Novel therapeutic strategy for osteosarcoma targeting osteoclast differentiation, bone-resorbing activity, and apoptosis pathway

Osteosarcoma is the most common bone sarcoma, which mainly affects adolescents and young adults. Although the combination of modern surgery and systemic chemotherapy has improved osteosarcoma treatment dramatically, no substantial change in survival has been seen over the past 20 years. Therefore, novel therapeutic strategies for osteosarcoma are required if the 35% of patients with fatal metastases are to be successfully treated. Recently, osteoclasts have drawn attention as a therapeutic target in various bone disorders including osteosarcoma. The osteoclast is the sole cell that resorbs bone and is central in pathologic situations, where bone destruction is intricately involved. Osteosarcoma cells are of the osteoblastic lineage, the latter of which is characterized by cells secreting the osteoclast-inducing factor, receptor activator of nuclear factor-kappa B ligand. Hence, osteosarcoma is a better candidate for osteoclast-targeted therapy than other primary and metastatic bone tumors. The rapid progress on the molecular mechanism regulating osteoclast has propelled a development of new therapeutic approaches. In this review article, we present the prospects of osteoclast-targeted therapy as a novel treatment strategy for osteosarcoma. Receptor activator of nuclear factor-kappa B-Fc, osteoprotegerin, bisphosphonates, and Src inhibitor are shown as positive candidates and can control various aspects of osteoclast function. This review article will attempt to discuss these issues in term. [Mol Cancer Ther 2008; 701111:3461-9]