et al. 2001). As androgen activity influences bone metabolism (see Chapter 7), respective observations apply to the CAG repeat polymorphism in the AR gene as well: in 110 healthy younger males, a high number of CAG repeats was significantly associated with lower bone density (Zitzmann et al. 2001b). This result is corroborated by a negative association between AR CAG repeat length and bone density at the femoral neck in a group of 508 Caucasian men aged over 65 years (Zmuda et al. 2000a). The same workgroup also observed a more pronounced bone loss at the hip and increased vertebral fracture risk among older men with longer AR CAG repeat length (Zmuda etal. 2000b). In a group of 140 Finnish men aged 50-60 years, lumbar and femoral bone mineral density values were higher in those men with shorter CAG repeats in comparison to those with longer CAG repeats (Remes et al. 2003). The differences reach statistical significance when the groups with CAG repeat length of 15-17 and 22-26 are compared directly. In contrast, in a group of 273 healthy Belgian men aged 71 and 86 years, no influence of the androgen receptor gene polymorphism was seen, but about 30% of these men had androgen levels below the lower limit of normal and were thus lacking sufficient androgen receptor activation (van Pottelbergh etal. 2001).

Higher androgenization will lead to higher peak bone mass (Khosla 2002); thus, the AR polymorphism effects on bone density are likely to be visible among healthy younger males, while the difference could be mitigated by the overall age-dependent bone loss and may no longer be visible in old men, in whom confounders have exerted influence on bone tissue. Thus, the longer the CAG repeat in the AR gene, the lower peak bone density in males will be, while it is inconclusive whether this effect reaches clinical significance in terms of higher fracture risk.

In women, low androgen levels and, hence, low activation of the AR are present. In addition, two alleles of the AR gene will cause a less pronounced effect in terms of influence exerted by the CAG repeat polymorphism. Nevertheless, reports concerning such impact on bone density in women exist, demonstrating an association of reduced bone mass and/or osteoporotic fractures in women with longer CAG repeats (Chen et al. 2003; Sowers et al. 1999; Tofteng et al. 2003; Langdahl et al. 2003). As can be expected from physiology, the AR polymorphism does not influence the effects of hormone replacement therapy by estrogens on bone tissue in postmenopausal women (Salmen etal. 2003).

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