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)-alpha and -beta 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-alpha and AluI ER-beta polymorphisms. The X/P and x/p alleles of the ER-alpha gene were in strong linkage disequilibrium. BMD at multiple sites did not differ as a function of either the ER-alpha or -beta genotype. However, the ER-alpha (but not ER-beta) genotypes did modulate the previously described relationships between BMD or rates of bone loss and bioavailable estradiol (E(2)) levels in these men. At the femoral neck, BMD was associated with bioavailable E(2) 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 E(2) 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 E(2) 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 E(2) levels were low (<40 pmol/liter) but not for the PvuII polymorphism. These data thus indicate that the ER-alpha genotype may modulate the relationship between BMD or rates of bone loss and estrogen levels in men and that bone mass in men with the X or P alleles may be more susceptible to the consequences of estrogen deficiency (and conversely, benefit most from estrogen sufficiency) than in men with the xx or pp genotypes.