Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

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.

Introduction

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.

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Woo SB, Hellstein JW, Kalmar JR (2006) Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144:753–761

    PubMed  CAS  Google Scholar 

  2. Khosla S, Burr D, Cauley J 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 

  3. Migliorati CA (2003) Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 21:4253–4254

    Article  PubMed  Google Scholar 

  4. Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117

    Article  PubMed  Google Scholar 

  5. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B (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

    PubMed  Google Scholar 

  6. Khan AA, Sandor GK, Dore E et al (2008) Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 35:1391–1397

    PubMed  Google Scholar 

  7. Assael LA (2009) Oral bisphosphonates as a cause of bisphosphonate-related osteonecrosis of the jaws: clinical findings, assessment of risks, and preventive strategies. J Oral Maxillofac Surg 67:35–43

    Article  PubMed  Google Scholar 

  8. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62:527–534

    Article  PubMed  Google Scholar 

  9. Marx RE, Sawatari Y, Fortin M, Broumand V (2005) Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63:1567–1575

    Article  PubMed  Google Scholar 

  10. Sarasquete ME, Gonzalez M, San Miguel JF, Garcia-Sanz R (2009) Bisphosphonate-related osteonecrosis: genetic and acquired risk factors. Oral Dis 15:382–387

    Article  PubMed  CAS  Google Scholar 

  11. Marini F, Tonelli P, Cavalli L, Cavalli T, Masi L, Falchetti A, Brandi ML (2011) Pharmacogenetics of bisphosphonate-associated osteonecrosis of the jaw. Front Biosci (EliteEd) 3:364–370

    Article  Google Scholar 

  12. Fusco V, Loidoris A, Colella G, Vescovi P, Campisi G (2010) Osteonecrosis of the jaw (ONJ) risk in breast cancer patients after zoledronic acid treatment. Breast 19:432–433

    Article  PubMed  Google Scholar 

  13. Vescovi P, Campisi G, Fusco V et al (2011) Surgery-triggered and non surgery-triggered Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ): a retrospective analysis of 567 cases in an Italian multicenter study. Oral Oncol 47:191–194

    Article  PubMed  CAS  Google Scholar 

  14. Mavrokokki T, Cheng A, Stein B, Goss A (2007) Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 65:415–423

    Article  PubMed  Google Scholar 

  15. Bilezikian JP (2006) Osteonecrosis of the jaw—do bisphosphonates pose a risk? N Engl J Med 355:2278–2281

    Article  PubMed  CAS  Google Scholar 

  16. Edwards BJ, Gounder M, McKoy JM et al (2008) Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw. Lancet Oncol 9:1166–1172

    Article  PubMed  Google Scholar 

  17. Jung TI, Hoffmeister B (2007) Osteonecrosis of jaw under bisphosphonate therapy: patient profile and risk assessment. J Bone Miner Res 22:S113–S113

    Google Scholar 

  18. Lo JC, O’Ryan FS, Gordon NP et al (2010) Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 68:243–253

    Article  PubMed  Google Scholar 

  19. Zavras AI, Zhu S (2006) Bisphosphonates are associated with increased risk for jaw surgery in medical claims data: is it osteonecrosis? J Oral Maxillofac Surg 64:917–923

    Article  PubMed  Google Scholar 

  20. Pazianas M, Blumentals W, Miller P (2008) Lack of association between oral bisphosphonates and osteonecrosis using jaw surgery as a surrogate marker. Osteoporos Int 19:773–779

    Article  PubMed  CAS  Google Scholar 

  21. Barasch A, Cunha-Cruz J, Curro FA et al (2011) Risk factors for osteonecrosis of the jaws: a case–control study from the CONDOR dental PBRN. J Dent Res 90:439–444

    Article  PubMed  CAS  Google Scholar 

  22. Devold HM, Doung GM, Tverdal A, Furu K, Meyer HE, Falch JA, Sogaard AJ (2010) Prescription of anti-osteoporosis drugs during 2004–2007—a nationwide register study in Norway. Eur J Clin Pharmacol 66:299–306

    Article  PubMed  Google Scholar 

  23. Piscitelli P, Gimigliano F, Gatto S et al (2009) Hip fractures in Italy: 2000–2005 extension study. Osteoporos Int 21:1323–1330

    Article  PubMed  Google Scholar 

  24. Lapi F, Simonetti M, Michieli R, Pasqua A, Brandi ML, Frediani B, Cricelli C, Mazzaglia G (2011) Assessing 5-year incidence rates and determinants of osteoporotic fractures in primary care. Bone 50:85–90

    Article  PubMed  Google Scholar 

  25. Curtis JR, Mudano AS, Solomon DH, Xi J, Melton ME, Saag KG (2009) Identification and validation of vertebral compression fractures using administrative claims data. Med Care 47:69–72

    Article  PubMed  Google Scholar 

  26. Curtis JR, Taylor AJ, Matthews RS et al (2009) "Pathologic" fractures: should these be included in epidemiologic studies of osteoporotic fractures? Osteoporos Int 20:1969–1972

    Article  PubMed  CAS  Google Scholar 

  27. Austin PC (2008) The performance of different propensity-score methods for estimating relative risks. J Clin Epidemiol 61:537–545

