Benefits of Bisphosphonate Therapy: Beyond the Skeleton

Recent evidence from clinical trials and observational studies raises the possibility that bisphosphonate use might confer a lower risk of cardiovascular disease and cancer, resulting in a mortality benefit. This review summarizes clinical and preclinical studies examining the non-skeletal effects of bisphosphonates. Data from clinical trials are conflicting regarding whether or not bisphosphonates have beneficial effects on mortality, cardiovascular events, or cancer incidence. No clinical trials have assessed these outcomes as primary endpoints, and most trials were shorter than 4 years. Observational data suggest that bisphosphonate users may have lower mortality, delayed progression of vascular calcification and atherosclerotic burden, and reduced incidence of breast and colorectal cancer compared to non-users. Preclinical studies confirm that bisphosphonates can be taken up by macrophages and monocytes, and nitrogen-containing bisphosphonates have the ability to disrupt the mevalonate pathway within these cells. In this manner, bisphosphonates exert anti-atherogenic and anti-cancer effects. Bisphosphonates also appear to exert protective effects on vascular smooth muscle cells and endothelial cells and may have direct cytotoxic effects on cancer cells. The balance of evidence does not support bisphosphonate treatment for the primary purpose of improving non-skeletal outcomes, although appropriately designed controlled trials that further explore this possibility are both justified and required. Patients with skeletal indications for bisphosphonate therapy can be reassured that these agents are not associated with increased mortality, cardiovascular disease, or cancer incidence.