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Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study

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A Correction to this article was published on 26 July 2023

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Abstract

Summary

Pre-existing inflammation, corticosteroid therapy, periapical periodontitis, longer duration of denosumab therapy, and female sex were significantly associated with an increased risk of denosumab-related osteonecrosis of the jaw after tooth extraction in patients with cancer on oncologic doses of denosumab. A short drug holiday did not protect against this complication.

Introduction

This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent.

Methods

Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses.

Results

A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not.

Conclusions

These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

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References

  1. 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

    PubMed  Google Scholar 

  2. Otto S, Pautke C, Van den Wyngaert T, Niepel D, Schiødt M (2018) Medication-related osteonecrosis of the jaw: prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat Rev 69:177–187

    PubMed  Google Scholar 

  3. Berenson JR, Rajdev L, Broder M (2006) Treatment strategies for skeletal complications of cancer. Cancer Biol Ther 5:1074–1077

    CAS  PubMed  Google Scholar 

  4. 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 377:813–822

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  6. Migliorati CA (2003) Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 21(22):4253–4254

    PubMed  Google Scholar 

  7. 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 14:127–136

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Mavrokokki T, Cheng A, Stein B, Goss A (2007) Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 65:415–423

    PubMed  Google Scholar 

  9. Kunchur R, Need A, Hughes T, Goss A (2009) Clinical investigation of C-terminal cross-linking telopeptide test in prevention and management of bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 67:1167–1173

    PubMed  Google Scholar 

  10. Hasegawa T, Kawakita A, Ueda N, Funahara R, Tachibana A, Kobayashi M, Kondou E, Takeda D, Kojima Y, Sato S, Yanamoto S, Komatsubara H, Umeda M, Kirita T, Kurita H, Shibuya Y, Komori T, 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 28:2465–2473

    CAS  PubMed  Google Scholar 

  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 23:826–836

    CAS  PubMed  Google Scholar 

  12. Hasegawa T, Hayashida S, Kondo E, Takeda Y, Miyamoto H, Kawaoka Y, Ueda N, Iwata E, Nakahara H, Kobayashi M, Soutome S, Yamada SI, Tojyo I, Kojima Y, Umeda M, Fujita S, Kurita H, Shibuya Y, Kirita T, Komori T, Japanese Study Group of Co-operative Dentistry with Medicine (JCDM) (2019) Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study. Osteoporos Int 30(1):231–239

    CAS  PubMed  Google Scholar 

  13. Brown JP, Fortier M, Frame H, Lalonde A, Papaioannou A, Senikas V, Yuen CK, Osteoporosis Guidelines Committee (2006) Canadian Consensus Conference on osteoporosis, 2006 update. J Obstet Gynaecol Can 28(2 Suppl 1):S95–S112

    PubMed  PubMed Central  Google Scholar 

  14. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, de Boer R, Berardi R, Gascon P, Tonkin KS, Coleman RE, Paterson AH, Gao GM, Kinsey AC, Peterson MC, Jun S (2008) Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res 14(20):6690–6696

    CAS  PubMed  Google Scholar 

  15. Anastasilakis AD, Toulis KA, Polyzos SA, Anastasilakis CD, Makras P (2012) Long-term treatment of osteoporosis: safety and efficacy appraisal of denosumab. Ther Clin Risk Manag 8:295–306

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Amgen, Inc. Prolia (denosumab) prescribing information. 2010 updated 2014

  17. 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(6):649–655

    CAS  PubMed  Google Scholar 

  18. Fizazi K, Lipton A, Mariette X, Body JJ, Rahim Y, Gralow JR, Gao G, Wu L, Sohn W, Jun S (2009) Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27(10):1564–1571

    CAS  PubMed  Google Scholar 

  19. Lipton A, Steger GG, Figueroa J, Alvarado C, Solal-Celigny P, Body JJ, de Boer R, Berardi R, Gascon P, Tonkin KS, Coleman R, Paterson AH, Peterson MC, Fan M, Kinsey A, Jun S (2007) Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol 25(28):4431–4437

    CAS  PubMed  Google Scholar 

  20. Smith MR, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F, Heracek J, Szwedowski M, Ke C, Kupic A, Leder BZ, Goessl C, Denosumab HALT Prostate Cancer Study Group (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361(8):745–755

