Mechanisms of action of bisphosphonates

• Published in: Annual review of pharmacology and toxicology 1998-01, Vol.38 (1), p.375-388
• Main Author: Rodan, G A
• Format: Article
• Language: English
• Subjects: Animals; Bone and Bones - cytology; Bone and Bones - drug effects; Diphosphonates - pharmacology; Diphosphonates - therapeutic use; Humans; Osteoporosis - drug therapy
• ISSN: 0362-1642; 1545-4304
• DOI: 10.1146/annurev.pharmtox.38.1.375

Bisphosphonates (BPs) are pyrophosphate analogs in which the oxygen bridge has been replaced by carbon and diverse carbon side chains have generated a large family of compounds. Several are potent inhibitors of bone destruction (resorption) and are in clinical use for the treatment and prevention of osteoporosis, Paget's disease, hypercalcemia caused by malignancy, tumor metastases in bone, and other bone ailments. Selective action on bone is based on the binding of the BP moiety to the bone mineral. The molecular mode of action of BPs, which may differ from compound to compound, is unknown. However, at the tissue level, all BPs inhibit bone destruction and lead to an increase in bone mineral density by decreasing bone resorption and bone turnover. At the cellular level, the ultimate target of BP action is the osteoclast, the bone resorbing cell. In vitro evidence shows BP inhibition of osteoclast formation, via action on osteoblasts, and there is in vitro and in vivo evidence for BP inhibition of osteoclast activity. There is in vivo and in vitro evidence for increased apoptosis. The relative contribution of these various effects on the therapeutic action of BPs remains to be established. At the molecular level, it is not known if BPs act on a single or multiple targets. Enzymes in the cholesterol biosynthesis pathway and protein tyrosine phosphatases were shown to be inhibited by BPs.