Bisphosphonates
- 1 April 2006
- journal article
- review article
- Published by Wiley in Annals of the New York Academy of Sciences
- Vol. 1068 (1), 367-401
- https://doi.org/10.1196/annals.1346.041
Abstract
Abstract: The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating journey that is still not over. In clinical medicine, several BPs are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate, and are resistant to breakdown by enzymatic hydrolysis. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone‐resorbing osteoclasts. Bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non‐nitrogen‐containing bisphosphonates (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate (ATP) that may inhibit ATP‐dependent intracellular enzymes. The more potent, nitrogen‐containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate, and zoledronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTP‐binding proteins (which are also GTPases) such as rab, rho, and rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explain the loss of osteoclast activity and induction of apoptosis. The key target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS) within osteoclasts, and the recently elucidated crystal structure of this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, and their mode of action is being unraveled. As a result their full therapeutic potential is gradually being realized.This publication has 183 references indexed in Scilit:
- Genetics of Paget's disease of boneClinical Science, 2005
- Zoledronic acid improves femoral head sphericity in a rat model of perthes diseaseJournal of Orthopaedic Research, 2005
- Effect of pamidronate on bone turnover and implant migration after total hip arthroplasty: A randomized trialJournal of Orthopaedic Research, 2005
- 31P NMR of Apicomplexans and the Effects of Risedronate on Cryptosporidium parvum GrowthBiochemical and Biophysical Research Communications, 2001
- Nitrogen-Containing Bisphosphonates as Carbocation Transition State Analogs for Isoprenoid BiosynthesisBiochemical and Biophysical Research Communications, 1999
- Nitrogen-Containing Bisphosphonates Inhibit Isopentenyl Pyrophosphate Isomerase/Farnesyl Pyrophosphate Synthase Activity with Relative Potencies Corresponding to Their Antiresorptive Potenciesin Vitroandin VivoBiochemical and Biophysical Research Communications, 1999
- A randomized trial of the effect of clodronate on skeletal morbidity in multiple myelomaBritish Journal of Haematology, 1998
- Metabolism of halogenated bisphosphonates by the cellular slime mould dictyostelium discoideumBiochemical and Biophysical Research Communications, 1992
- Effect of Intermittent Cyclical Etidronate Therapy on Bone Mass and Fracture Rate in Women with Postmenopausal OsteoporosisNew England Journal of Medicine, 1990
- The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivoCalcified Tissue International, 1968