Skip to main content

Advertisement

SpringerLink
Log in

Bisphosphonate Related Osteonecrosis of the Jaw: An Update

  • Review Paper
  • Published:
Journal of Maxillofacial and Oral Surgery Aims and scope Submit manuscript

Abstract

Objectives

The aim of this paper is to summarize different diagnostic criteria as well as probable aetiopathogenesis of bisphosphonates related osteonecrosis of the jaw.

Materials and Methods

The electronic search of peer-reviewed journals were performed in MEDLINE (PubMed) database in order to find the relevant articles on bisphosphonates related osteonecrosis of the jaw (BP-related ONJ). The search was restricted to English language articles, published from January 2002 to May 2013. On the basis of these articles, probable aetiopathogenesis and different diagnostic criteria of BP-related ONJ were summarized.

Results

BP-related ONJ is related to the development of avascular necrosis or dead jaw bones. In recent literature many given hypotheses show the aetiopathogenesis and diagnosis of BP-related ONJ which are interlinked and have multifactorial nature. Their diagnosis revolves around four main diagnostic criteria that differentiate it from other conditions which can delay bone healing.

Conclusions

Factors like potency of bisphosphonates, biology of jaw bone, antiangiogenic property of bisphosphonates and soft tissue toxicity in combination with present infection, other drugs, pre-existing pathologies, compromised immune response and dentoalveolar trauma may lead to development of BP-related ONJ.

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

Similar content being viewed by others

References

  1. Bertoldo F, Santini D, Lo Cascio V (2007) Bisphosphonates and osteomyelitis of the jaw: a pathological puzzle. Nat Clin Pract Oncol 4(12):711–721

    Article  CAS  PubMed  Google Scholar 

  2. Bagan JV, Jimenez Y, Hernandez S, Murillo J, Diaz JM, Poveda R et al (2009) Osteonecrosis of the jaws by intravenous bisphosphonates and osteoradionecrosis: a comparative study. Med Oral Patol Oral Cir Bucal 14(12):e616–e619

    Article  PubMed  Google Scholar 

  3. Papapetrou PD (2009) Bisphosphonates: associated adverse events. Hormones 8(2):96–110

    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(9):1115–1117

    Article  PubMed  Google Scholar 

  5. Reid IR, Cornish J (2012) Epidemiology and pathogenesis of osteonecrosis of the jaw. J Nat Rev Rheumatol 8:90–96

    CAS  Google Scholar 

  6. Sharma D, Ivanovski S, Slevin M, Hamlet S, Pop TS, Brinzaniuc K et al (2013) Bisphosphonate-related osteonecrosis of the jaw (BRONJ): diagnostic criteria and possible pathogenic mechanisms of an unexpected anti-angiogenic side effect. Vascular Cell 5:1. http://www.vascularcell.com/content/5/1/1

  7. Russell RGG (2006) Bisphosphonates from bench to bedside. Ann NY Acad Sci 1068:367–401

    Article  CAS  PubMed  Google Scholar 

  8. Russell RGG (2007) Bisphosphonates: mode of action and pharmacology. Pediatrics 119:S150

    Article  PubMed  Google Scholar 

  9. Russell RGG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanism of actions of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759

    Article  CAS  PubMed  Google Scholar 

  10. Sunyecz JA (2008) The use of calcium and vitamin D in the management of osteoporosis. Ther Clin Risk Manag 4(4):827–836

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Hewitt C, Farah CS (2007) Bisphosphonate-related osteonecrosis of the jaws: a comprehensive review. J Oral Pathol Med 36:319–328

    Article  CAS  PubMed  Google Scholar 

  12. Kumar V, Shahi AK (2012) Bisphosphonates induced osteonecrosis of the jaw: a review. Int J Sci Eng Res 3(11):1–5

    CAS  Google Scholar 

  13. Borgioli A, Duvina M, Brancato L, Viviani C, Brandi ML, Tonelli P (2007) Bisphosphonate-related osteonecrosis of the jaw: the Florence experience. Clin Cases Miner bone Metab 4(1):48–52

    PubMed Central  PubMed  Google Scholar 

  14. AJ Roelofs, Thompson K, Gordon S, Rogers MJ (2006) Molecular mechanism of action of bisphosphonates: current status. Clin Cancer Res 12:6222s–6230s

