The discovery of the RANK/RANKL/osteoprotegerin (OPG) signaling axis represents another milestone in bone biology: the finding that RANKL-deficient mice develop severe osteoclast-deficient osteopetrosis, whereas overexpression of RANKL or the lack of the decoy receptor for RANKL, OPG, result in osteoporosis, due to excessive osteoclast formation (103–105), emphasize the critical role of these pathways in osteoclastogenesis. This evidence concerns the gene TNFSF11 and osteoporosis.