Advertisement

Osteoporosis International

, Volume 30, Issue 1, pp 231–239 | Cite as

Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study

  • T. HasegawaEmail author
  • S. Hayashida
  • E. Kondo
  • Y. Takeda
  • H. Miyamoto
  • Y. Kawaoka
  • N. Ueda
  • E. Iwata
  • H. Nakahara
  • M. Kobayashi
  • S. Soutome
  • SI. Yamada
  • I. Tojyo
  • Y. Kojima
  • M. Umeda
  • S. Fujita
  • H. Kurita
  • Y. Shibuya
  • T. Kirita
  • T. Komori
  • Japanese Study Group of Co-operative Dentistry with Medicine (JCDM)
Original Article

Abstract

Summary

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents.

Introduction

No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure–related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab.

Methods

Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed.

Results

We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ.

Conclusions

Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Keywords

Bisphosphonate Denosumab Discontinuation Drug holiday MRONJ 

Notes

Acknowledgements

We thank Rebecca Tollefson, DVM, from the Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

Compliance with ethical standards

Conflicts of interest

None.

Supplementary material

198_2018_4746_MOESM1_ESM.doc (140 kb)
Supplemental Table 1 (DOC 139 kb)

References

  1. 1.
    Berenson JR, Rajdev L, Broder M (2006) Treatment strategies for skeletal complications of cancer. Cancer Biol Ther 5:1074–1077CrossRefGoogle Scholar
  2. 2.
    Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822CrossRefGoogle Scholar
  3. 3.
    Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117CrossRefGoogle Scholar
  4. 4.
    Yoshimura H, Ohba S, Yoshida H, Saito K, Inui K, Yasui R, Ichikawa D, Aiki M, Kobayashi J, Matsuda S, Imamura Y, Sano K (2017) Denosumab-related osteonecrosis of the jaw in a patient with bone metastases of prostate cancer: a case report and literature review. Oncol Lett 14:127–136CrossRefGoogle Scholar
  5. 5.
    Cartsos VM, Zhu S, Zavras AI (2008) Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people. J Am Dent Assoc 139:23–30CrossRefGoogle Scholar
  6. 6.
    Doggrell SA (2002) Zoledronate once-yearly increases bone mineral density—implications for osteoporosis. Expert Opin Pharmacother 3:1007–1009CrossRefGoogle Scholar
  7. 7.
    Lodi G, Sardella A, Salis A, Demarosi F, Tarozzi M, Carrassi A (2010) Tooth extraction in patients taking intravenous bisphosphonates: a preventive protocol and case series. J Oral Maxillofac Surg 68:107–110CrossRefGoogle Scholar
  8. 8.
    Scoletta M, Arata V, Arduino PG, Lerda E, Chiecchio A, Gallesio G, Scully C, Mozzati M (2013) Tooth extractions in intravenous bisphosphonate-treated patients: a refined protocol. J Oral Maxillofac Surg 71:994–999CrossRefGoogle Scholar
  9. 9.
    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 72:1938–1956CrossRefGoogle Scholar
  10. 10.
    Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, Taguchi A, Toyosawa S, Nagata T, Urade M (2010) Bisphosphonate-related osteonecrosis of the jaw: position paper from the allied task force committee of Japanese society for bone and mineral research, Japan Osteoporosis Society, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology, and Japanese Society of Oral and Maxillofacial Surgeons. J Bone Miner Metab 28:365–383CrossRefGoogle Scholar
  11. 11.
    Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel RF, Hortobagyi GN (2008) Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23:826–836CrossRefGoogle Scholar
  12. 12.
