Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Osteonecrosis of the jaw and bisphosphonates in cancer: a narrative review

Abstract

Bisphosphonate-associated osteonecrosis (BON) is a complication that almost exclusively affects the jaw bones. The clinical presentation of BON often mimics that of other conditions, such as routine dental disease, osteoradionecrosis or avascular necrosis; therefore, diagnosis can be difficult. As this complication has only been recognized within the past 10 years, management strategies for patients with BON are poorly defined. Physicians must choose between continuing the bisphosphonate therapy (to reduce the risk of skeletal complications in patients with metastatic bone disease or osteoporosis) and discontinuing the drug (to possibly improve the odds for tissue healing). A conservative or aggressive management strategy must be chosen with limited evidence that the outcome of either strategy will be successful. BON is most prevalent in patients with cancer using intravenous nitrogen-containing bisphosphonates. The pathobiology of this complication is not fully understood and the diagnosis relies on the clinical manifestations of the condition. Future research should focus on the pathobiological mechanisms involved in the development of BON, which could help explain why this complication affects only a small number of those who use bisphosphonates, and also suggest strategies for prevention and management.

Key Points

  • Higher levels of evidence than those currently available are needed to help establish the natural history, true prevalence, prevention and treatment strategies and prognosis for bisphosphonate-associated osteonecrosis (BON)

  • Most studies of BON are case series, which are susceptible to bias as they lack a comparator group

  • Prospective studies with well-documented follow-up of patients and participation of a dental expert seem to yield higher prevalence rates than other study designs, such as retrospective studies

  • Diagnosis of BON requires exposed necrotic bone that does not respond to conventional therapy for osteonecrosis in a patient receiving bisphosphonates with no history of head and neck irradiation

  • Patients with BON refractory to conservative local debridement and use of topical and systemic antibiotics might respond positively to more aggressive surgical flaps and bone resection

  • The assessment of healing after patients have been treated for BON is not well defined; evidence of healing should comprise improvements in symptoms, mucosal healing and radiographic parameters

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: An area of osteonecrosis of the torus palatino in a patient who was taking a bisphosphonate and with no history of radiation therapy to the head and neck.

Similar content being viewed by others

References

  1. Cosman, F. Treatment of osteoporosis and prevention of new fractures: role of intravenously administered bisphosphonates. Endocr. Pract. 15, 483–493 (2009).

    Article  PubMed  Google Scholar 

  2. Bilezikian, J. P. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am. J. Med. 122 (Suppl.), S14–S21 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Berenson, J. R., Rajdev, L. & Broder, M. Treatment strategies for skeletal complications of cancer. Cancer Biol. Ther. 5, 1074–1077 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Body, J. J. Breast cancer: bisphosphonate therapy for metastatic bone disease. Clin. Cancer Res. 12, 6258s–6263s (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Body, J. J. et al. International Society of Geriatric Oncology (SIOG) clinical practice recommendations for the use of bisphosphonates in elderly patients. Eur. J. Cancer 43, 852–858 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Arum, S. M. New developments surrounding the safety of bisphosphonates. Curr. Opin. Endocrinol. Diabetes Obes. 15, 508–513 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Diel, I. J., Bergner, R. & Grötz, K. A. Adverse effects of bisphosphonates: current issues. J. Support. Oncol. 5, 475–482 (2007).

    CAS  PubMed  Google Scholar 

  8. Ing-Lorenzini, K. et al. Low-energy femoral fractures associated with the long-term use of bisphosphonates: a case series from a Swiss university hospital. Drug Saf. 32, 775–785 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Capeci, C. M. & Tejwani, N. C. Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J. Bone Joint Surg. Am. 91, 2556–2561 (2009).

    Article  PubMed  Google Scholar 

  10. King, A. E. & Umland, E. M. Osteonecrosis of the jaw in patients receiving intravenous or oral bisphosphonates. Pharmacotherapy 28, 667–677 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. Migliorati, C. A., Siegel, M. A. & Elting, L. S. Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol. 7, 508–514 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Ruggiero, S. L. et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J. Oral Maxillofac. Surg. 67 (Suppl.), 2–12 (2009).

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  14. Migliorati, C. A. Bisphosphanates and oral cavity avascular bone necrosis. J. Clin. Oncol. 21, 4253–4254 (2003).

