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

Soma, Tomoya; Iwasaki, Ryuichiro; Sato, Yuiko; Kobayashi, Tami; Kaneko, Yosuke; Ito, Eri; Okada, H.; Watanabe, Hironosuke; Miyamoto, Kana; Matsumoto, Morio; Nakamura, Masaya; Asoda, Seiji; Kawana, Hiromasa; Nakagawa, Taneaki; Miyamoto, Takeshi

doi:10.1007/s00774-020-01174-2

Cited by 20 publications

(27 citation statements)

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“…ONJ development in mice is induced by tooth extraction during administration of zoledronate 17 , 24 – 26 . Here, we administered zoledronate to wild-type mice once a week for 2 weeks before tooth extraction, and continued treatment on a weekly basis thereafter for 6 weeks (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…2 a–c). Elevation of inflammatory cytokine levels reportedly promotes osteonecrosis development 12 , 17 . Thus, we asked whether treatment with vitamin D analogues could reverse the zoledronate effects in osteoclast progenitors.…”

Section: Resultsmentioning

confidence: 99%

“…Thus preventive treatments are needed. ONJ develops due to an inflammatory cytokine storm induced by anti-resorptive agents, local infection, tooth extraction or any combination of these conditions 17 , 35 , 36 . We show here that ONJ can be prevented in mice by either active vitamin D analogues, anti-inflammatory drugs or antibiotics, all of which inhibit inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

“…We previously showed that inflammatory cytokine expression is inhibited by RANKL treatment of cultured osteoclast progenitor cells but stimulated by treatment with anti-resorptive agents or bacterial infection, even in the presence of RANKL 17 . Inflammatory cytokine levels, which likely underlie ONJ development, also increase following invasive dental treatment, such as tooth extraction, or oral bacterial infection 17 . As a result, those cytokine levels likely reach or exceed threshold levels necessary to induce osteocyte apoptosis 17 .…”

Section: Discussionmentioning

confidence: 99%

“…Recently we developed an animal model in which ONJ is induced by tooth extraction in mice treated with zoledronate, a bisphosphonate used to treat patients with bone metastasis or osteoporosis 14 – 16 . Using that model, we previously reported that the inflammatory cytokine storm underlying ONJ development was significantly inhibited by either targeting inflammatory cytokines such as TNFα, IL-6 or IL-1, or treatment with the TNFα inhibitor etanercept or a neutralizing IL-6 antibody 17 . However, such reagents are expensive, and their use in prevention of rare ONJ development is impractical.…”

Section: Introductionmentioning

confidence: 99%

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Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics

Soma

Iwasaki

Sato

et al. 2022

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Invasive dental treatment such as tooth extraction following treatment with strong anti-bone resorptive agents, including bisphosphonates and denosumab, reportedly promotes osteonecrosis of the jaw (ONJ) at the extraction site, but strategies to prevent ONJ remain unclear. Here we show that in mice, administration of either active vitamin D analogues, antibiotics or anti-inflammatory agents can prevent ONJ development induced by tooth extraction during treatment with the bisphosphonate zoledronate. Specifically, tooth extraction during treatment with zoledronate induced osteonecrosis in mice, but administration of either 1,25(OH)2D3 or ED71, both active vitamin D analogues, significantly antagonized osteonecrosis development, even under continuous zoledronate treatment. 1,25(OH)2D3 or ED71 administration also significantly inhibited osteocyte apoptosis induced by tooth extraction and bisphosphonate treatment. Administration of either active vitamin D analogue significantly inhibited elevation of serum inflammatory cytokine levels in mice in response to injection of lipopolysaccharide, an infection mimetic. Furthermore, administration of either anti-inflammatory or antibiotic reagents significantly blocked ONJ development following tooth extraction and zoledronate treatment. These findings suggest that administration of active vitamin D, anti-inflammatory agents or antibiotics could prevent ONJ development induced by tooth extraction in patients treated with zoledronate.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics

Soma

Iwasaki

Sato

et al. 2022

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Pathophysiology of Medication‐Related Osteonecrosis of the Jaw—A Minireview

2023

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Medication‐related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect of antiresorptive medications administered for control of osseous malignancy, osteoporosis, or other bone metabolic diseases. Despite being reported in the literature two decades ago, MRONJ etiology, pathophysiology, and progression remain largely unknown, and current nonoperative or operative treatment strategies are mostly empirical. Several hypotheses that attempt to explain the mechanisms of MRONJ pathogenesis have been proposed. However, none of these hypotheses alone is able to capture the complex mechanistic underpinnings of the disease. In this minireview, we aim to highlight key findings from clinical and translational studies and propose a unifying model for the pathogenesis and progression of MRONJ. We also identify aspects of the disease process that require further investigation and suggest areas for future research efforts toward calibrating methodologic approaches and validating experimental findings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Medication-related osteonecrosis of the jaw: evolving research for multimodality medical management

Abdolrahmani,

Epstein,

Samim

2024

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

Cited by 20 publications

References 52 publications

Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics

Osteonecrosis development by tooth extraction in zoledronate treated mice is inhibited by active vitamin D analogues, anti-inflammatory agents or antibiotics

Pathophysiology of Medication‐Related Osteonecrosis of the Jaw—A Minireview

Medication-related osteonecrosis of the jaw: evolving research for multimodality medical management

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