Antitumour effects of bisphosphonates: first evidence and possible mechanisms

Bisphosphonates have been used successfully for many years in the treatment of hypercalcaemia and to reduce skeletal complications of metastases. In the first years of bisphosphonate use the efficacy of these substances was thought to lie purely in the inhibition of osteoclasts. However, there is recent evidence to suggest that an antitumour effect may also play a role. As well as having an apoptotic and antiproliferative effect on osteoclasts, bisphosphonates may exert a similar influence on macrophages and tumour cells. Whether this effect (at low doses) also plays a role in vivo remains unclear and requires further investigation. Improvements in the survival time of certain subpopulations have been found in many phase III studies with bisphosphonates to date, both in the setting of metastatic breast cancer and in multiple myeloma. However, because survival time in subgroups of patients was neither a primary nor a secondary objective in these studies, these advantages could only be seen as important pointers for future studies. Some preclinical studies have shown that down-regulation of bone metabolism by bisphosphonates is associated with a lower incidence of bone metastases and destruction in animals, whereas activation is correlated with a higher number of metastases. However, varying results were found in animal experiments with regard to the effect of bisphosphonates on the incidence and growth pattern of non-osseous metastases. The results of 3 randomised studies in patients with primary breast cancer who received clodronate 1600 mg/day orally have now been evaluated and presented. All 3 studies arrived at different results. In the Heidelberg study there was a reduction in both osseous and non-osseous metastases, whereas in a much larger study performed in Great Britain, Canada and Scandinavia there was a reduction only in the incidence of skeletal metastases. A third study from Finland found no effect on bone metastases, but an increase in the number of visceral metastases and a deterioration in overall survival. Because the dosage was identical in all 3 studies, the differing results can only be either random or methodological (for example inclusion criteria or sample size). Overall, the results are very promising, but there is a need for further studies.