    Article  PubMed  Google Scholar 

  15. Migliorati, C. A., Schubert, M. M., Peterson, D. E. & Seneda, L. M. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 104, 83–93 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Ruggiero, S. L., Mehrotra, B., Rosenberg, T. J. & Engroff, S. L. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J. Oral Maxillofac. Surg. 62, 527–534 (2004).

    Article  PubMed  Google Scholar 

  17. Lazarovici, T. S. et al. Bisphosphonate-related osteonecrosis of the jaws: a single-center study of 101 patients. J. Oral Maxillofac. Surg. 67, 850–855 (2009).

    Article  PubMed  Google Scholar 

  18. Junquera, L., Gallego, L., Cuesta, P., Pelaz, A. & de Vicente, J. C. Clinical experiences with bisphosphonate-associated osteonecrosis of the jaws: analysis of 21 cases. Am. J. Otolaryngol. 30, 390–395 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Favia, G., Pilolli, G. P. & Maiorano, E. Osteonecrosis of the jaw correlated to bisphosphonate therapy in non-oncologic patients: clinicopathological features of 24 patients. J. Rheumatol. 36, 2780–2787 (2009).

    Article  PubMed  Google Scholar 

  20. Magopoulos, C. et al. Osteonecrosis of the jaws due to bisphosphonate use. A review of 60 cases and treatment proposals. Am. J. Otolaryngol. 28, 158–163 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Thumbigere-Math, V. et al. Bisphosphonate-related osteonecrosis of the jaw: clinical features, risk factors, management, and treatment outcomes of 26 patients. J. Oral Maxillofac. Surg. 67, 1904–1913 (2009).

    Article  PubMed  Google Scholar 

  22. Hong, J. W. et al. Oral bisphosphonate-related osteonecrosis of the jaw: the first report in Asia. Osteoporos. Int. 21, 847–853 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Saussez, S. et al. Bisphosphonate-related osteonecrosis of the jaw and its associated risk factors: a Belgian case series. Laryngoscope 119, 323–329 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Pozzi, S. et al. Bisphosphonates-associated osteonecrosis of the jaw: A long-term follow-up of a series of 35 cases observed by GISL and evaluation of its frequency over time. Am. J. Hematol. 84, 850–852 (2009).

    Article  PubMed  Google Scholar 

  25. Kos, M., Kuebler, J. F., Luczak, K. & Engelke, W. Bisphosphonate-related osteonecrosis of the jaws: A review of 34 cases and evaluation of risk. J. Craniomaxillofac. Surg. 38, 255–259 (2009).

    Article  PubMed  Google Scholar 

  26. Woo, S. B., Hellstein, J. W. & Kalmar, J. R. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann. Intern. Med. 144, 753–761 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Lipton, A. et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 88, 1082–1090 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Berenson, J. R. et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J. Clin. Oncol. 16, 593–602 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Rosen, L. S. et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 7, 377–387 (2001).

    CAS  PubMed  Google Scholar 

  30. Rosen, L. S. et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98, 1735–1744 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Rosen, L. S. et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer 100, 2613–2621 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Saad, F. et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J. Natl Cancer Inst. 96, 879–882 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Coleman, R. E. Risks and benefits of bisphosphonates. Br. J. Cancer 98, 1736–1740 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kyle, R. A. et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J. Clin. Oncol. 25, 2464–2472 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Terpos, E., Berenson, J., Cook, R. J., Lipton, A. & Coleman, R. E. Prognostic variables for survival and skeletal complications in patients with multiple myeloma osteolytic bone disease. Leukemia 24, 1043–1049 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Green, J. R. Antitumor effects of bisphosphonates. Cancer 97 (Suppl.), 840–847 (2003).

    Article  PubMed  Google Scholar 

  37. Morgan, G. et al. Evaluating the effects of zoledronic acid (ZOL) on overall survival (OS) in patients (Pts) with multiple myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX study. J. Clin. Oncol. (Meeting Abstracts) 28, 8021 (2010).

    Article  Google Scholar 

  38. Gnant, M. et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N. Engl. J. Med. 360, 679–691 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Ripamonti, C. I. et al. Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann. Oncol. 20, 137–145 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Black, D. M. et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 296, 2927–2938 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Bone, H. G. et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N. Engl. J. Med. 350, 1189–1199 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. ClinicalTrials.gov Zoledronic acid treatment (every 4 or 12 weeks) to prevent skeletal complications in advanced multiple myeloma patients (Z-MARK) [online], (2010).

