Abstract:
BACKGROUND:Bisphosphonates currently are the most important class of antiresorptive agents used in the treatment of metabolic bone diseases, including tumor-associated osteolysis and hypercalcemia, Paget's disease, and osteoporosis. These compounds have high affinity for calcium and therefore target to bone mineral, where they appear to be internalized selectively by bone-resorbing osteoclasts and inhibit osteoclast function. METHODS:This article reviews the pharmacology of bisphosphonates and the relation between the chemical structure of bisphosphonates and antiresorptive potency, and describes recent new discoveries of their molecular mechanisms of action in osteoclasts. RESULTS:Bisphosphonates can be grouped into two pharmacologic classes with distinct molecular mechanisms of action. Nitrogen-containing bisphosphonates (the most potent class) act by inhibiting the mevalonate pathway in osteoclasts, thereby preventing prenylation of small GTPase signaling proteins required for osteoclast function. Bisphosphonates that lack a nitrogen in the chemical structure do not inhibit protein prenylation and have a different mode of action that may involve the formation of cytotoxic metabolites in osteoclasts or inhibition of protein tyrosine phosphatases. CONCLUSIONS:Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect osteoclasts. After more than 30 years of clinical use, their molecular mechanisms of action are only just becoming clear.
journal_name
Cancerjournal_title
Cancerauthors
Rogers MJ,Gordon S,Benford HL,Coxon FP,Luckman SP,Monkkonen J,Frith JCdoi
10.1002/1097-0142(20000615)88:12+<2961::aid-cncr12subject
Has Abstractpub_date
2000-06-15 00:00:00pages
2961-78issue
12 Suppleissn
0008-543Xissn
1097-0142pii
10.1002/1097-0142(20000615)88:12+<2961::AID-CNCR12journal_volume
88pub_type
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