Differentiation and function of osteoclasts is regulated by RANKL and OPG, both of which are produced by osteoblasts. Osteoclast precursors express RANK, the receptor of RANKL. The activation of the RANKL-RANK system stimulates osteoclast differentiation and function. OPG is a decoy receptor of RANKL, which inhibits the RANKL-RANK interaction. Several genetic disorders in RANKL, RANK and OPG genes cause osteoclast abnormalities. Therefore, the development of anti-osteoporosis drugs that suppress the RANKL-RANK system is advanced now. Recently, anti-RANKL antibody, denosumab, is developed and being used as a new treatment for osteoporosis.