Relationship of Estrogen Receptor Genotypes to Bone Mineral Density and to Rates of Bone Loss in Men

Estrogen is now known to play an important role in bone metabolism in men. Thus, we examined possible relationships between polymorphisms of the estrogen receptor (ER)-α and -β genes, bone mineral density (BMD), and rates of bone loss in an age-stratified random sample of 283 Rochester, Minnesota, men aged 22–90 yr. DNA was analyzed for the XbaI and PvuII ER-α and AluI ER-β polymorphisms. The X/P and x/p alleles of the ER-α gene were in strong linkage disequilibrium. BMD at multiple sites did not differ as a function of either the ER-α or -β genotype. However, the ER-α (but not ER-β) genotypes did modulate the previously described relationships between BMD or rates of bone loss and bioavailable estradiol (E2) levels in these men. At the femoral neck, BMD was associated with bioavailable E2 levels in men with the XX (R = 0.66) or PP (R = 0.51) genotypes (P < 0.001 for both) but not in men with the xx (R = 0.15; P = 0.188) or pp (R = 0.12; P = 0.356) genotypes. The interactions between bioavailable E2 levels and the XbaI and PvuII genotypes were significant at the P < 0.001 and P < 0.009 levels, respectively. Moreover, rates of bone loss at the midradius in men aged 60–90 yr were modestly correlated with serum bioavailable E2 levels in subjects with the X (R = 0.47) or P (R = 0.42) alleles (P < 0.001 for both) but not in those with the xx (R = 0.15; P = 0.430) or pp (R = 0.21; P = 0.372) genotypes. The overall effect of genotype on midradius rate of bone loss was clearly significant for the XbaI polymorphism (P = 0.009) when bioavailable E2 levels were low (