  43. McMahon, R. E. et al. Staging bisphosphonate-related osteonecrosis of the jaw should include early stages of disease. J. Oral Maxillofac. Surg. 65, 1899–1900 (2007).

    Article  PubMed  Google Scholar 

  44. Khosla, S. et al. 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 (2007).

    Article  PubMed  Google Scholar 

  45. Mawardi, H. et al. Sinus tracts—an early sign of bisphosphonate-associated osteonecrosis of the jaws? J. Oral Maxillofac. Surg. 67, 593–601 (2009).

    Article  PubMed  Google Scholar 

  46. Wilde, F. et al. Positron-emission tomography imaging in the diagnosis of bisphosphonate-related osteonecrosis of the jaw. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 107, 412–419 (2009).

    Article  PubMed  Google Scholar 

  47. Krishnan, A., Arslanoglu, A., Yildirm, N., Silbergleit, R. & Aygun, N. Imaging findings of bisphosphonate-related osteonecrosis of the jaw with emphasis on early magnetic resonance imaging findings. J. Comput. Assist. Tomogr. 33, 298–304 (2009).

    Article  PubMed  Google Scholar 

  48. O'Ryan, F. S. et al. Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator. J. Oral Maxillofac. Surg. 67, 1363–1372 (2009).

    Article  PubMed  Google Scholar 

  49. Dore, F. et al. Bone scintigraphy and SPECT/CT of bisphosphonate-induced osteonecrosis of the jaw. J. Nucl. Med. 50, 30–35 (2009).

    Article  PubMed  Google Scholar 

  50. Arce, K., Assael, L. A., Weissman, J. L. & Markiewicz, M. R. Imaging findings in bisphosphonate-related osteonecrosis of jaws. J. Oral Maxillofac. Surg. 67 (Suppl.), 75–84 (2009).

    Article  PubMed  Google Scholar 

  51. Morag, Y. et al. Bisphosphonate-related osteonecrosis of the jaw: a pictorial review. Radiographics 29, 1971–1984 (2009).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  53. Treister, N. et al. Dental panoramic radiographic evaluation in bisphosphonate-associated osteonecrosis of the jaws. Oral Dis. 15, 88–92 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Migliorati, C. A., Hsu, C. J., Chopra, S. & Kaltman, S. S. Dental management of patients with a history of bisphosphonate therapy: clinical dilemma. J. Calif. Dent. Assoc. 36, 769–774 (2008).

    PubMed  Google Scholar 

  55. Takaishi, Y., Ikeo, T., Nakajima, M., Miki, T. & Fujita, T. A pilot case-control study on the alveolar bone density measurement in risk assessment for bisphosphonate-related osteonecrosis of the jaw. Osteoporos. Int. 21, 815–825 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Stockmann, P. et al. Panoramic radiograph, computed tomography or magnetic resonance imaging. Which imaging technique should be preferred in bisphosphonate-associated osteonecrosis of the jaw? A prospective clinical study. Clin. Oral Investig. 14, 311–317 (2009).

    Article  PubMed  Google Scholar 

  57. Bianchi, S. D., Scoletta, M., Cassione, F. B., Migliaretti, G. & Mozzati, M. Computerized tomographic findings in bisphosphonate-associated osteonecrosis of the jaw in patients with cancer. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 104, 249–258 (2007).

    Article  PubMed  Google Scholar 

  58. Treister, N. S., Friedland, B. & Woo, S. B. Use of cone-beam computerized tomography for evaluation of bisphosphonate-associated osteonecrosis of the jaws. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 109, 753–764 (2010).

    Article  PubMed  Google Scholar 

  59. Bamias, A. et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J. Clin. Oncol. 23, 8580–8587 (2005).

    Article  PubMed  Google Scholar 

  60. Durie, B. G., Katz, M. & Crowley, J. Osteonecrosis of the jaw and bisphosphonates. N. Engl. J. Med. 353, 99–102 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Zervas, K. et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br. J. Haematol. 134, 620–623 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Dimopoulos, M. A. et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid. Haematologica 91, 968–971 (2006).

