Osteoporosis and its complications represent one of the most important causes of morbidity and mortality around the world. Moreover, its management presents an important economic problem. Although osteoporosis is a worldwide health problem, there are many differences in ethnic groups regarding disease morbidity and drug treatment efficacy. This review analyzed clinical response data of two major osteoporotic treatments (vitamin D and estrogens) regarding four major human races (Asian, Caucasian, Hispanic and Negroid). From clinical studies, Asians seem to be more vitamin-D-sensitive while Caucasians appear more estrogen-sensitive than other human races. Different drug responses may be related to allelic variants in their signaling genes such as those for the vitamin D receptor (VDR) and estrogen receptor-alpha (ER alpha). Some polymorphisms of VDR and ER alpha loci appear to be genetic determinants of osteoporotic risk: ApaI-BsmI-TaqI, FokI variants and poly(A) repeats in VDR; PvuII-XbaI variants and (TA) repeats in ER alpha. Also, because of specific ethnic allele distributions, these VDR and ER alpha polymorphisms may be involved in race differences of osteoporosis treatment responses. Future studies and preventive strategies for the management of osteoporosis need to take into account these racial and genetic factors.