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Oral Dis. 2016 Dec 31. doi: 10.1111/odi.12632. [Epub ahead of print]

Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study.

Author information

  • 1University College London / University College London Hospital Eastman Dental Institute and Hospital, London, UK.
  • 2Liver Research Centre, Clinical Epidemiology Unit, Basovizza, Trieste, Italy.
  • 3University of Verona, Department of Maxillofacial Surgery, Verona, Italy.
  • 4University of Padua, Department of Maxillofacial Surgery, Padua, Italy.
  • 5University of Palermo, Dip. Discipline Chirurgiche, Oncologiche e Stomatologiche, Palermo, Italy.
  • 6Valencia University, Oral Medicine, University General Hospital, Department of Oral and Maxillofacial Surgery, Valencia, Spain.
  • 7Ospedale SS Antonio e Biagio e C Arrigo, Department of Oncology and Haematology, Medical Oncology Unit, Alessandria, Italy.
  • 8Medical University of Graz, University Clinic of Dental Health and Oral Medicine, Department of Oral Surgery and Orthodontics, Graz, Austria.
  • 9IRCCS, Referral Cancer Center of Basilicata, Scientific Direction, Rionero in Vulture (Potenza), Italy.
  • 10"Sapienza" University, Department of Cellular Biotechnologies and Haematology, Rome, Italy.
  • 11Santiago de Compostela University, School of Medicine and Dentistry, Santiago de, Compostela, Spain.
  • 12Second University of Naples, Department of Medical, Surgical and Dental Specialties, Naples, Italy.
  • 13Federico II University, Department of Neurosciences, Reproductive and Odontostomatological Sciences, Head & Neck Clinical Section, Naples, Italy.
  • 14University of Torino, Department of Oncology, Oral Medicine and Oral Oncology Unit, Turin, Italy.
  • 15University of Turin, CIR Dental School, Turin, Italy.
  • 16Università degli Studi di Milano, Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Milan, Italy.
  • 17Fondazione IRCCS Policlinico Cà Granda, Ospedale Maggiore Policlinico, and University of Milan, Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Italy.
  • 18Parma University, Dipartimento di Scienze Biomediche, Biotecnologiche e Traslazionali - S.Bi.Bi.T., Unità di Odontostomatologia, Parma, Italy.
  • 19Uppsala University, Department of Medical Sciences, Clinical Pharmacology and Science for Life Laboratory, Uppsala, Sweden.
  • 20Hyogo College of Medicine, Department of Oral and Maxillofacial Surgery, Japan.
  • 21Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong.
  • 22Department of Dentistry, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
  • 23Department of Oral and Maxillofacial Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • 24First Department of Medicine, Semmelweis University Medical School, Budapest, Hungary.
  • 25Department of Oral Surgery, King's College Hospital, London, UK.
  • 26Department of Maxillofacial Surgery, University Hospital of Sassari, Italy.
  • 27Department of Dentistry, San Francesco Hospital, Nuoro, Italy.
  • 28University Hospital Aintree, Liverpool, UK.
  • 29Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
  • 30Department of Systems Biology, Columbia University, New York, US.
  • 31GENVABO Consortium: a list of contributing members is provided below.
  • 32University College London Hospitals Biomedical Research Centre, London, UK.



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.


Retrospective analysis of data from 22 secondary care centres in 7 countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012.


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 cancer patients treated with zoledronate.


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 of 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. This article is protected by copyright. All rights reserved.

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