Now that RANKL–RANK has been successfully harnessed for purposes of therapeutic treatments of osteoporosis, bone loss, and bone metastasis, it will be important to answer additional questions – specifically with respect to how RANK signaling is modulated, and how and on what cells RANKL is physiologically expressed under normal versus disease conditions – if therapeutic RANKL–RANK targeting is to be refined and potentially applied to additional disease conditions. This evidence concerns the gene TNFSF11 and osteoporosis.