ABSTRACT Osteosarcoma is the most common primary malignant tumor of bone and accounts for around 50% of all primary skeletal malignancies. In addition to novel chemotherapies, there is a need for adjuvant therapies designed to inhibit osteosarcoma proliferation and tumor‐induced osteolysis to attenuate tumor expansion and metastasis. As such, studies on the efficacy of bisphosphonates on human osteosarcoma are planned after feasibility studies determined that the bisphosphonate zoledronic acid (ZOL) can be safely combined with conventional chemotherapy. However, the molecular mechanisms responsible for, and means of inhibiting, osteosarcoma‐induced osteolysis are largely unknown. We establish that osteosarcoma growth directly correlates with tumor‐induced osteolysis and activation of osteoclasts in vivo. In vitro, tumor cells were determined to expresses surface, but not soluble, receptor activator of NF‐κB ligand (RANKL) and stimulated osteoclastogenesis in a manner directly proportional to their malignant potential. In addition, an aggressive osteosarcoma cell line was shown to secrete monocyte chemoattractant protein‐1 (MCP‐1), resulting in robust monocyte migration. Because MCP‐1 is a key cytokine for monocyte recruitment and surface‐bound RANKL strongly supports local osteoclastogenesis, we suggest that high levels of these signaling molecules are associated with the aggressive potential of osteosarcoma. Consistent with these findings, abundant expression of RANKL/MCP‐1 was observed in tumor in vivo, and MCP‐1 plasma levels strongly correlated with tumor progression and osteolysis. ZOL administration directly attenuates osteosarcoma production of RANKL/MCP‐1, reducing tumor‐induced bone destruction. In vivo, these findings also correlated with significant reduction in osteosarcoma growth. ZOL attenuates tumor‐induced osteolysis, not only through direct inhibition of osteoclasts, but also through direct actions on tumor expression of osteoclast activators. These data provide insight regarding the effect of ZOL on osteosarcoma essential for designing the planned upcoming prospective randomized trials to determine the efficacy of bisphosphonates on osteosarcoma in humans. © 2014 American Society for Bone and Mineral Research.