Skip to main content

Advertisement

SpringerLink
Log in

Reliability of early stage symptoms/clinical findings of osteonecrosis of the jaw: Japanese Osteoporosis Intervention Trial-05 (JOINT-05)

  • Original Article
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Introduction

To investigate the differences in the incidence rates of suspected stage 0/1 osteonecrosis of the jaw (ONJ) and incidence risk of relevant clinical findings of suspected stage 0 ONJ between patients treated with sequential therapy comprising weekly teriparatide for 72 weeks followed by alendronate for 48 weeks vs. those who received monotherapy with alendronate for 120 weeks.

Materials and methods

Suspected stage 0/1 ONJ was defined by non-specific symptoms. Tooth mobility and periodontal symptoms (gingival bleeding, swelling, and/or pain) were selected as clinical findings of suspected stage 0 ONJ. Poisson regression models were applied to calculate the incidence rate ratios of suspected stage 0/1 between the teriparatide group (TG) and alendronate group (AG). Generalized linear models were used to calculate the risk ratios of clinical findings between groups.

Results

Two hundred and sixty-one participants in the TG and 344 in the AG answered a structured questionnaire on oral health and were included in this study. There were no significant differences between the groups in the incidence rate of suspected stage 0/1 ONJ at both 72 and 120 weeks. The risk ratio of the TG to AG for tooth mobility was 0.34 (95% confidence interval [CI] 0.13–0.88, p = 0.02) at 72 weeks and 0.90 (95% CI 0.40–2.03, p = 0.83) at 120 weeks. The incidence rate of tooth mobility related to periodontal symptoms decreased in the TG and increased in the AG during the study.

Conclusion

Tooth mobility accompanied by clinical periodontal symptoms may be a useful early sign of stage 0 ONJ.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117

    Article  PubMed  Google Scholar 

  2. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62:527–534

    Article  PubMed  Google Scholar 

  3. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28:5132–5139

    Article  CAS  PubMed  Google Scholar 

  4. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F, American Association of Oral and Maxillofacial Surgeons (2014) American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw–2014 update. J Oral Maxillofac Surg 72:1938–1956

    Article  PubMed  Google Scholar 

  5. Advisory Task Force on Bisphosphonate-Related Osteonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons (2007) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369–376

    Article  Google Scholar 

  6. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B, American Association of Oral and Maxillofacial Surgeons (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws–2009 update. J Oral Maxillofac Surg 67:2–12

    PubMed  Google Scholar 

  7. Fedele S, Porter SR, D’Aiuto F, Aljohani S, Vescovi P, Manfredi M, Arduino PG, Broccoletti R, Musciotto A, Di Fede O, Lazarovici TS, Campisi G, Yarom N (2010) Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 123:1060–1064

    Article  CAS  PubMed  Google Scholar 

  8. Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, Reid IR, Ruggiero SL, Taguchi A, Tetradis S, Watts NB (2015) Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 30:3–23

    Article  PubMed  Google Scholar 

  9. Taguchi A, Uemura Y, Imai T, Tanaka S, Ohta H, Nakamura T, Orimo H, Sugimoto T, Soen S, Shiraki M, Adequate Treatment of Osteoporosis (A-TOP) research group (2019) Incidence of osteonecrosis of the jaw in Japanese osteoporosis patients taking minodronic acid. J Bone Miner Metab 37:886–892

    Article  CAS  PubMed  Google Scholar 

  10. Ohbayashi Y, Iwasaki A, Nakai F, Mashiba T, Miyake M (2020) A comparative effectiveness pilot study of teriparatide for medication-related osteonecrosis of the jaw: daily versus weekly administration. Osteoporos Int 31:577–585

    Article  CAS  PubMed  Google Scholar 

  11. Dos Santos FL, Abreu LG, Calderipe CB, Martins MD, Schuch LF, Vasconcelos ACU (2021) Is teriparatide therapy effective for medication-related osteonecrosis of the jaw? A systematic review and meta-analysis. Osteoporos Int 32:2449–2459

    Article  Google Scholar 

  12. Tanaka S, Mori S, Hagino H, Sugimoto T (2020) Design of a randomized trial of teriparatide followed by alendronate: Japanese Osteoporosis Intervention Trial-05 (JOINT-05). J Bone Miner Metab 38:412–417

    Article  CAS  PubMed  Google Scholar 

  13. Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D (2022) American Association of Oral and Maxillofacial Surgeons’ position paper on medication-related osteonecrosis of the jaws–2022 update. J Oral Maxillofac Surg 80:920–943

    Article  PubMed  Google Scholar 

  14. Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, Taguchi A, Nagata T, Urade M, Shibahara T, Toyosawa S, Japanese Allied Committee on Osteonecrosis of the Jaw (2017) Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw. J Bone Miner Metab 35:6–19

    Article  CAS  PubMed  Google Scholar 

  15. Patel S, Choyee S, Uyanne J, Nguyen AL, Lee P, Sedghizadeh PP, Kumar SK, Lytle J, Shi S, Le AD (2012) Non-exposed bisphosphonate-related osteonecrosis of the jaw: a critical assessment of current definition, staging, and treatment guidelines. Oral Dis 18:625–632

