Abstract
Bisphosphonates (BPs), powerful anti-bone-resorptive drugs, are effective at treating various diseases involving enhanced bone resorption. However, recent clinical applications have disclosed an unexpected side effect, osteonecrosis of the jaw bone and its subsequent exposure. This bisphosphonaterelated osteonecrosis of the jaw (BRONJ) occurs after repeated treatments with nitrogen-containing bisphosphonates (NBPs).However, there is no clear evidence that clodronate and etidronate (nonnitrogen-containing bisphosphonates : non-NBPs) induce BRONJ. Concerning the inflammatory side effects of BPs, we found the followings. (i) Intravenous injection of LPS into mice induces the histamine-forming enzyme histidine decarboxylase in the mandible,and this induction is markedly augmented in NBP-treated mice. (ii) A single intraperitoneal injection of a BP into young mice induces a clear sclerotic band (tentatively called “BP-band”) in the tibia, which is detectable by radiography a few weeks after the injection, reflecting inhibition of bone-resorption. (iii) Clodronate, when injected together with an NBP, reduces or prevents the inflammatory effects of the NBP, but not its anti-bone-resorptive effect. (iv) Coadministration of etidronate with an NBP inhibits both of the inflammatory and anti-bone-resorptive effects of the NBP. (v) Subcutaneous injection of NBPs into ear pinnas of mice induces inflammation and necrosis at the site of the injection. Clodronate and etidronate, when injected together with an NBP, reduces or prevents the inflammatory and necrotic effects of the NBP, whereas LPS enhances these reactions. These findings, together with those of previous studies, suggest that there are mutual augmentations between oral LPS and NBPs in inflammatory and necrotic effects. Clodronate could be useful as a combination drug with an NBP for preventing their necrotic actions while retaining their anti-bone-resorptive effects. Etidronate could be useful as a substitution drug for NBPs for preventing BRONJ or reducing its risk.
