Excessive bone destruction is a major cause of morbidity in myeloma patients. However, the biological mechanisms involved in the pathogenesis of myeloma-induced bone disease are not fully understood. Heparanase, an enzyme that cleaves the heparan sulfate chains of proteoglycans, is upregulated in a variety of human tumors, including multiple myeloma. We previously showed that heparanase promotes robust myeloma tumor growth and supports spontaneous metastasis of tumor cells to bone. In the present study, we show, for the first time, that the expression of heparanase by myeloma tumor cells remarkably enhances bone destruction locally within the tumor microenvironment. In addition, enhanced heparanase expression in the primary tumor also stimulated systemic osteoclastogenesis and osteolysis, thus mimicking the systemic osteoporosis often seen in myeloma patients. These effects occur, at least in part, as the result of a significant elevation in the expression and secretion of receptor activator of NF-κB ligand (RANKL) by heparanase-expressing myeloma cells. Moreover, analysis of bone marrow biopsies from myeloma patients reveals a positive correlation between the level of expression of heparanase and RANKL. Together, these discoveries reveal a novel and key role for heparanase in promoting tumor osteolysis and show that RANKL is central to the mechanism of heparanase-mediated osteolysis in myeloma. ©2010 AACR.