Tooth extraction in mice administered zoledronate increases inflammatory cytokine levels and promotes osteonecrosis of the jaw

Tomoya Soma, Ryotaro Iwasaki, Yuiko Sato, Tami Kobayashi, Satoshi Nakamura, Yosuke Kaneko, Eri Ito, Hiroyuki Okada, Hisato Watanabe, Kana Miyamoto, Morio Matsumoto, Masaya Nakamura, Seiji Asoda, Hiromasa Kawana, Taneaki Nakagawa, Takeshi Miyamoto

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Introduction: Osteonecrosis of the jaw (ONJ) occurring after invasive dental treatment often adversely affects patients’ activities of daily living. Long-term administration of strong anti-bone resorptive agents such as bisphosphonates prior to invasive dental treatment is considered an ONJ risk factor; however, pathological mechanisms underlying ONJ development remain unclear. Materials and Methods: We developed an ONJ mouse model in which a tooth is extracted during treatment with the bisphosphonate zoledronate. Results: We observed induction of apoptosis in osteocytes, resulting in formation of empty lacunae in jaw bones at sites of tooth extraction but not in other bones of the same mice. We also observed elevated levels of inflammatory cytokines such as TNFα, IL-6 and IL-1 in jaw bone at the extraction site relative to other sites in zoledronate-treated mice. We also report that treatment in vitro with either zoledronate or an extract from Porphyromonas gingivalis, an oral bacteria, promotes expression of inflammatory cytokines in osteoclast progenitor cells. We demonstrate that gene-targeting of either TNFα, IL-6 or IL-1 or treatment with etanercept, a TNFα inhibitor, or a neutralizing antibody against IL-6 can antagonize ONJ development caused by combined tooth extraction and zoledronate treatment. Conclusions: Taken together, the cytokine storm induced by invasive dental treatment under bisphosphonate treatment promotes ONJ development due to elevated levels of inflammatory cytokine-producing cells. Our work identifies novel targets potentially useful to prevent ONJ.

Original languageEnglish
Pages (from-to)372-384
Number of pages13
JournalJournal of Bone and Mineral Metabolism
Issue number3
Publication statusPublished - 2021 May


  • Bisphosphonate
  • Cytokine
  • Inflammation
  • Osteoclast
  • Osteocyte

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine
  • Endocrinology


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