title: Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: University College London/University College London Hospital Eastman Dental Institute and Hospital, London, UK.
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authors.affiliation: Clinical Epidemiology Unit, Liver Research Centre, Basovizza, Trieste, Italy.
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authors.lastname: Bedogni
authors.affiliation: Department of Maxillofacial Surgery, University of Verona, Italy.|Department of Maxillofacial Surgery, University of Padua, Italy.
authors.forename: A
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authors.lastname: Bedogni
authors.affiliation: University College London/University College London Hospital Eastman Dental Institute and Hospital, London, UK.
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authors.lastname: Petrie
authors.affiliation: University College London/University College London Hospital Eastman Dental Institute and Hospital, London, UK.
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authors.affiliation: Dip. Discipline Chirurgiche, Oncologiche e Stomatologiche, University of Palermo, Italy.
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authors.affiliation: Department of Oral and Maxillofacial Surgery, Oral Medicine, University General Hospital, Valencia University, Spain.
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authors.affiliation: Medical Oncology Unit, Department of Oncology and Haematology, Ospedale SS Antonio e Biagio e C Arrigo, Alessandria, Italy.
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authors.lastname: Fusco
authors.affiliation: Department of Maxillofacial Surgery, University of Padua, Italy.
authors.forename: G
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authors.affiliation: Department of Oral Surgery and Orthodontics, University Clinic of Dental Health and Oral Medicine, Medical University of Graz, Austria.
authors.forename: S
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authors.lastname: Acham
authors.affiliation: Scientific Direction, Referral Cancer Center of Basilicata, IRCCS, Rionero in Vulture, Potenza, Italy.
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authors.affiliation: Department of Cellular Biotechnologies and Haematology, "Sapienza" University, Rome, Italy.
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authors.initials: MT
authors.lastname: Petrucci
authors.affiliation: School of Medicine and Dentistry, Santiago de Compostela University, Spain.
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authors.lastname: Diz
authors.affiliation: Department of Medical, Surgical and Dental Specialties, Second University of Naples, Italy.
authors.forename: G
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authors.affiliation: Head & Neck Clinical Section, Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy.
authors.forename: M D
authors.initials: MD
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authors.affiliation: Oral Medicine and Oral Oncology Unit, Department of Oncology, University of Turin, Italy.
authors.forename: M
authors.identifier: http://orcid.org/0000-0003-3972-1203
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authors.lastname: Pentenero
authors.affiliation: CIR Dental School, University of Turin, Italy.
authors.forename: P
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authors.lastname: Arduino
authors.affiliation: Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Lodi
authors.affiliation: Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Fondazione IRCCS Policlinico Cà Granda, Ospedale Maggiore Policlinico, University of Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Maiorana
authors.affiliation: Dipartimento di Scienze Biomediche, Biotecnologiche e Traslazionali - S.Bi.Bi.T., Unità di Odontostomatologia, Parma University, Italy.
authors.forename: M
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authors.lastname: Manfredi
authors.affiliation: Clinical Pharmacology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden.
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authors.lastname: Hallberg
authors.affiliation: Clinical Pharmacology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Sweden.
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authors.lastname: Wadelius
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Hyogo, Japan.
authors.forename: K
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authors.lastname: Takaoka
authors.affiliation: Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Leung
authors.affiliation: Department of Dentistry, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Bonacina
authors.affiliation: Department of Oral and Maxillofacial Surgery, Rigshospitalet, Copenhagen University Hospital, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Schiødt
authors.affiliation: First Department of Medicine, Semmelweis University Medical School, Budapest, Hungary.
authors.forename: P
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authors.lastname: Lakatos
authors.affiliation: Department of Oral Surgery, King's College Hospital, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Taylor
authors.affiliation: Department of Maxillofacial Surgery, University Hospital of Sassari, Italy.
authors.forename: G
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authors.lastname: De Riu
authors.affiliation: Department of Dentistry, San Francesco Hospital, Nuoro, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Favini
authors.affiliation: University Hospital Aintree, Liverpool, UK.
authors.forename: S N
authors.initials: SN
authors.lastname: Rogers
authors.affiliation: Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Nicoletti
authors.affiliation: University College London/University College London Hospital Eastman Dental Institute and Hospital, London, UK.|NIHR University College London Hospitals Biomedical Research Centre, London, UK.
authors.forename: S
authors.identifier: http://orcid.org/0000-0001-9006-9412
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mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw / Q000453:epidemiology / Q000209:etiology*; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003430:Cross-Sectional Studies; D004164:Diphosphonates / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates
keywords: bisphosphonates; breast cancer; jaw osteonecrosis; multiple myeloma; osteoporosis; prostate cancer