    CAS  PubMed  Google Scholar 

  63. Wang, E. P., Kaban, L. B., Strewler, G. J., Raje, N. & Troulis, M. J. Incidence of osteonecrosis of the jaw in patients with multiple myeloma and breast or prostate cancer on intravenous bisphosphonate therapy. J. Oral Maxillofac. Surg. 65, 1328–1331 (2007).

    Article  PubMed  Google Scholar 

  64. Walter, C., Grötz, K. A., Kunkel, M. & Al-Nawas, B. Prevalence of bisphosphonate associated osteonecrosis of the jaw within the field of osteonecrosis. Support. Care Cancer 15, 197–202 (2007).

    Article  PubMed  Google Scholar 

  65. Walter, C. et al. Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate. Eur. Urol. 54, 1066–1072 (2008).

    Article  PubMed  Google Scholar 

  66. Boonyapakorn, T., Schirmer, I., Reichart, P. A., Sturm, I. & Massenkeil, G. Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol. 44, 857–869 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Walter, C. et al. Incidence of bisphosphonate-associated osteonecrosis of the jaws in breast cancer patients. Cancer 115, 1631–1637 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Edwards, B. J. et al. Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw. Lancet Oncol. 9, 1166–1172 (2008).

    Article  PubMed  Google Scholar 

  69. Vahtsevanos, K. et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J. Clin. Oncol. 27, 5356–5362 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Clarke, B. M. et al. Bisphosphonates and jaw osteonecrosis: the UAMS experience. Otolaryngol. Head Neck Surg. 136, 396–400 (2007).

    Article  PubMed  Google Scholar 

  71. Stumpe, M. R., Chandra, R. K., Yunus, F. & Samant, S. Incidence and risk factors of bisphosphonate-associated osteonecrosis of the jaws. Head Neck 31, 202–206 (2009).

    Article  PubMed  Google Scholar 

  72. Lo, J. C. et al. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J. Oral Maxillofac. Surg. 68, 243–253 (2010).

    Article  PubMed  Google Scholar 

  73. Migliorati, C. A. et al. A systematic review of bisphosphonate osteonecrosis (BON) in cancer. Support. Care Cancer 18, 1099–1106 (2010).

    Article  PubMed  Google Scholar 

  74. Reid, I. R., Bolland, M. J. & Grey, A. B. Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 41, 318–320 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Reid, I. R. Osteonecrosis of the jaw: who gets it, and why? Bone 44, 4–10 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Allen, M. R. & Burr, D. B. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J. Oral Maxillofac. Surg. 67 (Suppl.), 61–70 (2009).

    Article  PubMed  Google Scholar 

  77. Kumar, S. K. et al. The role of microbial biofilms in osteonecrosis of the jaw associated with bisphosphonate therapy. Curr. Osteoporos. Rep. 8, 40–48 (2010).

    Article  PubMed  Google Scholar 

  78. Hoefert, S., Schmitz, I., Tannapfel, A. & Eufinger, H. Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of symptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings. Clin. Oral Investig. 14, 271–284 (2009).

    Article  PubMed  Google Scholar 

  79. Favia, G., Pilolli, G. P. & Maiorano, E. Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy. Bone 45, 406–413 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Van den Wyngaert, T., Huizing, M. T., Fossion, E. & Vermorken, J. B. Scintigraphic evaluation of mandibular bone turnover in patients with solid tumors receiving zoledronic acid. Oral Oncol. 46, 214–218 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Pozzi, S. et al. High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties. Clin. Cancer Res. 15, 5829–5839 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Allen, M. R. & Burr, D. B. Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J. Oral Maxillofac. Surg. 66, 987–994 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Nastro, E. et al. Avascular necrosis of bone in leukemia and osteonecrosis of jaw by bisphosphonates. J. Oral Maxillofac. Surg. 67, 2701–2703 (2009).

    Article  PubMed  Google Scholar 

  84. Chen, H. et al. A novel angiogenesis model for screening anti-angiogenic compounds: the chorioallantoic membrane/feather bud assay. Int. J. Oncol. 37, 71–79 (2010).

    CAS  PubMed  Google Scholar 

  85. Lesclous, P. et al. Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation? Bone 45, 843–852 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Otto, S. et al. Bisphosphonate-related osteonecrosis of the jaw: Is pH the missing part in the pathogenesis puzzle? J. Oral Maxillofac. Surg. 68, 1158–1161 (2010).

