Basic research and clinical applications of bisphosphonates in bone disease: what have we learned over the last 40 years?

Abstract

It is now 40 years since bisphosphonates (BPs) were first used in the clinic. So, it is timely to provide a brief review of what we have learned about these agents in bone disease. BPs are bone-specific and have been classified into two major groups on the basis of their distinct molecular modes of action: amino-BPs and non-amino-BPs. The amino-BPs are more potent and they inhibit farnesyl pyrophosphate synthase (FPPS), a key enzyme of the mavalonate/cholesterol biosynthetic pathway, while the non-amino-BPs inhibit osteoclast activity, by incorporation into non-hydrolyzable analogs of ATP. Both amino-BPs and non-amino-BPs can protect osteoblasts and osteocytes against apoptosis. The BPs are widely used in the clinic to treat various diseases characterized by excessive bone resorption, including osteoporosis, myeloma, bone metastasis, Legg-Perthes disease, malignant hyperparathyroidism, and other conditions featuring bone fragility. This review provides insights into some of the adverse effects of BPs, such as gastric irritation, osteonecrosis of the jaw, atypical femoral fractures, esophageal cancer, atrial fibrillation, and ocular inflammation. In conclusion, this review covers the biochemical and molecular mechanisms of action of BPs in bone, particularly the discovery that BPs have direct anti-apoptotic effects on osteoblasts and osteocytes, and the current situation of BP use in the clinic.

Figure 1

Effects on osteoblasts. BPs can down-regulate “receptor activator of NF-κB ligand” (RANKL) and up-regulate osteoprotegerin (OPG) in osteoblasts, indicating indirect effects on the resorption. BPs can inhibit apoptosis of osteoblasts and osteocytes through Cx43 hemichannels. The opening of Cx43 hemichannels results in the activation of kinases, including Src and “extracellular signal-regulated kinases” (ERKs), which initiates the sequential phosphorylation of the ERK cytoplasmic target, p90RSK kinase, and final target substrates, BAD and C/EBPβ, thus suppressing apoptosis.

Figure 2

Effects on osteoclasts. Osteoclasts release BPs from the bone matrix. N-containing BPs potently inhibit farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate/cholesterol biosynthetic pathway. Non-N-BPs are incorporated metabolically into non-hydrolyzable cytotoxic analogs of ATP (AppCp).