Osteosarcoma (OS) is a highly aggressive primary bone tumour in children and adolescents but the basis for its metastatic properties is unclear. Pulmonary metastases can occur in up to 50% of cases and result in a long-term survival rate of only 10-20%. In a transcriptomic screen of primary OS biopsies, we found a significant correlation between OS and impaired osteoclastogenesis (Endo-Munoz et al. British J Cancer 103:73-81, 2010). Specifically, lesions from OS patients with pulmonary metastases had 2-fold less expression of the osteoclast-specific enzyme, ACP5, than lesions from patients without pulmonary metastases, and there was a direct correlation between ACP5 expression and time to metastasis. Based on these findings, we tested whether metastasis-competent OS cells could induce the loss of osteoclasts in the bone microenvironment as a mechanism to drive metastasis. We found that these cells could inhibit osteoclastogenesis in vivo and in vitro. In addition, osteoclasts inhibited the migration of metastasis-competent OS cells in vitro. Finally, ablation of osteoclasts with zoledronic acid increased the number of metastatic lung lesions in an orthotopic mouse model of OS, while treatment with fulvestrant, at a clinically-relevant dose, increased osteoclast numbers and reduced metastatic lesions (Endo-Munoz et al. Cancer Res 70:7063-7072, 2010). Our data indicates that the osteoclast is a key regulator of OS metastasis and that osteoclast-preserving therapies may be of clinical value in preventing OS metastasis.