    Article  CAS  PubMed  Google Scholar 

  16. Fedele S, Bedogni G, Scoletta M, Favia G, Colella G, Agrillo A, Bettini G, Di Fede O, Oteri G, Fusco V, Gabriele M, Ottolenghi L, Valsecchi S, Porter S, Fung PP, Saia G, Campisi G, Bedogni A (2015) Up to a quarter of patients with osteonecrosis of the jaw associated with antiresorptive agents remain undiagnosed. Br J Oral Maxillofac Surg 53:13–17

    Article  PubMed  Google Scholar 

  17. Bedogni A, Blandamura S, Lokmic Z, Palumbo C, Ragazzo M, Ferrari F, Tregnaghi A, Pietrogrande F, Procopio O, Saia G, Ferretti M, Bedogni G, Chiarini L, Ferronato G, Ninfo V, Lo Russo L, Lo Muzio L, Nocini PF (2008) Bisphosphonate-associated jawbone osteonecrosis: a correlation between imaging techniques and histopathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 105:358–364

    Article  PubMed  Google Scholar 

  18. Kunihara T, Tohmori H, Tsukamoto M, Kobayashi M, Okumura T, Teramoto H, Hamasaki T, Yamasaki T, Nakagawa T, Okimoto N, Fujiwara S (2023) Incidence and trend of antiresorptive agent-related osteonecrosis of the jaw from 2016 to 2020 in Kure, Japan. Osteoporos Int. https://doi.org/10.1007/s00198-023-06732-8

    Article  PubMed  PubMed Central  Google Scholar 

  19. Xu S, Zhang G, Guo JF, Tan YH (2021) Associations between osteoporosis and risk of periodontitis: a pooled analysis of observational studies. Oral Dis 27:357–369

    Article  PubMed  Google Scholar 

  20. Katz J, Rotstein I (2021) Prevalence of periapical lesions in patients with osteoporosis. J Endod 47:234–238

    Article  PubMed  Google Scholar 

  21. Taguchi A, Kamimura M, Nakamura Y, Sugino N, Ichinose A, Maezumi H, Fukuzawa T, Ashizawa R, Takahara K, Gushiken S, Mukaiyama K, Ikegami S, Uchiyama S, Kato H (2016) Delayed wound healing after tooth extraction and self-reported kyphosis in Japanese men and women. Sci Rep 6:36309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Taguchi A, Ikegami S, Tokida R, Kamimura M, Sakai N, Horiuchi H, Takahashi J, Kato H (2020) Fragility fractures and delayed wound healing after tooth extraction in Japanese older adults. J Bone Miner Metab 38:357–362

    Article  PubMed  Google Scholar 

  23. Beth-Tasdogan NH, Mayer B, Hussein H, Zolk O, Peter JU (2022) Interventions for managing medication-related osteonecrosis of the jaw. Cochrane Database Syst Rev 7:CD012432

    PubMed  Google Scholar 

  24. Taguchi A, Hagino H, Inoue D, Endo N, Society JO (2023) Cooperation between physicians and dentists for osteonecrosis of the jaw: a 2022 Japanese survey. J Bone Miner Metab. https://doi.org/10.1007/s00774-023-01458-3

    Article  PubMed  Google Scholar 

  25. Penoni DC, Leão ATT, Torres SR, Farias MLF, Fernandes TM, Crivelli M, Vettore MV (2018) Effects of bone fragility and antiresorptive drugs on periodontal disease and tooth loss: a longitudinal study. JDR Clin Trans Res 3:378–387

    CAS  PubMed  Google Scholar 

  26. Taguchi A, Shiraki M, Tanaka S, Ohshige H, Nakamura T (2019) Improved periodontal disease and prevention of tooth loss in osteoporosis patients receiving once-yearly zoledronic acid: a randomized clinical trial. Menopause 26:1277–1283

    Article  PubMed  Google Scholar 

  27. Bashutski JD, Eber RM, Kinney JS, Benavides E, Maitra S, Braun TM, Giannobile WV, McCauley LK (2010) Teriparatide and osseous regeneration in the oral cavity. N Engl J Med 363:2396–2405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the clinical investigators in the JOINT-05, members of the central ethics committee, and members of the data monitoring committee. The authors would also like to express their sincere thanks to the chairman, Dr. Itsuo Gorai, and the members of the central ethics committee for the JOINT trials. Finally, the authors thank Mr. Teruhiko Miyazaki and Ms. Yuko Iwata for their secretarial help, and Kelly Zammit, BVSc, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript.

Funding

This Japanese Osteoporosis Intervention Trial-05 (JOINT-05) study was sponsored by the Public Health Research Foundation. This study was also supported in part by funding through the Project Promoting Clinical Trials for Development of New Drugs (19lk0201061t0004) from the Japan Agency for Medical Research and Development (AMED) to Shiro Tanaka and partially funded by Japan Society for the Promotion of Science (JSPS) KAKENHI grants provided to A.T. (grant nos. 21K09885 and 22K10208).

