Osteolysis and cancer.

ment 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 (1). Tumor cells, in turn, can produce a spectrum of skeletal manifestations which spans diffuse osteopenia, focal osteolysis, focal osteogenesis, and osteomalacia (2). 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 (3), 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 (4) (Figure 1). Concomitantly, production of a soluble decoy receptor for RANKL, termed osteoprotegerin (OPG) (5), may be downregulated (6), thus eliminating one means by which the ensuing osteolysis could be repressed. Mineralized bone matrix is a rich source of stored growth factors such as TGF-β. Such growth factors, once released from degraded bone matrix, may further accelerate growth of the tumor, which can now expand within the lysed area. Such growth factors also appear capable of further increasing the release from tumor cells of osteolytic mediators, such as parathyroid hormone–related peptide (PTHrP) (7, 8). A cycle may therefore be initiated that consists of release of osteolytic mediators by tumor cells, bone degradation, release of growth factors from degraded bone, enhanced tumor cell growth, and further release of osteolytic mediators (9). Therapeutic implications for osteolytic cancers The osteoclast offers a critical target for therapies designed to break this pathological cycle and help manage malignancy-induced osteolysis. By binding and neutralizing RANKL, OPG can diminish the production of functioning osteoclasts, and, indeed, this factor has been reported to block bone resorption in animal models of hypercalcemia of malignancy (10). Nevertheless, OPG appears to have little direct effect on tumor cell growth or survival. Bisphosphonates are potent bone resorption inhibitors that have a high affinity for mineralized matrix and are taken up by osteoclasts, in which they induce apop-