Osteoporosis is a common skeletal disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Although osteoporosis is a worldwide problem, there are many differences in human ethnics regarding both disease morbidity and drug treatment efficacy. Polymorphisms of vitamin D receptor (VDR) and estrogen receptor-alpha (ERalpha) loci are proposed as genetic determinants of bone quality, skeletal geometry and bone turnover markers. Furthermore, varying responsiveness to vitamin D and estrogen-based treatments may reflect allele variation in their signaling pathway genes (e.g., VDR or ERalpha). Because of their specific ethnic distribution, VDR and ERalpha polymorphisms may be involved in reported human differences of osteoporosis treatment responses.