Bisphosphonates are a class of antiresorptive agents used to treat diseases characterized by osteoclast-mediated bone resorption. Non-nitrogen containing bisphosphonates (such as etidronate) are metabolized into non-functioning ATP analogues which cause eventual osteoclast apoptosis. Nitrogen containing bisphsphonates (alendrolate/Fosamax and Zoledronic acid/Zometa) act by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases.
Reszka et al reviewed nitrogen containing bisphosphonates. They outlined the mechanism of action on farnesyl diphosphate synthase in the cholesterol biosynthesis pathway.
Guo et al also reviewed the mechanism of nitrogen-containing bisphosphonates. In addition to showing the decrease in prenylation of GTPase, they were shown to inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS).
Morris et al reviewed the bisphosphonates currently approved by the FDA. They outlined their use in the treatment of Paget disease, metastatic bone disease and widening applications in OI and fibrous dysplasia.
1,3,4,5: Mechanism of nitrogen-containing bisphosphonates.
Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH. Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29.
PMID:17535895 (Link to Abstract)
Reszka AA, Rodan GA. Nitrogen-containing bisphosphonate mechanism of action. Mini Rev Med Chem. 2004 Sep;4(7):711-9.
PMID:15379639 (Link to Abstract)
Morris CD, Einhorn TA. Bisphosphonates in orthopaedic surgery. J Bone Joint Surg Am. 2005 Jul;87(7):1609-18.
PMID:15995133 (Link to Abstract)