    Article  CAS  PubMed  Google Scholar 

  15. Tanvetyanon T, Stiff PJ (2006) Management of the adverse effects associated with intravenous diphosphonates. Ann Oncol 17:897–907

    Article  CAS  PubMed  Google Scholar 

  16. Melo MD, Obeid G (2005) Osteonecrosis of the maxilla in a patient with a history of bisphosphonate therapy. J Can Dent Assoc 71(2):111–113

    PubMed  Google Scholar 

  17. Somerman MJ, McCauley LK (2006) Bisphosphonates: sacrificing the jaw to save the skeleton? BoneKEy-Osteovision 3(9):12–18

  18. Walter C, Al-Nawas B, Frickhofen N, Gamm H, Beck J, Reinsch et al (2010) Prevalence of bisphosphonate associated osteonecrosis of the jaws in multiple myeloma patients. Head Face Med 6:11. http://www.head-face-med.com/content/6/1/11

  19. Froelich K, Radeloff A, Köhler C, Mlynski R, Müller J, Hagen R, Kleinsasser NH (2011) Bisphosphonate-induced osteonecrosis of the external ear canal: a retrospective study. Eur Arch Otorhinolaryngol 268(8):1219–1225

    Article  CAS  PubMed  Google Scholar 

  20. Polizzotto MN, Cousins V, Schwarer AP (2006) Bisphosphonate-associated osteonecrosis of the auditory canal. Br J Haematol 132(1):114

    Article  PubMed  Google Scholar 

  21. Gupta S, Jain P, Kumar P, Parikh PM (2009) Zoledronic acid induced osteonecrosis of tibia and femur. Indian J Cancer 46(3):249–250

    Article  CAS  PubMed  Google Scholar 

  22. Kim YG, Lee YD, Kwon YD, Suh JH, Jeen SM (2010) Study on bisphosphonates-related osteonecrosis of the jaw (BRONJ): case report and literature review. J Korean Assoc Oral Maxillofac Surg 36:291–302

    Article  Google Scholar 

  23. Borgioli A, Viviani C, Duvina M, Brancato L, Spinelli G, Brandi ML, Tonelli P (2009) Bisphosphonate-related osteonecrosis of the jaws: clinical and Physiopathological considerations. Ther Clin Risk Manag 5:217–227

    PubMed Central  PubMed  Google Scholar 

  24. Lam DK, Sandor GKB, Holmes HI, Evans AW, Clokie CML (2007) A review on bisphosphonate-associated osteonecrosis of the jaws and its management. JCDA 73(5):417–422

    PubMed  Google Scholar 

  25. Wehrhan F, Hyckel P, Ries J, Stockmann P, Nkenke E, Schlegel KA et al (2010) Expression of Msx-1 is suppressed in bisphosphonate associated osteonecrosis related jaw tissue—etiopathology considerations respecting jaw developmental biology-related unique features. J Transl Med 8:96. http://www.translational-medicine.com/content/8/1/96

  26. Ardine M, Generali D, Donadio M (2006) Could the long term persistent 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

    Article  CAS  PubMed  Google Scholar 

  27. Saavedra MS, Bordallo CF, Teres RI, Vallina AM, Calcagno ML (2012) PTH levels in patients treated with bisphosphonates. Rev Argent Endocrinol Metab 49:62–69

    CAS  Google Scholar 

  28. Hellstein JW, Marek CL (2005) Bisphosphonate osteochemonecrosis (Bis-Phossy Jaw): is this Phossy jaw of the 21st century? J Oral Maxillofacial Surg 63:682–689

    Article  Google Scholar 

  29. Woo SB, Hellstein JW, Kalmar JR (2006) Systemic review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144(10):753–761

    Article  CAS  PubMed  Google Scholar 

  30. Vincenzi B, Napolitano A, Zoccoli A, Luliani M, Pantano F, Papapietro N et al (2012) Serum VEGF levels as predictive marker of bisphosphonate related osteonecrosis of the jaw. J Hematol Oncol (Letter to the Editor). doi:10.1186/1756-8722-5-56

  31. Mcleod NMH, Brennan PA, Ruggiero SL (2012) Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review. doi:10.1016/j.surge.2011.09.002

