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Prevalence of bisphosphonate-related osteonecrosis of the jaw-like lesions is increased in a chemotherapeutic dose-dependent manner in mice


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タイトル: Prevalence of bisphosphonate-related osteonecrosis of the jaw-like lesions is increased in a chemotherapeutic dose-dependent manner in mice
著者: Kuroshima, Shinichiro / Sasaki, Muneteru / Nakajima, Kazunori / Tamaki, Saki / Hayano, Hiroki / Sawase, Takashi
発行日: 2018年 7月
出版者: Elsevier Inc.
引用: Bone, 112, pp.177-186; 2018
抄録: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) worsens oral health-related quality of life. Most BRONJ occurs in multiple myeloma or metastatic breast cancer patients treated with bisphosphonate/chemotherapeutic combination therapies. Cyclophosphamide (CY), an alkylating chemotherapeutic drug, is used to treat multiple myeloma, although its use has been recently reduced. The aim of this study was to clarify the effects of CY dose on tooth extraction socket healing when CY is used with or without bisphosphonate in mice. Low-dose CY (50 mg/kg; CY-L), moderate-dose CY (100 mg/kg; CY-M), high-dose CY (150 mg/kg; CY-H), and bisphosphonate [Zometa (ZA): 0.05 mg/kg] were administered for 7 weeks. Each dose of CY and ZA in combination was also administered for 7 weeks. Both maxillary first molars were extracted at 3 weeks after the initiation of drug administration. Euthanasia was performed at 4 weeks post-extraction. Gross wound healing, microcomputed tomography analysis, histomorphometry, and immunohistochemistry were used to quantitatively evaluate osseous and soft tissue wound healing of tooth extraction sockets. ZA monotherapy induced no BRONJ-like lesions in mice. CY monotherapy rarely induced open wounds, though delayed osseous wound healing occurred in a CY dose-dependent manner. In contrast, CY/ZA combination therapy prevalently induced BRONJ-like lesions with compromised osseous and soft tissue healing in a CY dose-dependent manner. Interestingly, anti-angiogenesis was noted regardless of CY dose and ZA administration, even though only CY-M/ZA and CY-H/ZA combination therapies induced BRONJ-like lesions. Our findings suggest that high-dose CY may be associated with the development of BRONJ following tooth extraction only when CY is used together with ZA. In addition to anti-angiogenesis, other factors may contribute to the pathoetiology of BRONJ.
キーワード: Bisphosphonate-related osteonecrosis of the jaw / Bisphosphonates / Cyclophosphamide / Dose effect / Wound healing
URI: http://hdl.handle.net/10069/38450
ISSN: 87563282
DOI: 10.1016/j.bone.2018.05.001
権利: © 2018 Elsevier Inc. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
資料タイプ: Journal Article
原稿種類: author
出現コレクション:110 学術雑誌論文

引用URI : http://hdl.handle.net/10069/38450

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