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Radiology, School of Dentistry, Matsumoto Dental University, 1780 Hirooka Gobara, Shiojiri, Nagano, 399-0781, Japan

    Akira Taguchi

  2. Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Shiro Tanaka

  3. Clinical Biostatistics Course, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Tatsuro Ozaki & Koshiro Arai

  4. Bone and Joint Surgery, Seirei Hamamatsu General Hospital, Shizuoka, 430-8558, Japan

    Satoshi Mori

  5. Kawasaki Medical School General Medical Center, 2-6-1 Nakayama-shita, Kita-ku, Okayama, 700-8505, Japan

    Hiroaki Ohta

  6. Department of Rehabilitation, Sanin Rosai Hospital, 1-8-1 Shinden, Kaike, Tottori, 683-8605, Japan

    Hiroshi Hagino

  7. Department of Orthopaedic Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Sakae Tanaka

  8. Department of Internal Medicine, Research Institute and Practice for Involutional Diseases, 1610-1 Meisei, Misato, Azumino, Nagano, 399-8101, Japan

    Masataka Shiraki

  9. Japan Osteoporosis Foundation, 2-14 Odenmacho, Nihonbashi, Chuo-ku, Tokyo, 103-11, Japan

    Toshitaka Nakamura

  10. Soen Orthopaedics, Osteoporosis and Rheumatology Clinic, 2-14-10 Okamoto, Higashinada-ku, Kobe, Hyogo, 658-0072, Japan

    Satoshi Soen

  11. Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University, 1780 Gobara, Hirooka, Shiojiri, Nagano, 399-0781, Japan

    Akira Taguchi

Authors
  1. Akira Taguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shiro Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatsuro Ozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koshiro Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Satoshi Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hiroaki Ohta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hiroshi Hagino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sakae Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masataka Shiraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Toshitaka Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Satoshi Soen
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Adequate Treatment of Osteoporosis (A-TOP) Research Group

Contributions

AT: conceptualization, methodology, validation, formal analysis, investigation, resources, writing—original draft, writing—review and editing, and funding acquisition. ST: methodology, software, formal analysis, writing—original draft. TO: methodology, software, formal analysis. KA: methodology, software, formal analysis. SM: conceptualization, methodology, validation, project administration, writing—review and editing. HO: investigation, resources, data curation, visualization, project administration, writing—review and editing. HH: conceptualization, methodology, validation, project administration, writing—review and editing. ST: conceptualization, methodology, validation, project administration, writing—review and editing. MS: investigation, visualization, project administration, writing—review and editing. TN: conceptualization, methodology, investigation, writing—review and editing. SS: conceptualization, methodology, validation, project administration, writing—review and editing.

Corresponding author

Correspondence to Akira Taguchi.

Ethics declarations

Conflict of interest

A. Taguchi has received lecture fees from Asahi Kasei Pharma Corp., Daiichi Sankyo Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Teijin Pharma Ltd. He has received a consultation fee from Media Corp. Ltd. Shiro Tanaka has received lecture fees from Bayer Yakuhin, Amgen Astellas BioPharma K.K., and the Research Institute of Healthcare Data Science. He has received consultation fees and outsourcing fees from Daiichi Sankyo Company, Limited, Boehringer Ingelheim, Satt, and the Public Health Research Foundation. He has received research grants from the Japan Agency for Medical Research and Development, the Japanese Ministry of Health Labor and Welfare, the Japanese Ministry of Education, Science, and Technology, and Novo Nordisk. He engaged in a research project of the Japan Agency for Medical Research and Development. H. Hagino has received lecture fees or grants outside the submitted work from Amgen Inc., Asahi Kasei Pharma Corp., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mochida Pharma Corp., Taisho Pharmaceutical Co., Ltd., Teijin Pharma Co., Ltd., and UCB Japan. S. Soen has received consulting fees, speaking fees, and/or honoraria from Amgen, Asahi Kasei Pharma, Astellas Pharma, Chugai, Daiichi Sankyo, Eisai, Ono, Teijin Pharma, and UCB Japan. T. Ozaki, K. Arai, S. Mori, H. Ohta, Sakae Tanaka, M. Shiraki, and T. Nakamura have no conflicts of interests.

Ethics approval

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. The protocol of the Japanese Osteoporosis Intervention Trial-05 (JOINT-05) was approved by the certified review board of Toranomon Hospital and the central ethics committee of the Adequate Treatment of Osteoporosis (A-TOP) research group.

Consent to participate

All patients provided written informed consent.

Consent for publication

All patients provided written informed consent.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Taguchi, A., Tanaka, S., Ozaki, T. et al. Reliability of early stage symptoms/clinical findings of osteonecrosis of the jaw: Japanese Osteoporosis Intervention Trial-05 (JOINT-05). J Bone Miner Metab 41, 854–864 (2023). https://doi.org/10.1007/s00774-023-01466-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-023-01466-3

Keywords

Search

Navigation