Chapter 81 – Bisphosphonates: Mechanisms of Action

Publisher Summary The bisphosphonates are a class of drugs used in various diseases of calcium metabolism. This chapter describes the history of the development, chemistry, biological actions, and molecular mechanisms of action of bisphosphonates. It also highlights the newer developments in the field of study of bisphosphonates. Great progress has been made over the past two decades in understanding the mechanism of action of the bisphosphonates. Bisphosphonates are widely used in the treatment of osteoporosis, Paget's disease, tumor-associated bone disease, with potential uses in several other skeletal conditions. Owing to their bone-binding characteristics, bisphosphonates target to the skeleton, where they primarily act by inhibiting osteoclastic bone resorption. Whether they directly affect other cell types such as osteoblasts, osteocytes, and tumor cells in vivo, is still a matter of debate. The simple bisphosphonates, clodronate, etidronate and tiludronate, are intracellularly metabolized to cytotoxic analogues of ATP, whereas the more potent, nitrogen containing bisphosphonates act by inhibiting the enzyme FPP synthase, thereby preventing the prenylation of small GTPases that are necessary for the normal function and survival of osteoclasts. With emerging differences between bisphosphonates in bone affinity and enzyme inhibitory potency, it is becoming apparent that each bisphosphonate may have a unique pharmacological profile. Unraveling the exact molecular mechanisms underlying differences in efficacy and adverse effects may help to expand the utility of bisphosphonates and ensure their overall safe use in the treatment of a variety of bone diseases.