Cellular and molecular mechanisms of action of bisphosphonates.
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.
Rogers
M J
MJ
Department of Medicine and Therapeutics, University of Aberdeen Medical School, Foresterhill, Scotland, United Kingdom.
Gordon
S
S
Benford
H L
HL
Coxon
F P
FP
Luckman
S P
SP
Monkkonen
J
J
Frith
J C
JC
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000187:drug effects; D004164:Diphosphonates / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D017368:Protein Prenylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D004164:Diphosphonates; D017027:Protein Tyrosine Phosphatases; D006180:Proton-Translocating ATPases