RECENT ADVANCES Bisphosphonate treatment of bone disease

MECHANISM OF ACTION AND RELATIVE POTENCY Bisphosphonates are chemical analogues of pyrophosphate. The presence of a carbon rather than oxygen atom at the centre of the molecule prevents its breakdown. The two phosphonate groups are attached directly to the carbon atom from which also extend the R1 and R2 side chains (fig 1). The R1 side chain is usually a hydroxyl group and is often referred to as the ‘‘bone hook’’ in association with the phosphonic groups. It is the R2 side chain that confers the differential potency of the different molecules. The older bisphosphonates, etidronate and clodronate, form cytotoxic acyclic ATP analogues which accumulate in osteoclasts (following endocytosis from bone surfaces), leading to apoptosis (programmed cell death). The more recent nitrogen containing bisphosphonates cause inhibition of farnesyl diphosphate synthase. This inhibition leads to failure of prenylation (transfer of fatty acid chains) of a variety of intracellular proteins, particularly small GTP binding proteins such as Ras, Rab, Rho, and Rac. Failure of prenylation leads to the inability of these small proteins to translocate into cell membranes. The resulting interference with cellular processes leads to earlier apoptosis of several cell types including osteoclasts. At the cellular level, the loss of osteoclast function leads to a reduction in bone resorption and, hence, a cascade of events (fig 2). The commonly used nitrogen containing bisphosphonates comprise pamidronate, olpadronate, ibandronate, alendronate, risedronate, and zoledronate. Their relative potency which has been assessed in in-vitro assays for osteoclast inhibition and the effect on pit formation of osteoclasts seeded onto dentine slices, are shown in table 1, taking etidronate as having a potency of 1. Debate continues about relative potency in vivo of the commonly used nitrogen containing bisphosphonates in adult osteoporosis trials, although similar levels of inhibition of bone function are achieved with alendronate and risedronate. Bone mass is maintained in adults after stopping bisphosphonate therapy. This introduces the concept of ‘‘residence time’’. Zoledronate clearly has the longest residence time of any of the bisphosphonates and a single dose is sufficient to inhibit bone resorption for up to 12 months in adult osteoporosis studies. A pharmacokinetic study of alendronate has been undertaken and reported in the literature of the FDA. The overall absorption of alendronate when given by mouth is similar in children to that in adults at around 0.5% of the administered dose.