    Otto S, Tröltzsch M, Jambrovic V, Panya S, Probst F, Ristow O, Ehrenfeld M, Pautke C (2015) Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development? J Craniomaxillofac Surg 43:847–854CrossRefGoogle Scholar
  13. 13.
    Ferlito S, Puzzo S, Liardo C (2011) Preventive protocol for tooth extractions in patients treated with zoledronate: a case series. J Oral Maxillofac Surg 69:e1–e4CrossRefGoogle Scholar
  14. 14.
    Mozzati M, Arata V, Gallesio G (2012) Tooth extraction in patients on zoledronic acid therapy. Oral Oncol 48:817–821CrossRefGoogle Scholar
  15. 15.
    Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655CrossRefGoogle Scholar
  16. 16.
    Vahtsevanos K, Kyrgidis A, Verrou E, Katodritou E, Triaridis S, Andreadis CG, Boukovinas I, Koloutsos GE, Teleioudis Z, Kitikidou K, Paraskevopoulos P, Zervas K, Antoniades K (2009) Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 27:5356–5362CrossRefGoogle Scholar
  17. 17.
    Saia G, Blandamura S, Bettini G, Tronchet A, Totola A, Bedogni G, Ferronato G, Nocini PF, Bedogni A (2010) Occurrence of bisphosphonate-related osteonecrosis of the jaw after surgical tooth extraction. J Oral Maxillofac Surg 68:797–804CrossRefGoogle Scholar
  18. 18.
    Gaudin E, Seidel L, Bacevic M, Rompen E, Lambert F (2015) Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: a systematic review and meta-analysis. J Clin Periodontol 42:922–932CrossRefGoogle Scholar
  19. 19.
    Migliorati CA, Saunders D, Conlon MS, Ingstad HK, Vaagen P, Palazzolo MJ, Herlofson BB (2013) Assessing the association between bisphosphonate exposure and delayed mucosal healing after tooth extraction. J Am Dent Assoc 144:406–414CrossRefGoogle Scholar
  20. 20.
    O’Connell JE, Ikeagwani O, Kearns GJ (2012) A role for C-terminal cross-linking telopeptide (CTX) level to predict the development of bisphosphonate-related osteonecrosis of the jaws (BRONJ) following oral surgery? Ir J Med Sci 181:237–242CrossRefGoogle Scholar
  21. 21.
    Filleul O, Crompot E, Saussez S (2010) Bisphosphonate-induced osteonecrosis of the jaw: a review of 2,400 patient cases. J Cancer Res Clin Oncol 136:1117–1124CrossRefGoogle Scholar
  22. 22.
    Saad F, Brown JE, Van Poznak C et al (2012) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23:1341–1347CrossRefGoogle Scholar
  23. 23.
    Yamazaki T, Yamori M, Ishizaki T, Asai K, Goto K, Takahashi K, Nakayama T, Bessho K (2012) Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. Int J Oral Maxillofac Surg 41:1397–1403CrossRefGoogle Scholar
  24. 24.
    Kajizono M, Sada H, Sugiura Y, Soga Y, Kitamura Y, Matsuoka J, Sendo T (2015) Incidence and risk factors of osteonecrosis of the jaw in advanced cancer patients after treatment with zoledronic acid or denosumab: a retrospective cohort study. Biol Pharm Bull 38:1850–1855CrossRefGoogle Scholar
  25. 25.
    Katsarelis H, Shah NP, Dhariwal DK, Pazianas M (2015) Infection and medication-related osteonecrosis of the jaw. J Dent Res 94:534–539CrossRefGoogle Scholar
  26. 26.
    Pazianas M (2011) Osteonecrosis of the jaw and the role of macrophages. J Natl Cancer Inst 103:232–240CrossRefGoogle Scholar
  27. 27.
    Soutome S, Hayashida S, Funahara M, Sakamoto Y, Kojima Y, Yanamoto S, Umeda M (2018) Factors affecting development of medication-related osteonecrosis of the jaw in cancer patients receiving high-dose bisphosphonate or denosumab therapy: is tooth extraction a risk factor? PLoS One 13:e0201343CrossRefGoogle Scholar
  28. 28.
    Bodem JP, Kargus S, Eckstein S, Saure D, Engel M, Hoffmann J, Freudlsperger C (2015) Incidence of bisphosphonate-related osteonecrosis of the jaw in high-risk patients undergoing surgical tooth extraction. J Craniomaxillofac Surg 43:510–514CrossRefGoogle Scholar
