Incidence of osteonecrosis of the jaw in Japanese osteoporosis patients taking minodronic acid

  • Akira TaguchiEmail author
  • Yukari Uemura
  • Takumi Imai
  • Shiro Tanaka
  • Hiroaki Ohta
  • Toshitaka Nakamura
  • Hajime Orimo
  • Toshitsugu Sugimoto
  • Satoshi Soen
  • Masataka Shiraki
  • Adequate Treatment of Osteoporosis (A-TOP) research group
Original Article


Osteonecrosis of the jaw (ONJ) associated with bisphosphonate therapy is a rare but severe side effect in osteoporosis patients. Recently, the number of osteoporosis patients with ONJ has dramatically increased in Japan. This has contributed to an increase in the number of patients avoiding extractions. However, there has been no prospective study providing definitive incidence data for ONJ in Japanese patients. The purpose of this study was to elucidate the true as well as suspected incidence of ONJ. A total of 3229 subjects (1612 subjects in the minodronic acid group and 1617 subjects in the raloxifene group) in the Japanese Osteoporosis Intervention Trial protocol number 4 participated in this study. ONJ was diagnosed by experienced dentists. Suspected Stage 0 and 1 (bone exposure of the jaw) ONJ was assessed by a structured questionnaire at baseline and at 6, 12, 18, and 24 months. No established ONJ cases were diagnosed during the study. The incidence of suspected Stage 0 and/or Stage 1 ONJ was 6.14 per 1000 patient-years in the minodronic acid group and 3.38 per 1000 patient-years in the raloxifene group [hazard ratio (95% confidence interval) = 1.82 (0.84–3.93), P = 0.13]. Approximately 50–60% of bone exposures that appeared during the study had disappeared at the next observation. Although the subjects in this study may have developed a greater interest in the health of the oral cavity, the incidence of ONJ after minodronic acid treatment would be lower than the expected incident rate.


Osteonecrosis Jaw Osteoporosis Antiresorptives Bone exposure 



The authors express their thanks to the chairman, Dr Rikushi Morita, and the members of the ethics committee, Ms Mamiko Matsumura, Dr Tetsuro Inoue, Dr Isao Yoshimura, Dr Mitsuyoshi Nakajima, Tooru Ebihara RPh, and Mr Shinya Hattori. The authors would also like to thank those who participated as clinical investigators in JOINT-04. This JOINT study was sponsored by the Public Health Research Foundation. This study was also supported in part by funding from the Project Promoting Clinical Trials for Development of New Drugs (17lk0201061h0002) from the AMED (Japan Agency for Medical Research and Development) to ST. We thank Helen Jeays, BDSc AE, from Edanz Group ( for editing a draft of this manuscript.

Compliance with ethical standards

Conflict of interest

AT received consultancy or lecture fees from Asahikasei Pharmaceutical Co., Teijin Pharma, Ono Pharmaceutical Co., Chugai Pharmaceutical Co., Takeda Pharmaceutical Co., and Daiichi Sankyo Co. YU received a consultancy fee from Teijin Pharma. ST has received lecture fees from Astra-Zeneca, Taiho, and Ono Pharmaceutical Co. He has received consultation fees from DeNA Life Science and CanBus. He has received outsourcing fees from Satt and Asahi Kasei Pharma. His wife has been engaged in a research project for Bayer. HO received fees from Pfizer Japan Inc. TS has received research grants from Astellas Pharma, Eisai, Daiichi Sankyo, Chugai Pharmaceutical, and Eli Lilly Japan as well as consulting and/or lecture fees from Asahi Kasei Pharma and Daiichi Sankyo. SS received lecture and consultancy fees from Asahikasei Pharmaceutical Co., Astellas Pharma, Chugai Pharmaceutical Co., Daiichi Sankyo Co., Eisai Co., Eli Lilly Japan, Ono Pharmaceutical Co., Pfizer Co., and Takeda Pharmaceutical Co. MS received lecture and consultancy fees from Asahikasei Pharma and Teijin Pharma. TI, TN, and HO declare that they have no conflict of interest.

Human and animal rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  • Akira Taguchi
    • 1
    • 10
    Email author
  • Yukari Uemura
    • 2
  • Takumi Imai
    • 3
  • Shiro Tanaka
    • 3
  • Hiroaki Ohta
    • 4
  • Toshitaka Nakamura
    • 5
  • Hajime Orimo
    • 6
  • Toshitsugu Sugimoto
    • 7
  • Satoshi Soen
    • 8
  • Masataka Shiraki
    • 9
  • Adequate Treatment of Osteoporosis (A-TOP) research group
  1. 1.Department of Oral and Maxillofacial Radiology, School of DentistryMatsumoto Dental UniversityShiojiriJapan
  2. 2.Biostatistics Division, Central Coordinating Unit, Clinical Research Support CenterThe University of Tokyo HospitalTokyoJapan
  3. 3.Department of Clinical Biostatistics/Clinical Biostatistics Course, Graduate School of MedicineKyoto UniversityKyotoJapan
  4. 4.Clinical Medical Research CenterInternational University of Health and Welfare, Women’s Medical Center, Sanno Medical CenterTokyoJapan
  5. 5.Touto Sangenjaya Rehabilitation HospitalTokyoJapan
  6. 6.Japan Osteoporosis FoundationTokyoJapan
  7. 7.Internal Medicine 1Shimane University Faculty of MedicineIzumoJapan
  8. 8.Department of Orthopaedic Surgery and RheumatologyKindai University Nara HospitalIkomaJapan
  9. 9.Department of Internal MedicineResearch Institute and Practice for Involutional DiseasesAzuminoJapan
  10. 10.Department of Hard Tissue Research, Graduate School of Oral MedicineMatsumoto Dental UniversityShiojiriJapan

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