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- W3035966048 endingPage "115493" @default.
- W3035966048 startingPage "115493" @default.
- W3035966048 abstract "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." @default.
- W3035966048 created "2020-06-25" @default.
- W3035966048 creator A5020637669 @default.
- W3035966048 creator A5060192149 @default.
- W3035966048 creator A5081312172 @default.
- W3035966048 date "2020-10-01" @default.
- W3035966048 modified "2023-10-13" @default.
- W3035966048 title "Molecular mechanisms of action of bisphosphonates and new insights into their effects outside the skeleton" @default.
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