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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: Nov 2017. | This topic last updated: May 08, 2017.
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