Genes are important BMD determinants. We studied the association of an ESRRA gene functional variant with BMD in 1335 premenopausal women. The ESRRA genotype was an independent predictor of L₂‐L₄ BMD, with an effect similar to smoking and equivalent to a 10‐kg difference in weight.

Introduction: Several genetic polymorphisms have been associated with osteoporosis or osteoporosis fractures, but no functional effect has been shown for most of these gene variants. Because functional studies have implicated estrogen‐related receptor α (ESRRA) in bone metabolism, we evaluated whether a recently described regulatory variant of the ESRRA gene is associated with lumbar and hip BMD as measured by DXA and with heel bone parameters as measured by quantitative ultrasound (QUS).

Materials and Methods: Heel bone parameters were measured by right calcaneal QUS in 1335 healthy French‐Canadian premenopausal women, and one‐half of these women also had their BMD evaluated at two sites: femoral neck and lumbar spine (L₂‐L₄) by DXA. All bone measures were tested separately for association with the ESRRA genotype by analysis of covariance. The significance of the ESRRA contribution to the model was also assessed by two different permutation tests.

Results: A statistically significant association between ESRRA genotype and lumbar spine BMD was observed: women carrying the long ESRRA genotype had a 3.9% (0.045 g/cm²) higher lumbar spine BMD than those carrying the short ESRRA genotype (p = 0.004), independently of other risk factors measured. This effect of ESRRA genotype is similar to the effect of smoking and equivalent to a 10‐kg difference in weight. This association was confirmed by permutation tests (p = 0.004). The same trend was observed for femoral neck BMD (2.6%, p = 0.07). However, no association was observed between ESRRA and QUS heel bone measures.

Conclusion: These results support the genetic influence of this ESRRA regulatory variant on BMD.