Estrogens exert beneficial effects on the development and maintenance of the skeleton, and skeletal effects of estrogen are mediated by its binding to specific ER localized at the cytosol and intranucleus.19 It is clear that ERα gene plays an important role in bone homeostasis because of the occurrence of osteoporosis in men who have nonsense mutation of the ERα gene,39 or the BMD in the ERα gene knockout mouse was 20%–25% lower than that in the wildtype mouse.40 However, mechanisms about the effect of ERα gene polymorphisms on BMD are still unclear. Here, ESR1 is linked to osteoporosis.