Oestrogen-receptor-α gene polymorphism affects response in bone mineral density to oestrogen in post-menopausal women

OBJECTIVE An oestrogen-receptor-alpha (ER alpha) gene polymorphism has been variably reported to be related to bone mass. To investigate whether this ER alpha gene polymorphism is associated with a functional difference, we assessed the response in bone mineral density (BMD) to oestrogen therapy in postmenopausal women in relation to ER alpha gene polymorphism. PATIENTS AND MEASUREMENTS Subjects consisted of 124 Thai post-menopausal women, Sixty-three of the women were less than 6 years post-menopausal and 61 were more than 10 years post-menopausal with vertebral or femoral osteoporosis as defined by BMD T-score less than - 2.5. Subjects were randomly allocated to receive 0.3 mg (n = 67) or 0.625 mg (n = 57) of conjugated equine oestrogen (CEE), All subjects also took 5 mg medroxyprogesterone acetate, Vertebral and femoral neck BMD were measured at baseline and 1 year after treatment. Data were expressed as mean +/- SEM, Capital P represents the absence of the restriction site while lower-case p indicates the presence of the restriction site. RESULTS For subjects on 0.625 mg GEE, BMD at L2-4 increased significantly after 1 year in those with pp (n=20) Pp (n=29) and PP genotypes (n=8) (P<0.001). However, in subjects on 0.3 mg GEE, BMD at L2-4 increased significantly after 1 year in subjects with Pp (n = 34, + 7.6 +/- 1.5%, P< 0.001) and PP genotypes (n = 13, + 6.9 +/- 1.0%, P< 0.001), but not in those with pp genotype (n=20, +2.3 +/- 2.1%, P = NS). After adjusting for age and years since menopause, the change in vertebral BMD was still lower in those without the P allele compared to those with the P allele (P<0.05). Femoral BMD did not significantly change regardless of dose of CEE and genotype. CONCLUSIONS We conclude that ER alpha gene polymorphism affects skeletal response to oestrogen in post-menopausal women. The effect of ER alpha gene polymorphism appears to be site-specific and does not relate to biochemical markers of bone turnover, Determination of ER alpha genotype may help identify post-menopausal women who will have more skeletal benefit from oestrogen therapy.