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Adjudication of osteonecrosis of the jaw in phase III randomized controlled trials of denosumab: a systematic review

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Abstract

Purpose

Denosumab (an anti RANKL antibody) is known to be associated with an increased risk for osteonecrosis of the jaw (ONJ). Due to the variety of clinical presentation, many ONJ definitions are used. Evaluation of ONJ’s frequency during phase III randomized controlled trials (RCTs) is crucial to assess benefit-risk ratio. We verified that phase III RCTs involving denosumab reported the definition of ONJ used.

Methods

We systematically searched in Central, Medline, Cochrane, and Scopus, until 31 August 2015. We included original phase III RCTs, involving denosumab. Post hoc analysis and trial extension were excluded. Articles that did not mention ONJ in their methods or results were excluded. The primary outcome was the prevalence of a complete definition of ONJ. When no definition was provided, ONJ adjudication process was analyzed.

Results

Of 313 articles found, 13 RCTs were included. A definition of ONJ was detailed in two RCTs (15%). For the remaining 11 RCTs, adjudication process was mentioned for nine. In those processes, “blinded,” “expert,” and “independent” were the most used words.

Conclusion

Most of the published phase III RCTs involving denosumab did not specify the definition of ONJ used to adjudicate events in the study. Instead of definition, non-scientific and non-reproducible expressions were used. Because the chosen definition could impact the ONJ estimated frequency, it should be mandatory to give the precise definition used in each RCT publication involving denosumab.

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References

  1. Delmas PD (2008) Clinical potential of RANKL inhibition for the management of postmenopausal osteoporosis and other metabolic bone diseases. J Clin Densitom 11:325–338

    Article  PubMed  Google Scholar 

  2. U.S. Food and Drug Administration (2010) Press announcements: FDA approves new injectable osteoporosis treatment for postmenopausal women. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm214150.htm Accessed 02 Jan 2017

  3. European Medicines Agency (2010) Prolia. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001120/human_med_001324.jsp&mid=WC0b01ac058001d124. Accessed 02 Jan 2017

  4. U.S. Food and Drug Administration (2010) Press announcements: FDA approves Xgeva to help prevent cancer-related bone injury. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm234346.htm Accessed 02 Jan 2017

  5. European Medicines Agency (2011) Xgeva. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002173/human_med_001463.jsp&mid=WC0b01ac058001d124. Accessed 02 Jan 2017

  6. European Medicines Agency (2011) Assessment report for Xgeva. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002173/WC500110384.pdf. Accessed 02 Jan 2017

  7. U.S. Food and Drug Administration (2010) Prolia risk evaluation and mitigation strategy. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandproviders/UCM214383.pdf. Accessed 02 Jan 2017

  8. U.S. Food and Drug Administration (2013) Xgeva (denosumab) label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125320s094lbl.pdf. Accessed 02 Jan 2017

  9. Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS et al (2011) American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 29:1221–1227

    Article  CAS  PubMed  Google Scholar 

  10. Schiodt M, Reibel J, Oturai P, Kofod T (2014) Comparison of nonexposed and exposed bisphosphonate-induced osteonecrosis of the jaws: a retrospective analysis from the Copenhagen cohort and a proposal for an updated classification system. Oral Surg Oral Med Oral Pathol Oral Radiol 117:204–213

    Article  PubMed  Google Scholar 

  11. Junquera L, Gallego L (2008) Nonexposed bisphosphonate-related osteonecrosis of the jaws: another clinical variant? J Oral Maxillofac Surg 66:1516–1517

    Article  PubMed  Google Scholar 

  12. Mawardi H, Treister N, Richardson P, Anderson K, Munshi N, Faiella RA et al (2009) Sinus tracts—an early sign of bisphosphonate-associated osteonecrosis of the jaws? J Oral Maxillofac Surg 67:593–601

    Article  PubMed  Google Scholar 

  13. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B et al (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 

  14. Bedogni A, Fusco V, Agrillo A, Campisi G (2012) Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ). Oral Dis 18:621–623

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bedogni A, Fedele S, Bedogni G, Scoletta M, Favia G, Colella G et al (2014) Staging of osteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease. Br J Oral Maxillofac Surg 52:603–608

    Article  PubMed  Google Scholar 

  16. U.S. Food and Drug Administration: The drug development process—step 3: clinical research. http://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm. Accessed 02 Jan 2017

  17. Gnant M, all ABCSG-18 investigators (2015) Denosumab and fracture risk in women with breast cancer—author’s reply. Lancet 386:2057–2058

    Article  PubMed  Google Scholar 

  18. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269

    Article  PubMed  Google Scholar 

  19. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR et al (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765

    Article  CAS  PubMed  Google Scholar 

  20. Smith MR, Egerdie B, Toriz NH, Feldman R, Tammela TLJ, Saad F et al (2009) Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 361:745–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stopeck AT, Lipton A, Body J-J, Steger GG, Tonkin K, de Boer RH et al (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 

