Underlying mechanisms and therapeutic strategies for bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Y Endo, H Kumamoto, M Nakamura… - Biological and …, 2017 - jstage.jst.go.jp
Y Endo, H Kumamoto, M Nakamura, S Sugawara, T Takano-Yamamoto, K Sasaki…
Biological and Pharmaceutical Bulletin, 2017jstage.jst.go.jp
Bisphosphonates (BPs), with a non-hydrolysable PCP structure, are cytotoxic analogues of
pyrophosphate, bind strongly to bone, are taken into osteoclasts during bone-resorption and
exhibit long-acting anti-bone-resorptive effects. Among the BPs, nitrogen-containing BPs (N-
BPs) have far stronger anti-bone-resorptive effects than non-N-BPs. In addition to their
pyrogenic and digestive-organ-injuring side effects, BP-related osteonecrosis of jaws
(BRONJ), mostly caused by N-BPs, has been a serious concern since 2003. The mechanism …
Abstract
Bisphosphonates (BPs), with a non-hydrolysable PCP structure, are cytotoxic analogues of pyrophosphate, bind strongly to bone, are taken into osteoclasts during bone-resorption and exhibit long-acting anti-bone-resorptive effects. Among the BPs, nitrogen-containing BPs (N-BPs) have far stronger anti-bone-resorptive effects than non-N-BPs. In addition to their pyrogenic and digestive-organ-injuring side effects, BP-related osteonecrosis of jaws (BRONJ), mostly caused by N-BPs, has been a serious concern since 2003. The mechanism underlying BRONJ has proved difficult to unravel, and there are no solid strategies for treating and/or preventing BRONJ. Our mouse experiments have yielded the following results.(a) N-BPs, but not non-N-BPs, exhibit direct inflammatory and/or necrotic effects on soft tissues.(b) These effects are augmented by lipopolysaccharide, a bacterial-cell-wall component.(c) N-BPs are transported into cells via phosphate transporters.(d) The non-N-BPs etidronate (Eti) and clodronate (Clo) competitively inhibit this transportation (potencies, Clo> Eti) and reduce and/or prevent the N-BP-induced inflammation and/or necrosis.(e) Eti, but not Clo, can expel N-BPs that have accumulated within bones.(f) Eti and Clo each have an analgesic effect (potencies, Clo> Eti) via inhibition of phosphate transporters involved in pain transmission. From these findings, we propose that phosphate-transporter-mediated and inflammation/infection-promoted mechanisms underlie BRONJ. To treat and/or prevent BRONJ, we propose (i) Eti as a substitution drug for N-BPs and (ii) Clo as a combination drug with N-BPs while retaining their anti-bone-resorptive effects. Our clinical trials support this role for Eti (we cannot perform such trials using Clo because Clo is not clinically approved in Japan).
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