  29. 29.
    Hasegawa T, Kawakita A, Ueda N, Japanese Study Group of Cooperative Dentistry with Medicine (JCDM) (2017) A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ? Osteoporos Int 28:2465–2473CrossRefGoogle Scholar
  30. 30.
    Ensrud KE, Barrett-Connor EL, Schwartz A, Santora AC, Bauer DC, Suryawanshi S, Feldstein A, Haskell WL, Hochberg MC, Torner JC, Lombardi A, Black DM, for the Fracture Intervention Trial Long-Term Extension Research Group (2004) Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J Bone Miner Res 19:1259–1269CrossRefGoogle Scholar
  31. 31.
    Van den Wyngaert T, Huizing MT, Fossion E, Vermorken JB (2009) Bisphosphonates in oncology: rising stars or fallen heroes. Oncologist 14:181–191CrossRefGoogle Scholar
  32. 32.
    Huja SS, Fernandez SA, Hill KJ, Li Y (2006) Remodeling dynamics in the alveolar process in skeletally mature dogs. Anat Rec A Discov Mol Cell Evol Biol 288:1243–1249CrossRefGoogle Scholar
  33. 33.
    Ferlito S, Liardo C, Puzzo S (2010) Dental extractions in patient treated with intravenous bisphosphonates and risk of osteonecrosis of jaws: presentation of a preventive protocol and case series. Minerva Stomatol 59:593–601Google Scholar
  34. 34.
    Heufelder MJ, Hendricks J, Remmerbach T, Frerich B, Hemprich A, Wilde F (2014) Principles of oral surgery for prevention of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 117:e429–e435CrossRefGoogle Scholar
  35. 35.
    Hayashida S, Soutome S, Yanamoto S, Fujita S, Hasegawa T, Komori T, Kojima Y, Miyamoto H, Shibuya Y, Ueda N, Kirita T, Nakahara H, Shinohara M, Umeda M (2017) Evaluation of the treatment strategies for medication-related osteonecrosis of the jaws (MRONJ) and the factors affecting treatment outcome: a multicenter retrospective study with propensity score matching analysis. J Bone Miner Res 32:2022–2029CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  • T. Hasegawa
    • 1
    Email author
  • S. Hayashida
    • 2
  • E. Kondo
    • 3
  • Y. Takeda
    • 4
  • H. Miyamoto
    • 5
  • Y. Kawaoka
    • 6
  • N. Ueda
    • 7
  • E. Iwata
    • 1
    • 8
  • H. Nakahara
    • 9
  • M. Kobayashi
    • 10
  • S. Soutome
    • 2
  • SI. Yamada
    • 3
  • I. Tojyo
    • 4
  • Y. Kojima
    • 6
  • M. Umeda
    • 2
  • S. Fujita
    • 4
  • H. Kurita
    • 3
  • Y. Shibuya
    • 5
  • T. Kirita
    • 7
  • T. Komori
    • 1
  • Japanese Study Group of Co-operative Dentistry with Medicine (JCDM)
  1. 1.Department of Oral and Maxillofacial SurgeryKobe University Graduate School of MedicineKobeJapan
  2. 2.Department of Clinical Oral OncologyNagasaki University Graduate School of Biomedical SciencesNagasakiJapan
  3. 3.Department of Dentistry and Oral SurgeryShinshu University School of MedicineMatsumotoJapan
  4. 4.Department of Oral and Maxillofacial SurgeryWakayama Medical UniversityWakayamaJapan
  5. 5.Department of Oral Maxillofacial SurgeryNagoya City University Graduate School of Medical SciencesNagoyaJapan
  6. 6.Department of Dentistry and Oral SurgeryKansai Medical UniversityHirakataJapan
  7. 7.Department of Oral and Maxillofacial SurgeryNara Medical UniversityKashiharaJapan
  8. 8.Department of Oral and Maxillofacial SurgeryKakogawa Central City HospitalKakogawaJapan
  9. 9.Department of Oral and Maxillofacial SurgeryOsaka City University Graduate School of MedicineOsakaJapan
  10. 10.Department of Oral and Maxillofacial SurgeryShin-Suma General HospitalKobeJapan

Personalised recommendations