  22. Kendler DL, McClung MR, Freemantle N, Lillestol M, Moffett AH, Borenstein J et al (2011) Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate. Osteoporos Int 22:1725–1735

    Article  CAS  PubMed  Google Scholar 

  23. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J et al (2011) Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29:1125–1132

    Article  CAS  PubMed  Google Scholar 

  24. Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L et al (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Orwoll E, Teglbjærg CS, Langdahl BL, Chapurlat R, Czerwinski E, Kendler DL et al (2012) A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab 97:3161–3169

    Article  CAS  PubMed  Google Scholar 

  26. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B et al (2012) Denosumab and bone metastasis-free survival in men with castration-resistant prostate cancer: results of a global phase 3, randomised, placebo-controlled trial. Lancet 379:39–46

    Article  CAS  PubMed  Google Scholar 

  27. Recknor C, Czerwinski E, Bone HG, Bonnick SL, Binkley N, Palacios S et al (2013) Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. Obstet Gynecol 121:1291–1299

    Article  CAS  PubMed  Google Scholar 

  28. Nakamura T, Matsumoto T, Sugimoto T, Hosoi T, Miki T, Gorai I et al (2014) Clinical trials express: fracture risk reduction with denosumab in japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT). J Clin Endocrinol Metab 99:2599–2607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Roux C, Hofbauer LC, Ho PR, Wark JD, Zillikens MC, Fahrleitner-Pammer A et al (2014) Denosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate therapy: efficacy and safety results from a randomized open-label study. Bone 58:48–54

    Article  CAS  PubMed  Google Scholar 

  30. Pitale S, Thomas M, Rathi G, Deshmukh V, Kumar P, Reddy S et al (2015) A randomized placebo-controlled trial of the efficacy of denosumab in Indian postmenopausal women with osteoporosis. Indian J Endocrinol Metab 19:148–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R et al (2015) Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433–443

    Article  CAS  PubMed  Google Scholar 

  32. Office of the Law Revision Counsel (1938) United States Code, New drugs (sec. 505), Public laws - Ch. 675. http://uscode.house.gov/statviewer.htm?volume=52&page=1059#. Accessed 02 Jan 2017

  33. American Association of Oral and Maxillofacial Surgeons (2007) Position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 65:369–376

    Article  Google Scholar 

  34. Fedele S, Porter SR, D’Aiuto F, Aljohani S, Vescovi P, Manfredi M et al (2010) Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 123:1060–1064

    Article  CAS  PubMed  Google Scholar 

  35. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B et al (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

    Article  PubMed  Google Scholar 

  36. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D et al (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22:1479–1491

    Article  PubMed  Google Scholar 

  37. Colella G, Campisi G, Fusco V (2009) American Association of Oral and Maxillofacial Surgeons Position Paper: bisphosphonate-related osteonecrosis of the jaws—2009 update: the need to refine the BRONJ definition. J Oral Maxillofac Surg 67:2698–2699

    Article  PubMed  Google Scholar 

  38. Fusco V, Santini D, Armento G, Tonini G, Campisi G (2016) Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology. Expert Opin Drug Saf 15:925–935

    Article  CAS  PubMed  Google Scholar 

  39. Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT 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 23:1341–1347

    Article  CAS  PubMed  Google Scholar 

  40. Schulz KF, Altman DG, Moher D, CONSORT Group (2010) CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Trials11:32.

  41. CONSORT Group. CONSORT Outcomes 6a. http://www.consort-statement.org/checklists/view/32-consort/80-outcomes. Accessed 02 Jan 2017

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Acknowledgments

The authors thank Fiona Ecarnot (EA3920, University Hospital Besancon, France) for editorial assistance.

Contributors

PdB, LK, RM, AM, and TT were responsible for designing the study concept, data interpretation, and manuscript preparation. PdB, LK, RM, and MD developed the search strategy. MD and LK performed the initial screening on titles and abstracts. PdB, AM, and TT were responsible for data collection and analysis. All authors critically revised the manuscript and approved the final version.

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Authors and Affiliations

  1. Regional Center for Pharmacovigilance and Pharmacoepidemiology, Reims University Hospital, Avenue du Général Koenig, 51100, Reims, France

    Paul de Boissieu, A. Morel & T. Trenque

  2. Faculty of Medicine, EA 3797, University of Reims Champagne-Ardenne, Reims, France

    Paul de Boissieu, L. Kanagaratnam, R. Mahmoudi, M. Dramé & T. Trenque

  3. Department of Research and Innovation, Reims University Hospital, Reims, France

    L. Kanagaratnam & M. Dramé

  4. Department of Geriatrics and Internal Medicine, Reims University Hospital, Reims, France

    R. Mahmoudi

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  1. Paul de Boissieu
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Correspondence to Paul de Boissieu.

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de Boissieu, P., Kanagaratnam, L., Mahmoudi, R. et al. Adjudication of osteonecrosis of the jaw in phase III randomized controlled trials of denosumab: a systematic review. Eur J Clin Pharmacol 73, 517–523 (2017). https://doi.org/10.1007/s00228-017-2210-x

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