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Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in urological malignancies: a multi-center retrospective study

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Abstract

Introduction

We evaluated the incidence and risk factors for antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in prostate and kidney cancer patients.

Materials and methods

We retrospectively reviewed the clinical data of 547 patients from 13 hospitals. Prostate and kidney cancer patients with bone metastases who were treated with a bone-modifying agent (BMA) between January 2012 and February 2019 were enrolled. Exclusion criteria were BMA use for hypercalcemia, a lack of clinical data, a follow-up period of less than 28 days and a lack of evaluation by dentists before BMA administration. The diagnosis and staging of ARONJ were done by dentists.

Results

Two-hundred eighteen patients were finally enrolled in the study, including 168 prostate cancer patients and 50 kidney cancer patients. Of them, 49 (29%) prostate cancer patients and 18 (36%) kidney cancer patients needed tooth extraction prior to BMA initiation. The mean follow-up period after BMA initiation was 552.9 ± 424.7 days (mean ± SD). In the cohort, 23% of the patients were diagnosed with ARONJ in the follow-up period. The 1-year cumulative incidences of ARONJ were 9.4% and 15.4% in prostate and kidney cancer patients, respectively. Multivariate analysis indicated that kidney cancer, tooth extraction before BMA and a body mass index (BMI) ≥ 25 kg/m2 were significant predictors for ARONJ.

Conclusion

ARONJ is not a rare adverse event in urological malignancies. Especially, kidney cancer, high BMI patients and who needed tooth extraction before BMA were high risk for developing ARONJ.

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References

  1. Rosen LS, Gordon D, Tchekmedyian S, Yanagihara R, Hirsh V, Krzakowski M, Pawlicki M, de Souza P, Zheng M, Urbanowitz G, Reitsma D, Seaman JJ (2003) Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial––the zoledronic acid lung cancer and other solid tumors study group. J Clin Oncol 21:3150–3157

    Article  CAS  Google Scholar 

  2. Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, Richardson GE, Siena S, Maroto P, Clemens M, Bilynskyy B, Charu V, Beuzeboc P, Rader M, Viniegra M, Saad F, Ke C, Braun A, Jun S (2012) Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48:3082–3092

    Article  CAS  Google Scholar 

  3. NCCN Guideline on Prostate Cancer, Version 2. 2020. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. (Accessed 28 Sept 2020)

  4. Zekri J, Ahmed N, Coleman RE, Hancock BW (2001) The skeletal metastatic complications of renal cell carcinoma. Int J Oncol 19:379–382

    CAS  PubMed  Google Scholar 

  5. Omae K, Tsujimoto Y, Honda M, Kondo T, Tanabe K, Fukuhara S, Furukawa TA (2017) Comparative efficacy and safety of bone-modifying agents for the treatment of bone metastases in patients with advanced renal cell carcinoma: a systematic review and meta-analysis. Oncotarget 8:68890–68898

    Article  Google Scholar 

  6. 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  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

    Article  CAS  Google Scholar 

  8. Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar JR, Koka S, Migliorati CA, Ristic H (2011) Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 142:1243–1251

    Article  CAS  Google Scholar 

  9. 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

    Article  CAS  Google Scholar 

  10. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, Dimopoulos MA (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–8587

    Article  Google Scholar 

  11. Guillot A, Joly C, Barthélémy P, Meriaux E, Negrier S et al (2019) Denosumab toxicity when combined with anti-angiogenic therapies on patients with metastatic renal cell carcinoma: a GETUG study. Clin Genitourin Cancer 17:e38–e43

    Article  Google Scholar 

  12. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, Meiller T (2006) Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24:945–952

    Article  CAS  Google Scholar 

  13. Christodoulou C, Pervena A, Klouvas G, Galani E, Falagas ME, Tsakalos G, Visvikis A, Nikolakopoulou A, Acholos V, Karapanagiotidis G, Batziou E, Skarlos DV (2009) Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone. Oncology 76:209–211

    Article  CAS  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 (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  Google Scholar 

  15. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN (2017) Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377:352–360

    Article  CAS  Google Scholar 

  16. Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ et al (2019) Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 20:1370–1385

