Mechanisms of tumor-induced bone disease

Tumor-induced bone disease is a major cause of morbidity and mortality. Many cancers either grow predominantly in bone, such as multiple myeloma, or metastasize to bone, such as breast and prostate cancer. Irrespective of the organ of origin tumor cells induce significant changes in bone compromising skeletal integrity and resulting in bone pain, hypercalcemia and an increased likelihood of fracture. The cellular and molecular mechanisms responsible for the development of tumor-induced bone diseases are poorly understood, although increased osteoclast formation and/or activity appears to play a critical role, whether tumors are predominantly osteolytic or osteosclerotic. The identification of new signalling pathways that regulate osteoclast formation in cancers that grow in bone is a major research goal. The successful identification of such systems would provide new approaches to treating this aspect of cancer. The discovery of the ligand for receptor activator of NFkB (RANKL) system represents one such opportunity. RANKL, expressed by osteoblasts and/or stromal cells, binds to the receptor activator of NFkB (RANK) on osteoclast precursors and mediates normal osteoclast recruitment, differentiation and function. The decoy receptor, osteoprotegerin (OPG), is also produced by osteoblasts and can bind to RANKL preventing its association with RANK and inhibiting osteoclast formation and bone resorption.