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, Miller K, Sieber P, Karsh L, Damião R, Tammela TL, Egerdie B, Van Poppel H, Chin J, Morote J, Gómez-Veiga F, Borkowski T, Ye Z, Kupic A, Dansey R, Goessl C (2012) Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 379(9810):39–46

    CAS  PubMed  Google Scholar 

  22. Okuma S, Matsuda Y, Nariai Y, Karino M, Suzuki R, Kanno T (2020) A retrospective observational study of risk factors for denosumab-related osteonecrosis of the jaw in patients with bone metastases from solid cancers. Cancers (Basel) 12(5):1209

    CAS  PubMed  Google Scholar 

  23. Limones A, Sáez-Alcaide LM, Díaz-Parreño SA, Helm A, Bornstein MM, Molinero-Mourelle P (2020) Medication-related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab vs. zoledronic acid: a systematic review and meta-analysis. Med Oral Patol Oral Cir Bucal 25(3):e326–e336

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ueda N, Nakashima C, Aoki K, Shimotsuji H, Nakaue K, Yoshioka H, Kurokawa S, Imai Y, Kirita T (2020) Does inflammatory dental disease affect the development of medication-related osteonecrosis of the jaw in patients using high-dose bone-modifying agents? Clin Oral Investig [Online ahead of print]

  25. Matsumoto A, Sasaki M, Schmelzeisen R, Oyama Y, Mori Y, Voss PJ (2017) Primary wound closure after tooth extraction for prevention of medication-related osteonecrosis of the jaw in patients under denosumab. Clin Oral Investig 21(1):127–134

    PubMed  Google Scholar 

  26. Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, Diel IJ, Takahashi S, Shore N, Henry DH, Barrios CH, Facon T, Senecal F, Fizazi K, Zhou L, Daniels A, Carrière P, Dansey R (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 23:1341–1347

    CAS  PubMed  Google Scholar 

  27. 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 41:1397–1403

    CAS  PubMed  Google Scholar 

  28. 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(7):e0201343

    PubMed  PubMed Central  Google Scholar 

  29. Schwartz S, Joseph C, Iera D, Vu DD (2008) Bisphosphonates, osteonecrosis, osteogenesis imperfecta and dental extractions: a case series. J Can Dent Assoc 74(6):537–542

    PubMed  Google Scholar 

  30. Chahine C, Cheung MS, Head TW, Schwartz S, Glorieux FH, Rauch F (2008) Tooth extraction socket healing in pediatric patients treated with intravenous pamidronate. J Pediatr 153(5):719–720

    CAS  PubMed  Google Scholar 

  31. Guilbeau JM (2002 Sep) (2002) Delayed wound healing with sirolimus after liver transplant. Ann Pharmacother 36(9):1391–1395

    PubMed  Google Scholar 

  32. Cavalli RC, Tambara Filho R, Gomes Rde P, Veronez DA, Slongo J, Rd F (2014) Analysis of the histology of the scar bladder and biochemical parameters of rats with a solitary kidney undergoing immunosuppression with tacrolimus. Acta Cir Bras 29(8):508–514

    PubMed  Google Scholar 

  33. Weinstein RS (2012) Glucocorticoid-induced osteonecrosis. Endocrine 41(2):183–190

    CAS  PubMed  Google Scholar 

  34. Weinstein RS (2012) Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinol Metab Clin N Am 41(3):595–611

    Google Scholar 

  35. Takano-Murakami R, Tokunaga K, Kondo N, Ito T, Kitahara H, Ito M, Endo N (2009) Glucocorticoid inhibits bone regeneration after osteonecrosis of the femoral head in aged female rats. Tohoku J Exp Med 217(1):51–58

    PubMed  Google Scholar 

  36. Aljohani S, Gaudin R, Weiser J, Tröltzsch M, Ehrenfeld M, Kaeppler G, Smeets R, Otto S (2018) Osteonecrosis of the jaw in patients treated with denosumab: a multicenter case series. J Craniomaxillofac Surg 46(9):1515–1525

    PubMed  Google Scholar 

  37. Wong LS, Tay KK, Cheing YL (2015) Osteonecrosis of mandible: a rare complication of long-term steroid use. J Oral Maxillofac Surg Med Pathol 27:255–257

