Methylenediphosphonate (MDP)-conjugated adriamycin liposomes (MDP-LADMs) were prepared using mild dynamic dialysis equilibrium method, and their targeted therapeutic effects against osteosarcomas and metastatic SOSP-M lung nodules were evaluated in vivo. The drug loading and encapsulation efficiency of the MDP-LADMs were measured via high-performance liquid chromatography, and their size and morphology of the MDP-LADMs were determined using transmission electron microscopy and a particle size analyzer, respectively. Cells apoptosis were evaluated by flow cytometry and caspase-3 activity. The targeted therapeutic effects of MDP-LADMs against UMR106 and SOSP-M osteosarcoma cells were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor growth and animal survival rates were evaluated after UMR106 osteosarcomas were established in Sprague-Dawley rats and SOSP-M pulmonary metastatic osteosarcoma model were established in nude mice, respectively. The results show that the average diameter of the MDP-LADMs was 152 ± 14 nm, and their ADM encapsulation efficiency was 91.7% with respect to a 250 μg/ml of loading efficiency. The conjugation efficiency between technetium-MDP and LADMs was 87.6%. Infrared spectra results of the samples dissolved in deuterated water confirmed that the methylenediphosphonate (MDP) was conjugated with LADMs through hydrogen bonding. The toxicity assay revealed a median lethal dose of 26.78 mg/kg for MDP-LADMs, which was significantly higher than doses observed for free ADM of 9.64 mg/kg (P < 0.05) and LADMs of 15.02 mg/kg(P < 0.05). Tumor growth and animal survival in the MDP-LADMs group were significantly higher than those in the ADM-only, MDP-only (P < 0.01) and LADMs groups (P < 0.05). These findings indicate that MDP-LADMs have higher therapeutic efficacy against osteosarcomas, demonstrate lower toxicity and their clearly targets osteosarcomas more clearly than the stand-alone systems, making them as a promising novel targeted therapy for the treatment of osteosarcoma.