Synergistic effect of bisphosphonate and docetaxel on the growth of bone metastasis in an animal model of established metastatic bone disease.

Bisphosphonates decrease bone resorption and reduce significantly the rate of skeletal complications in patients with metastatic bone disease. Bisphosphonates have also been shown to exhibit antitumor activity in vitro but in vivo results have been equivocal. In the present study, we investigated the effects of bisphosphonate treatment alone or in combination with the cytostatic docetaxel on the growth of breast cancer cells in bone. Tumor gowth was studied in an athymic nude mice model inoculated with MDA-231-B/luc+ breast cancer cells. Two days after the inoculation, mice were treated with risedronate, zolendronate or docetaxel alone or with a combination of risedronate and docetaxel. Bone destruction and tumor growth were evaluated radiographically, histologically and by whole-body bioiluminescent reporter imaging (BLI). Five week treatment with high doses risedronate or zoledronate (37.5-150 microg/kg, 5 times/week), fully protected the bones from osteolysis, but did not affect tumour growth. Docetaxel (2, 4, and 8 mg/kg, 2 times/week) inhibited tumour growth dose-dependently and after 5 weeks treatment with the highest dose, there was no detectable tumour in bone. The combination of a dose of docetaxel (4 mg/kg) that demonstrated only a minimal effect on tumour growth, with risedronate (150 microg/kg), protected bone integrity and nearly completely inhibited the growth of the cancer cells. Risedronate and docetaxel act synergistically to protect bone and decrease tumour burden in an animal model of established bone metastases from breast cancer cells.