ABSTRACT
Bisphosphonates have been shown to reduce bone turnover by primarily inhibiting osteoclast function. It has been proposed that these drugs can be thought of as working at three levels.27 At the tissue level, they decrease bone turnover via initial inhibition of bone resorption, with suppressed bone formation following as a consequence of this. At the cellular level, bisphosphonates exert their activity principally via actions on osteoclasts, inhibiting their formation, migration, and osteolytic activity, as well as directly inducing apoptosis. It has been shown that bisphosphonates also act partly via modulation of signaling from osteoblasts to osteoclasts (Figure 43.5).28 At the molecular level, the mode of action of bisphosphonates depends on their structure. Non-nitrogen-containing bisphosphonates (in which the R chains contains no N atoms) are metabolized to nonhydrolysable ATP analogs, which become toxic as they accumulate.29
