Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Risk factors influencing the duration of treatment with bisphosphonates until occurrence of an osteonecrosis of the jaw in 963 cancer patients

Abstract

Objective

Osteonecrosis of the jaw (ONJ) is an adverse effect that is associated with bisphosphonate (BP) use. Little data are available on risk factors influencing the time of treatment until an osteonecrosis occurs.

Methods

From 1 Dec 2004 until 21 Sep 2012, the German Register collected all patients with validated diagnoses of ONJ (N = 1,229) that were reported to the national pharmaco-vigilance system or to the Register directly. We analysed 963 patients with cancerous disease and an ONJ during i.v. BP treatment. Duration of BP treatment until first diagnosis of ONJ and Kaplan–Meier curves of ONJ-free survival were analysed stratified by gender, type of BP and type of cancer.

Results

Main indications for BP treatment were breast cancer (36 %), multiple myeloma (24 %), prostate cancer (16 %) and kidney cancer (4 %). Men suffered from their ONJ earlier than women. A total of 780 patients (81 %) had their ONJ during zoledronate treatment, 93 (10 %) under pamidronate and 90 (9 %) under ibandronate treatment. ONJ-free survival in single BP users was significantly longer in pamidronate-treated patients than in zoledronate or ibandronate users. Ibandronate users had the shortest median duration of treatment (17 months), similar to that of zoledronate users (21.5 months). Sequential prescription of two different BPs prolonged the period of overall BP treatment until an ONJ occurred. Time of BP treatment was shortest in patients with kidney cancer. Age or a concomitant osteoporosis did not influence the time to event of an ONJ.

Conclusion

Systemic risk factors such as gender play a significant role in certain subgroups only. Comparative analysis of different cancer patients helps the treating oncologist/dentist to identify patients with a more imminent risk to develop an ONJ (i.e. kidney cancer, ibandronate/zoledronate use).

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Bamias A et al (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–8587. doi:10.1200/JCO.2005.02.8670

  2. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G (2008) Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 44:857–869

  3. 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 139:23–30

  4. Clines GA, Guise TA (2004) Mechanisms and treatment for bone metastases. Clin Adv Hematol Oncol 2:295–302

  5. Corso A, Varettoni M, Zappasodi P, Klersy C, Mangiacavalli S, Pica G, Lazzarino M (2007) A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma. Leukemia 21:1545–1548

  6. EU Law Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010. http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/dir_2010_84_en.pdf. http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/dir_2010_84_en.pdf. Accessed 27 June 2014

  7. Dodson TB (2009) Intravenous bisphosphonate therapy and bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:44–52. doi:10.1016/j.joms.2008.12.004

  8. Durie BG, Katz M, Crowley J (2005) Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 353:99–102 discussion 199–102

  9. Ebetino FH et al (2011) The relationship between the chemistry and biological activity of the bisphosphonates. Bone 49:20–33. doi:10.1016/j.bone.2011.03.774

  10. FDA (2014) US Food and Drug Administration. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed 09 September 2014

  11. Federal Statistical Office. German Statistical Yearbook 2014. https://www.destatis.de. Accessed 03 July 2014

  12. Felsenberg D, Lopez S, Gabbert T, Hoffmeister B (2012) Osteonecrosis of the jaw in patients with osteoporosis. Osteologie 21:207–212

  13. Hadji P, Gnant M, Aapro M, Lipton A, Coleman R (2011) Dosing of zoledronic acid throughout the treatment continuum in breast cancer. Crit Rev Oncol Hematol 79:175–188. doi:10.1016/j.critrevonc.2010.07.017

  14. Hoff AO et al (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. doi:10.1359/jbmr.080205

  15. Hoff AO, Toth B, Hu M, Hortobagyi GN, Gagel RF (2011) Epidemiology and risk factors for osteonecrosis of the jaw in cancer patients. Ann NY Acad Sci 1218:47–54. doi:10.1111/j.1749-6632.2010.05771.x

  16. Hoffmann F, Jung TI, Felsenberg D, Glaeske G (2008) Pattern of intravenous bisphosphonate use in outpatient care in Germany. Pharmacoepidemiol Drug Saf 17:896–903. doi:10.1002/pds.1634

  17. Jadu F, Lee L, Pharoah M, Reece D, Wang L (2007) A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients. Ann Oncol 18:2015–2019. doi:10.1093/annonc/mdm370