    Article  PubMed  Google Scholar 

  28. Patrick AR, Schneeweiss S, Brookhart MA, Glynn RJ, Rothman KJ, Avorn J, Sturmer T (2011) The implications of propensity score variable selection strategies in pharmacoepidemiology: an empirical illustration. Pharmacoepidemiol Drug Saf 20:551–559

    Article  PubMed  Google Scholar 

  29. Etminan M, Aminzadeh K, Matthew IR, Brophy JM (2008) Use of oral bisphosphonates and the risk of aseptic osteonecrosis: a nested case–control study. J Rheumatol 35:691–695

    PubMed  CAS  Google Scholar 

  30. Beiderbeck AB, Sturkenboom MC, Coebergh JW, Leufkens HG, Stricker BH (2004) Misclassification of exposure is high when interview data on drug use are used as a proxy measure of chronic drug use during follow-up. J Clin Epidemiol 57:973–977

    Article  PubMed  Google Scholar 

  31. Otto S, Pautke C, Opelz C, Westphal I, Drosse I, Schwager J, Bauss F, Ehrenfeld M, Schieker M (2010) Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism. J Oral Maxillofac Surg 68:2837–2845

    Article  PubMed  Google Scholar 

  32. Kimmel DB (2007) Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res 86:1022–1033

    Article  PubMed  CAS  Google Scholar 

  33. Hughes DE, MacDonald BR, Russell RG, Gowen M (1989) Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow. J Clin Invest 83:1930–1935

    Article  PubMed  CAS  Google Scholar 

  34. Diel IJ, Fogelman I, Al-Nawas B, Hoffmeister B, Migliorati C, Gligorov J, Vaananen K, Pylkkanen L, Pecherstorfer M, Aapro MS (2007) Pathophysiology, risk factors and management of bisphosphonate-associated osteonecrosis of the jaw: is there a diverse relationship of amino- and non-aminobisphosphonates? Crit Rev Oncol Hematol 64:198–207

    Article  PubMed  Google Scholar 

  35. Delmas PD, Siris ES (2008) NICE recommendations for the prevention of osteoporotic fractures in postmenopausal women. Bone 42:16–18

    Article  PubMed  Google Scholar 

  36. Siris ES, Harris ST, Rosen CJ, Barr CE, Arvesen JN, Abbott TA, Silverman S (2006) Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc 81:1013–1022

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

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

None.

Author information

Authors and Affiliations

  1. Regional Agency for Healthcare Services of Tuscany, Florence, Italy

    F. Lapi, F. Cipriani & G. Mazzaglia

  2. Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy

    F. Lapi

  3. Centre for Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, QC, Canada

    F. Lapi

  4. Department of Medicine and Pharmacology, University of Messina, Messina, Italy

    A. P. Caputi

  5. Unit of Biostatistics and Epidemiology, Department of Statistics, University of Milan-Bicocca, Milan, Italy

    G. Corrao

  6. Department of Pharmacology, University of Bologna, Bologna, Italy

    A. Vaccheri

  7. Department of Medical Informatics, Pharmacoepidemiology Unit, Erasmus University Medical Center, Rotterdam, The Netherlands

    M. C. Sturkenboom & G. Mazzaglia

  8. Department of Critical Care Medicine and Surgery, Unit of Gerontology and Geriatrics, University of Florence, Florence, Italy

    M. Di Bari

  9. Department of Public Health and Environmental Medicine, University of Padua, Padua, Italy

    D. Gregori

  10. Center of Epidemiology, Biostatistics, and Medical Information Technology, Polytechnic University of Marche, Ancona, Italy

    F. Carle

  11. Department of Medicine and Aging, University “G. d’Annunzio”, Chieti-Pescara, Italy

    T. Staniscia

  12. Department of Public Health and Infectious Disease, University “La Sapienza”, Rome, Italy

    A. Vestri

  13. Department of Internal Medicine, University of Florence, Florence, Italy

    M. Brandi

  14. Oncology Unit, Alessandria Hospital, Alessandria, Italy

    V. Fusco

  15. Department of Surgical and Oncological Disciplines, Sector of Oral Medicine, University of Palermo, Palermo, Italy

    G. Campisi

  16. Department of Preclinical and Clinical Pharmacology, University of Florence (Italy), Viale G. Pieraccini 6, 50139, Florence, Italy

    F. Lapi

Authors
  1. F. Lapi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Cipriani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. P. Caputi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Corrao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Vaccheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. C. Sturkenboom
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Di Bari
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. Gregori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F. Carle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T. Staniscia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. A. Vestri
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M. Brandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. V. Fusco
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. G. Campisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. G. Mazzaglia
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the Bisphosphonates Efficacy-Safety Tradeoff (BEST) study group

Corresponding author

Correspondence to F. Lapi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lapi, F., Cipriani, F., Caputi, A.P. et al. Assessing the risk of osteonecrosis of the jaw due to bisphosphonate therapy in the secondary prevention of osteoporotic fractures. Osteoporos Int 24, 697–705 (2013). https://doi.org/10.1007/s00198-012-2013-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-012-2013-y

Keywords

Search

Navigation