Ppl Fung1, G Bedogni2, A Bedogni3,4, A Petrie1, S Porter1, G Campisi5, J Bagan6, V Fusco7, G Saia4, S Acham8, P Musto9, M T Petrucci10, P Diz11, G Colella12, M D Mignogna13, M Pentenero14, P Arduino15, G Lodi16, C Maiorana17, M Manfredi18, P Hallberg19, M Wadelius19, K Takaoka20, Y Y Leung21, R Bonacina22, M Schiødt23, P Lakatos24, T Taylor25, G De Riu26, G Favini27, S N Rogers28, M Pirmohamed29, P Nicoletti30, S Fedele1,31. 1. University College London/University College London Hospital Eastman Dental Institute and Hospital, London, UK. 2. Clinical Epidemiology Unit, Liver Research Centre, Basovizza, Trieste, Italy. 3. Department of Maxillofacial Surgery, University of Verona, Italy. 4. Department of Maxillofacial Surgery, University of Padua, Italy. 5. Dip. Discipline Chirurgiche, Oncologiche e Stomatologiche, University of Palermo, Italy. 6. Department of Oral and Maxillofacial Surgery, Oral Medicine, University General Hospital, Valencia University, Spain. 7. Medical Oncology Unit, Department of Oncology and Haematology, Ospedale SS Antonio e Biagio e C Arrigo, Alessandria, Italy. 8. Department of Oral Surgery and Orthodontics, University Clinic of Dental Health and Oral Medicine, Medical University of Graz, Austria. 9. Scientific Direction, Referral Cancer Center of Basilicata, IRCCS, Rionero in Vulture, Potenza, Italy. 10. Department of Cellular Biotechnologies and Haematology, "Sapienza" University, Rome, Italy. 11. School of Medicine and Dentistry, Santiago de Compostela University, Spain. 12. Department of Medical, Surgical and Dental Specialties, Second University of Naples, Italy. 13. Head & Neck Clinical Section, Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy. 14. Oral Medicine and Oral Oncology Unit, Department of Oncology, University of Turin, Italy. 15. CIR Dental School, University of Turin, Italy. 16. Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Italy. 17. Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Fondazione IRCCS Policlinico Cà Granda, Ospedale Maggiore Policlinico, University of Milan, Italy. 18. Dipartimento di Scienze Biomediche, Biotecnologiche e Traslazionali - S.Bi.Bi.T., Unità di Odontostomatologia, Parma University, Italy. 19. Clinical Pharmacology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden. 20. Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo, Japan. 21. Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong. 22. Department of Dentistry, Ospedale Papa Giovanni XXIII, Bergamo, Italy. 23. Department of Oral and Maxillofacial Surgery, Rigshospitalet, Copenhagen University Hospital, Denmark. 24. First Department of Medicine, Semmelweis University Medical School, Budapest, Hungary. 25. Department of Oral Surgery, King's College Hospital, London, UK. 26. Department of Maxillofacial Surgery, University Hospital of Sassari, Italy. 27. Department of Dentistry, San Francesco Hospital, Nuoro, Italy. 28. University Hospital Aintree, Liverpool, UK. 29. Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 30. Department of Systems Biology, Columbia University, New York, NY, USA. 31. NIHR University College London Hospitals Biomedical Research Centre, London, UK.
Abstract
OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients. SUBJECTS AND METHODS: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012. RESULTS: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n = 88) and 2.2 years in those treated with zoledronate (n = 218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate. CONCLUSIONS: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2 years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2 years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.
OBJECTIVES:Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients. SUBJECTS AND METHODS: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012. RESULTS: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n = 88) and 2.2 years in those treated with zoledronate (n = 218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate. CONCLUSIONS: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2 years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2 years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.
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