Osteoporosis International

, Volume 24, Issue 2, pp 697–705 | Cite as

Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures

  • F. LapiEmail author
  • F. Cipriani
  • A. P. Caputi
  • G. Corrao
  • A. Vaccheri
  • M. C. Sturkenboom
  • M. Di Bari
  • D. Gregori
  • F. Carle
  • T. Staniscia
  • A. Vestri
  • M. Brandi
  • V. Fusco
  • G. Campisi
  • G. Mazzaglia
  • on behalf of the Bisphosphonates Efficacy-Safety Tradeoff (BEST) study group
Original Article



There is evidence that the use oral bisphosphonates can lead to osteronecrosis of the jaws (ONJ). Although the occurrence of ONJ appears rare among oral bisphosphonates (BPs) users, it is important to know that it exists and can be opportunely minimized.


The purpose of this study is to evaluate the association between BPs prescribed for the secondary prevention of osteoporotic fractures and the occurrence of ONJ.


An Italian record linkage claims database with a target population of around 18 million individuals (6 million over 55 years of age) constituted the data source. We conducted a nested case–control study within a cohort of individuals aged 55+ years old, who were discharged from hospitals with a primary diagnosis of incident osteoporotic fracture. The date related to the discharge diagnosis of ONJ was the index date. Conditional logistic regression for matched data was fitted to estimate the odds ratio (OR) along with 95 % confidence intervals (95 % CI) for the likely association between use of BPs and the risk of ONJ.


Any one of the 61 ascertained cases of ONJ (incidence rate, 36.6 per 100,000 person-years) was matched to 20 controls for a total of 1120 controls. When the exposure to BPs was modeled according to recency (i.e., exposure time window prior to the index date) of use, the adjusted OR (95 % CI) for current users was 2.8 (1.3–5.9) against never users. The cumulative use of BPs has shown to increase the incidence of ONJ among patients with primary osteoporotic fractures, although not statistically significant risk has been observed.


Although the risk of BP-related ONJ appears low in non-oncological indications, it is important to be aware that it exists and to know how it may be predicted and possibly minimized.


Bisphosphonates Nested case–control study Osteonecrosis of the jaw Osteoporotic fractures 



The study was supported by Agenzia Italiana del Farmaco (AIFA grant FARM06R9YY), Rome, Italy. We would like to thank Dr. Laurent Azoulay (Department of Oncology, McGill University, Montreal, Canada) for the paper revision which he conducted according to the standard peer-review process. We would also like to thank all the other components of the BEST study group who have contributed to the scientific content or provided technical support: Emiliano Sessa (Regional Agency for Healthcare Services of Tuscany, Florence, Italy); Vincenzo Arcoraci (Department of Medicine and Pharmacology, University of Messina, Italy); Arianna Ghirardi, Lorenza Scotti, Andrea Parodi, Antonella Zambon (Unit of Biostatistics and Epidemiology, Department of Statistics, University of Milan-Bicocca, Milan, Italy); Carlo Piccinni, Caterina Suzzi, Aurora Puccini, Alberto Vaccheri (Department of Pharmacology, University of Bologna, Bologna, Italy); Pierangelo Geppetti (Head Unit; Center of Pharmacoutilization, Pharmacoepidemiology, Pharmacovigilance, and Pharmacoeconomics, University of Florence, Florence, Italy), Lavinia Sati (Center of Pharmacoutilization, Pharmacoepidemiology, Pharmacovigilance, and Pharmacoeconomics, University of Florence, Florence, Italy); Francesca Forlan (Department of Public Health and Environmental Medicine, University of Padua, Padua, Italy); Rosaria Gesuita (Center of Epidemiology, Biostatistics, and Medical Information Technology, Polytechnic University of Marche, Ancona, Italy); Angelo Menna (Regional Agency of Healthcare Services of Abruzzi, Chieti, Italy); Alessandra Mingarelli, Gianluca Di Tanna (Department of Public health and Infectious Disease, University “La Sapienza”, Rome, Italy); and Marco Valenti (Head Unit; Department of Medicine and Public Health, University of L’Aquila, L’Aquila, Italy).

Conflicts of interest



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Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2012

Authors and Affiliations

  • F. Lapi
    • 1
    • 2
    • 3
    • 16
    Email author
  • F. Cipriani
    • 1
  • A. P. Caputi
    • 4
  • G. Corrao
    • 5
  • A. Vaccheri
    • 6
  • M. C. Sturkenboom
    • 7
  • M. Di Bari
    • 8
  • D. Gregori
    • 9
  • F. Carle
    • 10
  • T. Staniscia
    • 11
  • A. Vestri
    • 12
  • M. Brandi
    • 13
  • V. Fusco
    • 14
  • G. Campisi
    • 15
  • G. Mazzaglia
    • 1
    • 7
  • on behalf of the Bisphosphonates Efficacy-Safety Tradeoff (BEST) study group
  1. 1.Regional Agency for Healthcare Services of TuscanyFlorenceItaly
  2. 2.Department of Preclinical and Clinical PharmacologyUniversity of FlorenceFlorenceItaly
  3. 3.Centre for Clinical Epidemiology, Jewish General HospitalMcGill UniversityMontrealCanada
  4. 4.Department of Medicine and PharmacologyUniversity of MessinaMessinaItaly
  5. 5.Unit of Biostatistics and Epidemiology, Department of StatisticsUniversity of Milan-BicoccaMilanItaly
  6. 6.Department of PharmacologyUniversity of BolognaBolognaItaly
  7. 7.Department of Medical Informatics, Pharmacoepidemiology UnitErasmus University Medical CenterRotterdamThe Netherlands
  8. 8.Department of Critical Care Medicine and Surgery, Unit of Gerontology and GeriatricsUniversity of FlorenceFlorenceItaly
  9. 9.Department of Public Health and Environmental MedicineUniversity of PaduaPaduaItaly
  10. 10.Center of Epidemiology, Biostatistics, and Medical Information TechnologyPolytechnic University of MarcheAnconaItaly
  11. 11.Department of Medicine and AgingUniversity “G. d’Annunzio”Chieti-PescaraItaly
  12. 12.Department of Public Health and Infectious DiseaseUniversity “La Sapienza”RomeItaly
  13. 13.Department of Internal MedicineUniversity of FlorenceFlorenceItaly
  14. 14.Oncology UnitAlessandria HospitalAlessandriaItaly
  15. 15.Department of Surgical and Oncological Disciplines, Sector of Oral MedicineUniversity of PalermoPalermoItaly
  16. 16.Department of Preclinical and Clinical PharmacologyUniversity of Florence (Italy)FlorenceItaly

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