Normal bone remodeling maintains an appropriate balance between the action of osteoclasts (bone-resorbing cells) and osteoblasts (bone-forming cells). Skeletal malignancies, including bone metastases, disrupt the OPG-RANKL-RANK signal transduction pathway and promote enhanced osteoclast formation, thereby accelerating bone resorption and inducing bone loss. This osteolysis in turn leads to the release of bone-derived growth factors, contributing to a "vicious cycle" in which interactions between tumor cells and osteoclasts not only lead to increased osteoclastogenesis and osteolytic activity, but also aggressive growth and behavior of the tumor cells. The osteolytic complications associated with bone metastases are caused by tumor-induced alterations of the OPG-RANKL-RANK system, which are accompanied by enhanced bone resorption and disassociated from counterbalancing bone formation by osteoblasts.