The protective effect of hormone-replacement therapy on fracture risk is modulated by estrogen receptor alpha genotype in early postmenopausal women

Genetic factors regulate bone mineral density (BMD) and possibly developmen t of osteoporosis. It has been suggested that estrogen receptor alpha (ER a lpha) genotype is associated with BMD, but the association between ER alpha genotype, fracture risk, and postmenopausal hormone replacement therapy (H RT) has not been studied. Therefore, we evaluated whether ER alpha polymorp hism is associated with fracture risk in a 5-year trial with HRT in a popul ation-based, randomized group of 331 early postmenopausal women. The partic ipants consisted of two treatment groups: the HRT group (n = 151) received a sequential combination of 2 mg of estradiol valerate (E(2)Val) and 1 mg o f cyproterone acetate with or without vitamin D-3, 100-300 IU + 93 mg calci um as lactate per day; and the non-HRT group (n = 180) received 93 mg of ca lcium alone or in combination with vitamin D-3, 100300 IU/day. All new symp tomatic, radiographically defined fractures were recorded. Pvu II restricti on fragment length polymorphism of the ER alpha was determined using polyme rase chain reaction (PCR). In all, 28 women sustained 33 fractures during t he approximately 5.1-year follow-up. In the HRT group, the ER alpha genotyp e (PP, Pp, and pp) was not significantly associated with fracture risk (p = 0.138; Cox proportional hazards model). When the genotype was dichotomized (PP + Pp vs. pp), the incidence of new fractures in the HRT group was sign ificantly reduced in women with the P allele (p = 0.046) with the relative risk (HR) of 0.25 (95% CI, 0.07-0.98), in comparison with the non-P allele group. After adjustment for time since menopause and previous fracture, the association between the dichotomous genotype and fracture risk persisted w ith HR of 0.24 (95% CI, 0.06-0.95;p = 0.042). In the non-HRT group, the ER alpha genotype was not significantly associated with fracture risk. During HRT, women with the pp genotype have a greater fracture risk than those wit h the P allele. The results suggest that the pp genotype is a relatively ho rmone-insensitive genotype, and it appears that women with the P allele may benefit more from the protective effect of HRT on fracture risk than women with the pp genotype.