Cellular and molecular mechanisms of action of bisphosphonates

• Published in: Cancer Vol. 88; no. S12; pp. 2961 - 2978
• Main Authors: Rogers, Michael J., Gordon, S., Benford, H. L., Coxon, F. P., Luckman, S. P., Monkkonen, J., Frith, J. C.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 15-06-2000
• Subjects: Animals; apoptosis; ATP; bisphosphonates; Bone and Bones - drug effects; bone resorption; Bone Resorption - drug therapy; Diphosphonates - pharmacokinetics; Diphosphonates - pharmacology; Humans; mevalonate; osteoblast; Osteoblasts - drug effects; osteoclast; Osteoclasts - drug effects; prenylation; Protein Prenylation - drug effects; Protein Tyrosine Phosphatases - antagonists & inhibitors; Proton-Translocating ATPases - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/1097-0142(20000615)88:12+<2961::AID-CNCR12>3.0.CO;2-L

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. Cancer 2000;88:2961–78. © 2000 American Cancer Society.
Bisphosphonates are an important class of drugs used to inhibit bone resorption in tumor‐associated bone disease. Recent studies have identified two distinct classes of bisphosphonates with different molecular mechanisms of action, involving either inhibition of protein prenylation or the formation of cytotoxic metabolites in osteoclasts.