Pharmacology of bisphosphonates

Abstract

The biological effects of the bisphosphonates (BPs) as inhibitors of calcification and bone resorption were first described in the late 1960s. In the 50 years that have elapsed since then, the BPs have become the leading drugs for the treatment of skeletal disorders characterized by increased bone resorption, including Paget's disease of bone, bone metastases, multiple myeloma, osteoporosis and several childhood inherited disorders. The discovery and development of the BPs as a major class of drugs for the treatment of bone diseases is a paradigm for the successful journey from "bench to bedside and back again". Several of the leading BPs achieved "blockbuster" status as branded drugs. However, these BPs have now come to the end of their patent life, making them highly affordable. The opportunity for new clinical applications for BPs also exists in other areas of medicine such as ageing, cardiovascular disease and radiation protection. Their use as inexpensive generic medicines is therefore likely to continue for many years to come. Fifty years of research into the pharmacology of bisphosphonates have led to a fairly good understanding about how these drugs work and how they can be used safely in patients with metabolic bone diseases. However, while we seemingly know much about these drugs, a number of key aspects related to BP distribution and action remain incompletely understood. This review summarizes the existing knowledge of the (pre)clinical and translational pharmacology of BPs, and highlights areas in which understanding is lacking.

Keywords: Bisphosphonates; bone; osteoporosis; pharmacology.

Figure 1

Ten BPs that have been approved for clinical use in various countries and working by two different biochemical mechanisms, incorporation into ATP analogues or inhibition of farnesyl pyrophosphate synthase in the mevalonate pathway

Figure 2

The relationship between creatinine clearance and renal clearance of Pamidronate. From Berenson et al.26 © 1997 American College of Clinical Pharmacology. Reproduced with permission

Figure 3

Whole body retention (WBR) of the BP olpadronate in patients with Paget's disease of bone correlates with pretreatment renal function (Clcr) as well as pre‐treatment rate of bone turnover, biochemically assessed (uNTx/Cr). From46

Figure 4

BP uptake into osteoclast. Rabbit osteoclasts were seeded onto dentine discs that had been precoated with 100 mM fluorescently labelled alendronate (green) and incubated for 18 h. Cells were then fixed, and actin stained with TRITC‐phalloidin (red). Cells were examined by light scatter confocal microscopy (LSCM)50, 51

Figure 5

The nitrogen containing bisphosphonates (N‐BPs) work on the mevalonate pathway of cholesterol biosynthesis, just like statins. By inhibiting the enzyme, farnesyl pyrophosphate synthase (FPPS), they interfere with intracellular signalling that requires prenylated proteins