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.

We investigated the possible use of acrylic cement containing chemotherapeutic drugs in the treatment of malignant lesions in bone. The diffusion of methotrexate (MTX) from methylpolymethacrylate implants was studied in vitro: polymerisation of the cement did not destroy the drug; liberation began immediately and about 10% was released by 18 hours. Some release continued for as long as six months. In vivo experiments on rats with induced osteosarcoma showed that MTX in cement had both local and general effects which were dependent on the dosage. A series of 17 large dogs with spontaneous osteosarcoma were then treated by local resection and cement containing MTX. General chemotherapeutic effects were detectable from 2 hours to 5 days, survival was increased and local recurrence was reduced, but there were four cases of delayed wound healing. Preliminary studies in human patients confirm the possibility that this method of local chemotherapy could be a useful addition to the treatment of malignant tumours of bone.