Bone is a highly hospitable environment for colonization and growth of metastatic tumors, and some of the most common human malignancies, notably breast cancer and prostate cancer, have a strong propensity to produce skeletal metastases. Tumor cells, in turn, can produce a spectrum of skeletal manifestations which spans diffuse osteopenia, focal osteolysis, focal osteogenesis, and osteomalacia.

The most common skeletal manifestation of malignancy is focal osteolysis in association with metastases. In order for tumor cells to grow and invade mineralized bone, osteolysis must occur. Osteoclasts appear uniquely adapted to produce the microenvironment and the biochemical milieu that are needed to resorb bone. Although previous reports have indicated that some tumor cells appear capable of assuming an osteoclast phenotype and directly resorbing bone, the bulk of the evidence suggests that most tumor cells act indirectly by co-opting the physiologic mechanisms that normally favor bone resorption. Thus, they release agents such as hormones, eicosanoids, growth factors, and cytokines into the bone microenvironment, which act on osteoblastic stromal cells to enhance the production of osteoclast activating factors. Most notable of these is the cell membrane–associated protein termed receptor activator of NF-κB ligand (RANKL), which is a member of the TNF family of cytokines. RANKL can then bind to its cognate receptor (RANK) on osteoclast precursors and, in the presence of M-CSF, enhance the differentiation and fusion of these cells to produce functioning multinucleated osteoclasts (Figure 1). Concomitantly, production of a soluble decoy receptor for RANKL, termed osteoprotegerin (OPG), may be downregulated, thus eliminating one means by which the ensuing osteolysis could be repressed.