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Pharmacology of bisphosphonates

Harold N Rosen, MD
Section Editor
Clifford J Rosen, MD
Deputy Editor
Jean E Mulder, MD


This topic review provides an overview of the pharmacology of the bisphosphonates and of the differences between the preparations that are either currently available or undergoing clinical testing. Because bisphosphonates inhibit bone resorption, they are used in the treatment of hypercalcemia, osteoporosis, metastatic bone disease, and Paget disease. These uses are discussed separately.


Bisphosphonates all have in common the P-C-P structure, which is similar to the P-O-P structure of native pyrophosphate (figure 1) [1]. Bisphosphonates differ from each other only at the two "R" groups in the accompanying figures (figure 1 and figure 2). Alendronate, neridronate, ibandronate, pamidronate, risedronate, and zoledronic acid have a nitrogen group and are called nitrogen-containing bisphosphonates in contrast to etidronate and tiludronate, which do not (figure 2).

Mechanism of action — The bisphosphonates inhibit osteoclastic bone resorption via a mechanism that differs from that of other antiresorptive agents [2-4]. Bisphosphonates attach to hydroxyapatite binding sites on bony surfaces, especially surfaces undergoing active resorption. When osteoclasts begin to resorb bone that is impregnated with bisphosphonate, the bisphosphonate released during resorption impairs the ability of the osteoclasts to form the ruffled border, to adhere to the bony surface, and to produce the protons necessary for continued bone resorption [2,3,5]. Bisphosphonates also reduce osteoclast activity by decreasing osteoclast progenitor development and recruitment and by promoting osteoclast apoptosis [6].

In addition to their inhibitory effect on osteoclasts, bisphosphonates appear to have a beneficial effect on osteoblasts. In a murine model of glucocorticoid-induced osteoporosis, bisphosphonates prevented osteocyte and osteoblast apoptosis [7]. The mechanism of this effect involves connexin 43, a gap junction protein that facilitates activation of protein kinases. This anti-apoptotic effect, however, probably does not contribute significantly to the anti-osteoporotic efficacy of bisphosphonates, above their potent antiresorptive actions.

Bone formation is often reduced by bisphosphonates, which is probably an indirect effect of inhibition of bone resorption. In normal bone remodeling, bone resorption and formation are coupled. Changes in resorption drive formation, so, when bone resorption decreases, bone formation also decreases. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Remodeling'.)

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Literature review current through: Sep 2017. | This topic last updated: May 08, 2017.
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  1. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 2008; 83:1032.
  2. Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest 1996; 97:2692.
  3. Sato M, Grasser W, Endo N, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructure. J Clin Invest 1991; 88:2095.
  4. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998; 19:80.
  5. Colucci S, Minielli V, Zambonin G, et al. Alendronate reduces adhesion of human osteoclast-like cells to bone and bone protein-coated surfaces. Calcif Tissue Int 1998; 63:230.
  6. Hughes DE, Wright KR, Uy HL, et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995; 10:1478.
  7. Plotkin LI, Lezcano V, Thostenson J, et al. Connexin 43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts in vivo. J Bone Miner Res 2008; 23:1712.
  8. van beek E, Löwik C, van der Pluijm G, Papapoulos S. The role of geranylgeranylation in bone resorption and its suppression by bisphosphonates in fetal bone explants in vitro: A clue to the mechanism of action of nitrogen-containing bisphosphonates. J Bone Miner Res 1999; 14:722.
  9. Rogers MJ. From molds and macrophages to mevalonate: a decade of progress in understanding the molecular mode of action of bisphosphonates. Calcif Tissue Int 2004; 75:451.
  10. Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics 2007; 119 Suppl 2:S150.
  11. Dunford JE. Molecular targets of the nitrogen containing bisphosphonates: the molecular pharmacology of prenyl synthase inhibition. Curr Pharm Des 2010; 16:2961.
  12. Dunford JE, Thompson K, Coxon FP, et al. Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 2001; 296:235.
  13. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008; 19:733.
  14. Chavassieux PM, Arlot ME, Reda C, et al. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 1997; 100:1475.
  15. Fleisch H. Pharmacokinetics. In: Bisphosphonates in Bone Disease: From the Laboratory to the Patient, University of Berne, Berne, Switzerland 1993. p.50.