Clinically obtainable concentrations of zoledronic acid (ZOL) inhibited the production of vascular endothelial growth factor and reduced the migration, adhesion, and invasiveness of osteosarcoma (OS) cells in vitro. The in vivo effects of ZOL were investigated by using a murine model of spontaneous lung metastasis. The higher dose of ZOL (80 microg/kg three times/week) inhibited the growth of OS at the primary site, accompanied by inhibition of neovascularization in the tumor. Interestingly, while the lower dose of ZOL (80 microg/kg once a week) could not inhibit the growth of OS at the primary site, it significantly prevented lung metastasis.