骨吸収抑制薬 bisphosphonates による顎骨壊死の機序・予防・治療に関する基礎研究

Translated title of the contribution: Basic studies on the mechanism, prevention, and treatment of osteonecrosis of the jaw induced by bisphosphonates

Yasuo Endo, Hiromi Funayama, Kouji Yamaguchi, Yuko Monma, Zhiqian Yu, Xue Deng, Takefumi Oizumi, Yosuke Shikama, Yukinori Tanaka, Satoshi Okada, Siyoung Kim, Tomomi Kiyama, Kanan Bando, Kazuhiro Shima, Hikari Suzuki, Tetsu Takahashi

Research output: Contribution to journalArticle

Abstract

Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is common in elderly women, and bisphosphonates (BPs) are typical and widely used anti-osteoporotic or anti-bone-resorptive drugs. BRONJ is now a serious concern in dentistry. As BPs are pyrophosphate analogues and bind strongly to bone hydroxyapatite, and the P-C-P structure of BPs is nonhydrolysable, they accumulate in bones upon repeated administration. During bone-resorption, BPs are taken into osteoclasts and exhibit cytotoxicity, producing a long-lasting anti-bone-resorptive eŠect. BPs are divided into nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). N-BPs have far stronger anti-bone-resorptive effects than non-N-BPs, and BRONJ is caused by N-BPs. Our murine experiments have revealed the following. N-BPs, but not non-N-BPs, exhibit direct and potent infiammatory/necrotic effects on soft-tissues. These effects are augmented by lipopolysaccharide (the infiammatory component of bacterial cell-walls) and the accumulation of N-BPs in jawbones is augmented by infiammation. N-BPs are taken into soft-tissue cells via phosphate-transporters, while the non-N-BPs etidronate and clodronate inhibit this transportation. Etidronate, but not clodronate, has the effect of expelling N-BPs that have accumulated in bones. Moreover, etidronate and clodronate each have an analgesic effect, while clodronate has an anti-infiammatory effect via inhibition of phosphate-transporters. These findings suggest that BRONJ may be induced by phosphate-transporter-mediated and infection-promoted mechanisms, and that etidronate and clodronate may be useful for preventing and treating BRONJ. Our clinical trials support etidronate being useful for treating BRONJ, although additional clinical trials of etidronate and clodronate are needed.

Translated title of the contributionBasic studies on the mechanism, prevention, and treatment of osteonecrosis of the jaw induced by bisphosphonates
Original languageJapanese
Pages (from-to)63-79
Number of pages17
JournalYakugaku Zasshi
Volume140
Issue number1
DOIs
Publication statusPublished - 2020

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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  • Cite this

    Endo, Y., Funayama, H., Yamaguchi, K., Monma, Y., Yu, Z., Deng, X., Oizumi, T., Shikama, Y., Tanaka, Y., Okada, S., Kim, S., Kiyama, T., Bando, K., Shima, K., Suzuki, H., & Takahashi, T. (2020). 骨吸収抑制薬 bisphosphonates による顎骨壊死の機序・予防・治療に関する基礎研究. Yakugaku Zasshi, 140(1), 63-79. https://doi.org/10.1248/yakushi.19-00125