    Google Scholar 

  38. Hoefert S, Yuan A, Munz A, Grimm M, Elayouti A, Reinert S (2017) Clinical course and therapeutic outcomes of operatively and non-operatively managed patients with denosumab-related osteonecrosis of the jaw (DRONJ). J Craniomaxillofac Surg 45(4):570–578

    PubMed  Google Scholar 

  39. Bone HG, Bolognese MA, Yuen CK, Kendler DL, Miller PD, Yang YC, Grazette L, San Martin J, Gallagher JC (2011) Effects of denosumab treatment and discontinuation on BMD and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab 96(4):972–980

    CAS  PubMed  Google Scholar 

  40. Miller PD, Bolognese MA, Lewiecki EM, MR MC, Ding B, Austin M, Liu Y, San Martin J, Amg Bone Loss Study Group (2008) Effect of denosumab on BMD and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 43(2):222–229

    CAS  PubMed  Google Scholar 

  41. Malan J, Ettinger K, Naumann E, Beirne OR (2012) The relationship of denosumab pharmacology and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol 114(6):671–676

    PubMed  Google Scholar 

  42. Taylor KH, Middlefell LS, Mizen KD (2010) Osteonecrosis of the jaws induced by anti-RANK ligand therapy. Br J Oral Maxillofac Surg 48(3):221–223

    CAS  PubMed  Google Scholar 

  43. Hayashida S, Yanamoto S, Fujita S, Hasegawa T, Komori T, Kojima Y, Miyamoto H, Shibuya Y, Ueda N, Kirita T, Nakahara H, Shinohara M, Kondo E, Kurita H, Umeda M (2020) Drug holiday clinical relevance verification for antiresorptive agents in medication-related osteonecrosis cases of the jaw. J Bone Miner Metab 38(1):126–134

    PubMed  Google Scholar 

  44. McClung MR (2016) Cancel the denosumab holiday. Osteoporos Int 27(5):1677–1682

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Editage (https://www.editage.jp/) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    T. Hasegawa, E. Iwata & M. Akashi

  2. Department of Oral and Maxillofacial Surgery, Nara Medical University, Kashihara, Japan

    N. Ueda & T. Kirita

  3. Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Matsumoto, Japan

    SI. Yamada & H. Kurita

  4. Department of Oral and Maxillofacial Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    S. Kato & Y. Shibuya

  5. Department of Oral and Maxillofacial Surgery, Kakogawa Central City Hospital, Kakogawa, Japan

    E. Iwata

  6. Department of Clinical Oral Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    S. Hayashida

  7. Department of Dentistry and Oral Surgery, Kansai Medical University, Hirakata, Japan

    Y. Kojima

  8. Department of Oral and Maxillofacial Surgery, Juntendo University School of Medicine, Tokyo, Japan

    M. Shinohara

  9. Department of Oral and Maxillofacial Surgery, Wakayama Medical University, Wakayama, Japan

    I. Tojo

  10. Department of Oral and Maxillofacial Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan

    H. Nakahara

  11. Department of Preventive Dentistry, Research Field in Dentistry, Medical and Dental Sciences Area, Kagoshima University, Kagoshima, Japan

    T. Yamaguchi

  12. Department of Oral Health, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    S. Soutome

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  1. T. Hasegawa
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Japanese Study Group of Co-operative Dentistry with Medicine (JCDM)

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Correspondence to T. Hasegawa.

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The original online version of this article was revised: In Table 1 of this article, the data (18(46.2) and 54(55.7)) in the columns 2 and 3/row 48 (page 2326) headed “Drug holiday before tooth extraction, yes” were mistakenly listed. The correct expression is 10(40.0) and 18(38.3). In Table 1 of this article, the data (21(53.8) and 43(44.3)) in the column 2 and 3/row 49 (page 2326) headed “Drug holiday before tooth extraction, No” were mistakenly listed. The correct expression is 15(60.0) and 29(61.7). In Table 1 of this article, the data (P value: 0.347) in the column 4 /row 48 (page 2326) were mistakenly listed. The correct expression is 1.000.

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Hasegawa, T., Ueda, N., Yamada, S. et al. Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study. Osteoporos Int 32, 2323–2333 (2021). https://doi.org/10.1007/s00198-021-05995-3

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