    Article  CAS  Google Scholar 

  17. 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 28:365–383

    Article  CAS  Google Scholar 

  18. Skerjanec A, Berenson J, Hsu C, Major P, Miller WH Jr, Ravera C, Schran H, Seaman J, Waldmeier F (2003) The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function. J Clin Pharmacol 43:154–162

    Article  CAS  Google Scholar 

  19. Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48:452–458

    Article  CAS  Google Scholar 

  20. Nakai Y, Kanaki T, Yamamoto A, Tanaka R, Yamamoto Y, Nagahara A, Nakayama M, Kakimoto KI, Ishibashi M, Nishimura K (2020) Antiresorptive agent-related osteonecrosis of the jaw in prostate cancer patients with bone metastasis treated with bone-modifying agents. J Bone Miner Metab. https://doi.org/10.1007/s00774-020-01151-9

    Article  PubMed  Google Scholar 

  21. Eke PI, Borgnakke WS (2000) Genco RJ (2020) Recent epidemiologic trends in periodontitis in the USA. Periodontol 82:257–267

    Article  Google Scholar 

  22. Benzian H, Monse B, Heinrich-Weltzien R, Hobdell M, Mulder J, van Palenstein HW (2011) Untreated severe dental decay: a neglected determinant of low body mass index in 12-year-old Filipino children. BMC Public Health 11:558

    Article  Google Scholar 

  23. Taguchi A, Shiraki M, Morrison A, Khan AA (2017) Antiresorptive agent-related osteonecrosis of the jaw in osteoporosis patients from Asian countries. Osteoporos Sarcopenia 3:64–74

    Article  Google Scholar 

  24. van Cann T, Loyson T, Verbiest A, Clement PM, Bechter O et al (2018) Incidence of medication-related osteonecrosis of the jaw in patients treated with both bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors. Support Care Cancer 26:869–878

    Article  Google Scholar 

  25. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Kay A, Ravaud A (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116:4256–4265

    Article  CAS  Google Scholar 

  26. Koch FP, Walter C, Hansen T, Jäger E, Wagner W (2011) Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg 15:63–66

    Article  Google Scholar 

  27. Matsushita K, Hamaguchi M, Hashimoto M, Yamazaki M, Yamazaki T, Asai K, Yamori M, Bessho K, Toda H, Hasegawa G, Nakamura N, Fukui M (2015) The novel association between red complex of oral microbe and body mass index in healthy Japanese: a population based cross-sectional study. J Clin Biochem Nutr 57:135–139

    Article  Google Scholar 

  28. Adachi N, Kobayashi Y (2020) One-year follow-up study on associations between dental caries, periodontitis, and metabolic syndrome. J Oral Sci 62:52–56

    Article  CAS  Google Scholar 

  29. McGowan K, Ware RS, Acton C, Ivanovski S, Johnson NW (2019) Both non-surgical dental treatment and extractions increase the risk of medication-related osteonecrosis of the jaw: case-control study. Clin Oral Investig 23:3967–3975

    Article  Google Scholar 

  30. Owosho AA, Liang STY, Sax AZ, Wu K, Yom SK, Huryn JM, Estilo CL (2018) Medication-related osteonecrosis of the jaw: An update on the memorial sloan kettering cancer center experience and the role of premedication dental evaluation in prevention. Oral Surg Oral Med Oral Pathol Oral Radiol 125:440–445

    Article  Google Scholar 

  31. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Zheng M (2004) Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96:879–882

    Article  CAS  Google Scholar 

  32. Yokomizo A, Koga H, Shinohara N, Miyahara T, Machida N, Tsukino H, Uozumi J, Nishiyama K, Satoh F, Sakai H, Naito S (2010) Skeletal-related events in urological cancer patients with bone metastasis: a multicenter study in Japan. Int J Urol 17:332–336

    Article  Google Scholar 

  33. Tablazon IL, Howard LE, De Hoedt AM, Aronson WJ, Kane CJ, Amling CL, Cooperberg MR, Terris MK, Freedland SJ, Williams SB (2019) Predictors of skeletal-related events and mortality in men with metastatic, castration-resistant prostate cancer: results from the shared equal access regional cancer hospital (SEARCH) database. Cancer 125:4003–4010

    Article  Google Scholar 

Download references

Acknowledgements

The following urologists conducted data collection: Atsushi Wanifuchi, Daichi Morooka, Hideki Adachi, Kazutaka Maruo, Kimihito Tachikawa, Ko Okabe, Manabu Igarashi, Masanori Shigyo, Nobuo Shinkai, Ryuta Inoue, Shintaro Miyamoto, Shuichi Kato, Takahiro Kirisawa, Takashi Muranaka, Toshihiro Maeda, Tomoyo Kurisu, Yuki Kyoda and Yohei Matsuda. The following dentists conducted diagnosis and staging of ARONJ: Akira Yorozu, Masaki Donen, Makoto Shimanishi, Masuhiko Okada, Shoji Harada, Takayuki Mizuno, Yuuki Akimoto and Yusuke Nakamura. We also thank Mr. Kim Barrymore for his help in correcting the English of this manuscript.

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Authors and Affiliations

  1. Departments of Urology, Oral Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan

    Yasuyuki Sakai, Kohei Hashimoto, Toshiaki Tanaka & Naoya Masumori

  2. Department of Urology, Hakodate Goryoukaku Hospital, 38-3 Goryoukaku, Hakodate, 040-8611, Japan

    Tetsuya Shindo & Atsushi Takahashi

  3. Department of Urology, NTT East Sapporo Hospital, Sapporo, Japan

    Shunsuke Sato & Naoki Itoh

  4. Department of Urology, Sunagawa City Medical Center, Sunagawa, Japan

    Yasuharu Kunishima

  5. Department of Urology, Muroran City General Hospital, Muroran, Japan

    Ryuichi Kato

  6. Department of Urology, Obihiro Kyokai Hospital, Obihiro, Japan

    Manabu Okada

  7. Department of Urology, Steel Memorial Muroran Center, Muroran, Japan

    Hitoshi Tachiki

  8. Department of Urology, Oji General Hospital, Tomakomai, Japan

    Keisuke Taguchi

  9. Department of Urology, JCHO Hokkaido Hospital, Sapporo, Japan

    Akio Takayanagi

  10. Department of Urology, Japanese Red Cross Asahikawa Hospital, Asahikawa, Japan

    Hiroshi Hotta

  11. Department of Urology, Hokkaido Saiseikai Otaru Hospital, Otaru, Japan

    Hiroki Horita

  12. Department of Urology, Takikawa Municipal Hospital, Takikawa, Japan

    Masanori Matsukawa

  13. Department of Urology, Japanese Red Cross Kushiro Hospital, Kushiro, Japan

    Masahiro Matsuki

  14. Oral Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan

    Koyo Nishiyama & Akihiro Miyazaki

Authors
  1. Yasuyuki Sakai
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  2. Tetsuya Shindo
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  6. Ryuichi Kato
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  7. Naoki Itoh
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Contributions

YS: protocol development, data collection and management, data analysis, and manuscript writing. TS: protocol development, data collection and management, data analysis, and manuscript editing. SS: protocol development and data collection. AT: data collection, critical review and revisions. YK: data collection, critical review and revisions. RK: data collection, critical review and revisions. NI: data collection, critical review and revisions. MO: data collection, critical review and revisions. HT: data collection, critical review and revisions. KT: data collection, critical review and revisions. AT: data collection, critical review and revisions. HH: data collection, critical review and revisions. HH: data collection, critical review and revisions. MM: data collection, critical review and revisions. MM: data collection, critical review and revisions. KN: data collection, critical review and revisions. AM: critical review and revisions. KH: critical review and revisions. TT: data analysis, critical review and revisions. NM: project development and manuscript editing.

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Correspondence to Tetsuya Shindo.

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Sakai, Y., Shindo, T., Sato, S. et al. Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) in urological malignancies: a multi-center retrospective study. J Bone Miner Metab 39, 661–667 (2021). https://doi.org/10.1007/s00774-021-01207-4

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  • DOI: https://doi.org/10.1007/s00774-021-01207-4

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