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Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton


Bisphosphonates (BP) are a class of calcium-binding drug used to prevent bone resorption in skeletal disorders such as osteoporosis and metastatic bone disease. They act by selectively targeting bone-resorbing osteoclasts and can be grouped into two classes depending on their intracellular mechanisms of action. Simple BPs cause osteoclast apoptosis after cytoplasmic conversion into toxic ATP analogues. In contrast, nitrogen-containing BPs potently inhibit FPP synthase, an enzyme of the mevalonate (cholesterol biosynthesis) pathway. This results in production of a toxic metabolite (ApppI) and the loss of long-chain isoprenoid lipids required for protein prenylation, a process necessary for the function of small GTPase proteins essential for the survival and activity of osteoclasts. In this review we provide a state-of-the-art overview of these mechanisms of action and a historical perspective of how they were discovered. Finally, we challenge the long-held dogma that BPs act only in the skeleton and highlight recent studies that reveal insights into hitherto unknown effects on tumour-associated and tissue-resident macrophages.

Type Journal
ISBN 1873-2763 (Electronic) 1873-2763 (Linking)
Authors Rogers, M. J.; Monkkonen, J.; Munoz, M. A.
Responsible Garvan Author Prof Mike Rogers
Publisher Name BONE
Published Date 2020-10-01
Published Volume 139
Published Pages 115493
Status Published in-print
DOI 10.1016/j.bone.2020.115493
URL link to publisher's version