Purpose: In osteosarcoma, tumour progression leads to osteolysis via direct proteolytic mechanisms and/or osteoclast activation. Nitrogen biphosphonates (N-BP) like zolebronate inhibit osteoclast function and apoptosis of osteoclasts and other tumour cells. In animal models, N-BP decrease bony progression of myeloma, bone metastasis, and breast and prostatic tumours. In vitro studies have demonstrated a synergetic action with classical anti-cancer drugs on apoptosis for myeloma and breast cancer cell lines. The purpose of the present study was to investigate the effect of zoebronic acid on osteosarcoma growth, alone or in combination with ifosfamide.

Material and methods: A rat model accepting osteosarcoma transplant was used for the study. Four series of seven rats were treated with zoledronate (100 mg/kg on day 7, 14, 21 and 28 after implantation) in combination or not with ifosfamide (30 mg/kg on day 1”, 14 and 15). Thirty-five days after implantation, the rats were sacrificed to evaluate tumour volume, presence of metastasis, radiography, and pathological examination of the tumour. Zoledronate was also studied in vitro on an OSRGA osteosarcoma cell line isolated from the same tumour.

Results: Zoledronate demonstrated efficacy by reducing the osteolysis induced by the sarcoma, but also on local tumour progression (75%) in comparison with untreated animals. In vitro, zoledronate inhibited cell proliferation by 60%. The ifosfsamide-zoledrnoate combination produced greater reduction in tumour progression than ifosfamide alone.

Conclusion: This work demonstrates for the first time that zoledronate has an effect on osteosarcoma tumour progression, either by a direct effect or by an antiosteoclastic effect and that the effet increases the efficacy of classical antitumour drugs such as ifosfamide.