Bisphosphonates as anticancer drugs

The single most important advance in the last few years in the treatment of patients with osteolytic bone disease due to malignancy has been the widespread use of pamidronate; this drug has been used in patients with breast cancer metastatic to bone, and in patients with myeloma, with or without hypercalcaemia. However, data are now emerging which suggest that bisphosphonates have additional, and completely unanticipated, effects beyond those on bone resorption. Studies of the behaviour of human breast cancer cells that cause osteolytic bone disease in nude mice demonstrate that some bisphosphonates actually reduce tumour burden in bone, as well as reducing osteolysis. Two separate studies in a relatively small number of patients treated with clodronate have suggested that this bisphosphonate decreases tumour burden in bone. These preliminary findings have extremely important implications for the treatment of patients with advanced cancers affecting bone. It must now be questioned whether these effects are related to particular bisphosphonates and whether they hold true for different tumours. The nature of the mechanism responsible for bisphosphonates decreasing tumour burden must be determined, whether or not these effects are indirect or direct and if they are related to the capacity of bisphosphonates to cause apoptosis in vitro and in vivo. These questions are very difficult to address in patient studies. Patients with advanced cancer present many confounding variables, which make interpretation of the data very difficult. It may take many years of multi-centre studies to reach definitive conclusions.