    Article  PubMed  Google Scholar 

  87. Marx, R. E. Uncovering the cause of “phossy jaw” circa 1858 to 1906: oral and maxillofacial surgery closed case files-case closed. J. Oral Maxillofac. Surg. 66, 2356–2363 (2008).

    Article  PubMed  Google Scholar 

  88. Scheper, M. A., Badros, A., Chaisuparat, R., Cullen, K. J. & Meiller, T. F. Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis. Br. J. Haematol. 144, 667–676 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Sedghizadeh, P. P. et al. Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy. J. Am. Dent. Assoc. 140, 1259–1265 (2009).

    Article  PubMed  Google Scholar 

  90. Naik, N. H. & Russo, T. A. Bisphosphonate-related osteonecrosis of the jaw: the role of actinomyces. Clin. Infect. Dis. 49, 1729–1732 (2009).

    Article  PubMed  Google Scholar 

  91. Kikuiri, T. et al. Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice. J. Bone Miner. Res. 25, 1668–1679 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Abu-Id, M. H. et al. “Bis-phossy jaws”—high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J. Craniomaxillofac. Surg. 36, 95–103 (2008).

    Article  PubMed  Google Scholar 

  93. Migliorati, C. A., Schubert, M. M. & Peterson, D. E. Bisphosphonate osteonecrosis (BON): unanswered questions and research possibilities. Rev. Recent Clin. Trials 4, 99–109 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Ardine, M. et al. Could the long-term persistence of low serum calcium levels and high serum parathyroid hormone levels during bisphosphonate treatment predispose metastatic breast cancer patients to undergo osteonecrosis of the jaw? Ann. Oncol. 17, 1336–1337 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Hokugo, A. et al. Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats. J. Bone Miner. Res. 25, 1337–1349 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Migliorati, C. A. et al. Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J. Am. Dent. Assoc. 136, 1658–1668 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Marx, R. E. Reconstruction of defects caused by bisphosphonate-induced osteonecrosis of the jaws. J. Oral Maxillofac. Surg. 67 (Suppl.), 107–119 (2009).

    Article  PubMed  Google Scholar 

  98. Markose, G., Mackenzie, F. R., Currie, W. J. & Hislop, W. S. Bisphosphonate osteonecrosis: a protocol for surgical management. Br. J. Oral Maxillofac. Surg. 47, 294–297 (2009).

    Article  PubMed  Google Scholar 

  99. Pautke, C. et al. Tetracycline bone fluorescence: a valuable marker for osteonecrosis characterization and therapy. J. Oral Maxillofac. Surg. 68, 125–129 (2010).

    Article  PubMed  Google Scholar 

  100. Tirelli, G. et al. Bisphosphonate-associated osteonecrosis of the jaws: the limits of a conservative approach. Head Neck 31, 1249–1254 (2009).

    Article  PubMed  Google Scholar 

  101. Stanton, D. C. & Balasanian, E. Outcome of surgical management of bisphosphonate-related osteonecrosis of the jaws: review of 33 surgical cases. J. Oral Maxillofac. Surg. 67, 943–950 (2009).

    Article  PubMed  Google Scholar 

  102. Ruggiero, S. L., Mehrotra, B., Rosenberg, T. J. & Engroff, S. L. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J. Oral Maxillofac. Surg. 62, 527–534 (2004).

    Article  PubMed  Google Scholar 

  103. Freiberger, J. J. et al. Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J. Oral Maxillofac. Surg. 65, 1321–1327 (2007).

    Article  PubMed  Google Scholar 

  104. Ruggiero, S. L., Fantasia, J. & Carlson, E. Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 102, 433–441 (2006).

    Article  PubMed  Google Scholar 

  105. Wutzl, A. et al. Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head Neck 30, 1224–1230 (2008).

    Article  PubMed  Google Scholar 

  106. Badros, A. et al. Natural history of osteonecrosis of the jaw in patients with multiple myeloma. J. Clin. Oncol. 26, 5904–5909 (2008).

