Ibandronate in metastatic bone disease: a review of preclinical data

Bisphosphonates are widely used to prevent and treat skeletal complications of metastatic bone disease. There is increasing evidence that, besides inhibiting osteoclast activity and reducing bone resorption, bisphosphonates also have an anti-tumor effect. This paper reviews the preclinical data for ibandronate. Ibandronate increased the proportion of apoptotic tumor cells in vitro and in vivo, possibly following activation of caspase-like proteases. In vitro, ibandronate also prevented adhesion and spreading of tumor cells to bone, and tumor cell invasion. These inhibitory effects were additive when ibandronate was given with paclitaxel or docetaxel. In animal models of tumor-induced osteolysis, ibandronate significantly reduced the development of osteolytic lesions. Efficacy for the prevention and reduction of bone metastases was related to the timing of treatment; ibandronate treatment initiated prior to or shortly after tumor cell inoculation inhibited the growth of bone metastases and preserved skeletal integrity most effectively. As with other bisphosphonates, the influence of ibandronate on soft tissue metastases has been inconsistent. Overall, preclinical evidence supports the rationale for adjuvant treatment with ibandronate for patients at risk of metastatic bone disease. The renal safety profile of ibandronate supports its suitability for long-term adjuvant use, even with intermittent high dosing. Adjuvant clinical trials have been initiated. The ability of bisphosphonates to preserve skeletal integrity is also of benefit in other clinical settings. Recent studies in rat models demonstrate improved osseointegration of joint implants following ibandronate therapy, with potential application in patients with conditions such as degenerative arthritis or osteoporosis.