  18. Jung TI, Hoffmann F, Glaeske G, Felsenberg D (2010) Disease-specific risk for an osteonecrosis of the jaw under bisphosphonate therapy. J Cancer Res Clin Oncol 136:363–370. doi:10.1007/s00432-009-0662-9

  19. Kruger TB, Sharikabad MN, Herlofson BB (2013) Bisphosphonate-related osteonecrosis of the jaw in four Nordic countries and an indication of under-reporting. Acta Odontol Scand 71:1386–1390. doi:10.3109/00016357.2013.764007

  20. McKay RR, Lin X, Perkins JJ, Heng DY, Simantov R, Choueiri TK (2014) Prognostic Significance of Bone Metastases and Bisphosphonate Therapy in Patients with Renal Cell Carcinoma. Eur Urol. doi:10.1016/j.eururo.2014.02.040

  21. Rote Liste Rote Liste Service GmbH. www.rote-liste.de. Accessed 27 June 2014

  22. Rugani P, Luschin G, Jakse N, Kirnbauer B, Lang U, Acham S (2014) Prevalence of bisphosphonate-associated osteonecrosis of the jaw after intravenous zoledronate infusions in patients with early breast cancer. Clin Oral Invest 18:401–407. doi:10.1007/s00784-013-1012-5

  23. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B (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. doi:10.1016/j.joms.2009.01.009

  24. Scher HI, Motzer RJ (2005) Bladder and renal cell carcinomas. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL (eds) Harrison’s principles of internal medicine, vol I, 16th edn. McGraw-Hill Companies, New York, pp 541–543

  25. Shapiro CL (2013) Bisphosphonate-related osteonecrosis of jaw in the adjuvant breast cancer setting: risks and perspective. J Clin Oncol 31:2648–2650. doi:10.1200/JCO.2013.48.6837

  26. Sharma D et al. (2013) Bisphosphonate-related osteonecrosis of jaw (BRONJ): diagnostic criteria and possible pathogenic mechanisms of an unexpected anti-angiogenic side effect Vascular cell 5:1 doi:10.1186/2045-824X-5-1

  27. Ulmner M, Jarnbring F, Torring O (2014) Osteonecrosis of the jaw in Sweden associated with the oral use of bisphosphonate. J Oral Maxillofac Surg 72:76–82. doi:10.1016/j.joms.2013.06.221

  28. Walter C et al (2008) Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate. Eur Urol 54:1066–1072. doi:10.1016/j.eururo.2008.06.070

  29. Wessel JH, Dodson TB, Zavras AI (2008) Zoledronate, smoking, and obesity are strong risk factors for osteonecrosis of the jaw: a case-control study. J Oral Maxillofac Surg 66:625–631. doi:10.1016/j.joms.2007.11.032

  30. Wilkinson GS, Kuo YF, Freeman JL, Goodwin JS (2007) Intravenous bisphosphonate therapy and inflammatory conditions or surgery of the jaw: a population-based analysis. J Natl Cancer Inst 99:1016–1024

Download references

Acknowledgments

We thank Stefanie Lopez-Schueler for help with data entry and file organisation and Juliane Luettke (Dipl. Biomathematician) for help with statistical analysis and interpretation. This work was partially supported by the non-profit ‘Elsbeth Bonhoff Foundation’ and by the ‘Centre of Muscle and Bone Research (ZMK)’.

Conflict of interest

The Centre of Muscle and Bone Research (ZMK) received funding to finance clinical studies from several pharmaceutical companies in the past (Bayer, Amgen, Anwerina, Novartis, Procter and Gamble, Roche, MSD, Sanofi-Aventis, TEVA, Chugai, Lilly, Servier).

Author information

Correspondence to Tatjana I. Gabbert.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gabbert, T.I., Hoffmeister, B. & Felsenberg, D. Risk factors influencing the duration of treatment with bisphosphonates until occurrence of an osteonecrosis of the jaw in 963 cancer patients. J Cancer Res Clin Oncol 141, 749–758 (2015). https://doi.org/10.1007/s00432-014-1853-6

Download citation

Keywords

  • Bisphosphonates
  • Osteonecrosis of the jaw
  • Cancer
  • Kidney
  • Ibandronate
  • Germany