    Article  PubMed  Google Scholar 

  107. Estilo, C. L. et al. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. Oncologist 13, 911–920 (2008).

    Article  PubMed  Google Scholar 

  108. Vescovi, P. et al. Nd:YAG laser biostimulation in the treatment of bisphosphonate-associated osteonecrosis of the jaw: clinical experience in 28 cases. Photomed. Laser Surg. 26, 37–46 (2008).

    Article  PubMed  Google Scholar 

  109. Carlson, E. R. & Basile, J. D. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J. Oral Maxillofac. Surg. 67 (Suppl.), 85–95 (2009).

    Article  PubMed  Google Scholar 

  110. Saussez, S. et al. Bisphosphonate-related osteonecrosis of the jaw and its associated risk factors: a Belgian case series. Laryngoscope 119, 323–329 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Stübinger, S. et al. A preliminary report about treatment of bisphosphonate related osteonecrosis of the jaw with Er:YAG laser ablation. Lasers Surg. Med. 41, 26–30 (2009).

    Article  PubMed  Google Scholar 

  112. Junquera, L., Gallego, L., Cuesta, P., Pelaz, A. & de Vicente, J. C. Clinical experiences with bisphosphonate-associated osteonecrosis of the jaws: analysis of 21 cases. Am. J. Otolaryngol. 30, 390–395 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Chiu, C. T., Chiang, W. F., Chuang, C. Y. & Chang, S. W. Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw—a serial case analysis. J. Oral Maxillofac. Surg. 68, 1055–1063 (2010).

    Article  PubMed  Google Scholar 

  114. Stockmann, P. et al. Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support. Care Cancer 18, 449–460 (2010).

    Article  PubMed  Google Scholar 

  115. Williamson, R. A. Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int. J. Oral Maxillofac. Surg. 39, 251–255 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Groetz, K. A. & Al-Nawas, B. Persisting alveolar sockets-a radiologic symptom of BP-ONJ? J. Oral Maxillofac. Surg. 64, 1571–1572 (2006).

    Article  PubMed  Google Scholar 

  117. Fleisher, K. E. et al. Tetracycline-guided debridement and cone beam computed tomography for the treatment of bisphosphonate-related osteonecrosis of the jaw: a technical note. J. Oral Maxillofac. Surg. 66, 2646–2653 (2008).

    Article  PubMed  Google Scholar 

  118. Angiero, F. et al. Osteonecrosis of the jaws caused by bisphosphonates: evaluation of a new therapeutic approach using the Er:YAG laser. Lasers Med. Sci. 24, 849–856 (2009).

    Article  PubMed  Google Scholar 

  119. Vescovi, P. et al. Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med. Sci. 25, 101–113 (2010).

    Article  PubMed  Google Scholar 

  120. Yamaguchi, K. et al. Osteonecrosis of the jawbones in 2 osteoporosis patients treated with nitrogen-containing bisphosphonates: osteonecrosis reduction replacing NBP with non-NBP (etidronate) and rationale. J. Oral Maxillofac. Surg. 68, 889–897 (2010).

    Article  PubMed  Google Scholar 

  121. McLeod, N. M., Patel, V., Kusanale, A., Rogers, S. N. & Brennan, P. A. Bisphosphosnate osteonecrosis of the jaw: a literature review of UK policies versus international policies on the management of bisphosphonate osteonecrosis of the jaw. Br. J. Oral Maxillofac. Surg. doi:10.1016/j.bjoms.2010.08.005.

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed equally to researching the data, discussing the content, reviewing and editing the manuscript before submission. C. A. Migliorati, J. B. Epstein and J. R. Berenson contributed equally to writing the article. The image in Figure 1 was supplied by C. A. Migliorati.

Corresponding author

Correspondence to Cesar A. Migliorati.

Ethics declarations

Competing interests

C. A. Migliorati has been a consultant for Amgen. J. R. Berenson has been a speaker and consultant and received research grants from Celgene, Cephalon, Novartis and Millennium, and has been a speaker and consultant for OrthoBiotech. He has received research grants and been a consultant for Amgen, CuraGen, Cytogen and Seattle Genetics, and has received research grants from Pfizer and Ziopharm. The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Migliorati, C., Epstein, J., Abt, E. et al. Osteonecrosis of the jaw and bisphosphonates in cancer: a narrative review. Nat Rev Endocrinol 7, 34–42 (2011). https://doi.org/10.1038/nrendo.2010.195

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2010.195

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing