[Basic Studies on the Mechanism, Prevention, and Treatment of Osteonecrosis of the Jaw Induced by Bisphosphonates].

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 non-hydrolysable, 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 effect. 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 inflammatory/necrotic effects on soft-tissues. These effects are augmented by lipopolysaccharide (the inflammatory component of bacterial cell-walls) and the accumulation of N-BPs in jawbones is augmented by inflammation. 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-inflammatory 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.

• Authors: 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
• Journal: Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan (Yakugaku Zasshi) Vol. 140 Issue 1 Pg. 63-79 ( 2020) ISSN: 1347-5231 [Electronic] Japan
• PMID: 31902887 (Publication Type: Journal Article, Review)

Chemical References

• Bone Density Conservation Agents
• Diphosphonates
• Phosphate Transport Proteins
• Clodronic Acid
• Etidronic Acid
• Nitrogen

Topics

• Animals
• Bisphosphonate-Associated Osteonecrosis of the Jaw (drug therapy, etiology, prevention & control)
• Bone Density Conservation Agents (adverse effects, metabolism, therapeutic use)
• Clinical Trials as Topic
• Clodronic Acid (chemistry, metabolism, pharmacology, therapeutic use)
• Diphosphonates (adverse effects, chemistry, metabolism, therapeutic use)
• Etidronic Acid (chemistry, metabolism, pharmacology, therapeutic use)
• Humans
• Inflammation
• Jaw (metabolism)
• Mice
• Nitrogen
• Phosphate Transport Proteins (antagonists & inhibitors)
• Rats