Bisphosphonates

Abstract

The bisphosphonates (BPs) are well established as the treatments of choice for disorders of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. There is considerable new knowledge about how BPs work. Their classical pharmacological effects appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The inhibitory effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their inhibition of farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids used for the posttranslational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular pathways, such as preventing apoptosis in osteocytes, are emerging as other potentially important mechanisms of action. As a class, BPs share several common properties. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various individual BPs. Each BP has a unique profile that may help to explain potential important clinical differences among the BPs, in terms of speed of onset of fracture reduction, antifracture efficacy at different skeletal sites, and the degree and duration of suppression of bone turnover. As we approach the 40th anniversary of the discovery of their biological effects, there remain further opportunities for using their properties for medical purposes.

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

“…Bisphosphonates, such as zoledronic acid, are in use as effective therapeutic agents for diseases characterized by aberrantly increased bone resorption, including osteoporosis, Paget disease, osteogenesis imperfecta, and bone metastatic tumors in breast cancer, prostate cancer, and multiple myeloma. (57,58) The similarities in the effects of dasatinib and zoledronic acid on trabecular bone architecture observed in this study suggest that dasatinib may be an effective treatment for diseases characterized by increased OC activity.…”

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

“…There also may be additional factors inherent to the specific bisphosphonates. (44) Other studies evaluating combination therapy with teriparatide and bisphosphonates enrolled patients in whom bisphosphonates were given prior to the introduction of teriparatide treatment. In one trial, (23) alendronate was given for only 6 months prior to the introduction of teriparatide.…”

Differences in persistence, safety and efficacy of generic and original branded once weekly bisphosphonates in patients with postmenopausal osteoporosis: 1-year results of a retrospective patient chart review analysis

“…Two chemically distinct groups of bisphosphonates exist: Simple non-nitrogen-containing bisphosphonates (Non-N-BP's, e.g., Etidronate) and nitrogen-containing bisphosphonates (N-BP´s) e.g., Ibandronate, Alendronate, Zoledronate and Risedronate). There are two fundamentally, distinct components of the mechanism of action of nitrogen containing bisphosphonates (N-BPs) [19,20]: These are 1) binding to the bone, and 2) binding to and inhibition of a key osteoclast enzyme farnesyl pyrophosphate synthase (FPPS). Regarding the oral bisphosphonates, only Risedronate and Alendronate have been proven to reduce vertebral and hip fracture risk in clinical trials [8][9][10][11][12][13][14][15][21][22][23][24].…”