  32. Reid IR (2009) Osteonecrosis of the jaws—who gets it, and why? Bone 44:4–10

    Article  CAS  PubMed  Google Scholar 

  33. Coxon FP, Thompson K, Roelofs AJ, Ebetino FH, Rogers MJ (2008) Visualizing mineral binding and uptake of bisphosphonate by osteoclasts and non-resorbing cells. Bone 42:848–860

    Article  CAS  PubMed  Google Scholar 

  34. Fleisch H (2002) Development of bisphosphonates. Breast Cancer Res 4(1):30–34

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Fleisch H (2002) Bisphosphonates mechanism of action. Endocr Rev 19(1):80–100

    Article  Google Scholar 

  36. Park W, Lee SH, Park KR, Rho SH, Chung WY, Kim HJ (2012) Characteristics of bisphosphonate-related osteonecrosis of the jaw after kidney transplantation. J Craniofac Surg 23(5):e510–e514

    Article  PubMed  Google Scholar 

  37. Andriani A, Petrucci MT, Caravita T, Montanaro M, Villiva N, Levi A, Siniscalchi A et al (2012) Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom’s macroglobulinemia: a retrospective multicentric study. Blood Cancer J 2:e62

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. 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 jaw—2009 update. Approved by the board of trustees. http://www.aaoms.org/docs/position_paper/bronj_updatepdf

  39. NSW Health Guideline (2010) Prevention of osteonecrosis of the jaw (ONJ) in patients with bisphosphonates therapy. GL 2010_010 July 2010

  40. Carey JJ, Palomo L (2008) Bisphosphonates and osteonecrosis of the jaw: innocent association or significant risk? Clevel Clin J Med 75(12):871–879

    Article  Google Scholar 

  41. Borromeo GL, Tsao CE, Darby IB, Ebeling PR (2011) A review of the clinical implications of bisphosphonates in dentistry. Aust Dent J 56:2–9

    Article  CAS  PubMed  Google Scholar 

  42. Rizzoli R, Burlet N, Cahall D, Delmas PD, Eriksen EF, Felsenberg D et al (2008) Osteonecrosis of the jaw and bisphosphonates treatment for osteoporosis. Bone doi:10.1016/j.bone.2008.01.003

  43. Chiandussi S, Biasotto M, Dore F, Cavalli F, Cova MA, Lenarda RD (2006) Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaw. Dentomaxillofacial Radiol 35:236–243

    Article  CAS  Google Scholar 

  44. Olutayo J, Agbaje JO, Jacobs R, Verhaeghe V, Velde FV, Vinckier F (2010) Bisphosphonate-related osteonecrosis of the jaw bone: radiological pattern and the potential role of CBCT in early diagnosis. J Oral Maxillofac Res 1(2):e3 p.1–p.9

    Google Scholar 

  45. Popovic KS, Kocar M (2010) Imaging findings in bisphosphonates—induced osteonecrosis of the jaws. Radiol Oncol 44(4):215–219

    Article  PubMed Central  PubMed  Google Scholar 

  46. Hansen T, Kunkel M, Weber A, Kirkpatrick CJ (2006) Osteonecrosis of the jaws in patients treated with bisphosphonates—histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 35:155–160

    Article  PubMed  Google Scholar 

  47. Ficarra G, Beninati F (2007) Bisphosphonates-related osteonecrosis of the jaws: an update on clinical, pathological and management aspects. Head Neck Pathol 1:132–140

    Article  PubMed Central  PubMed  Google Scholar 

  48. Aas JA, Reime L, Pedersen K, Eribe ERK, Abesha-Belay E, Store G et al (2010) Osteoradionecrosis contains a wide variety of cultivable and non-cultivable bacteria. J Oral Microbiol 2:5072

    Article  Google Scholar 

  49. Markiewicz MR, Margarone JE, Campbell JH, Aguirre A (2005) Bisphosphonate associated osteonecrosis of the jaws: a review of current knowledge. JADA 136. http://jada.ada.org

  50. Stockmann P, Wehrhan F, Furlan SS, Stelzle F, Trabert S, Neukam FW, Nkenke E (2011) Increased human defensine levels hint at an inflammatory etiology of Bisphosphonate-associated osteonecrosis of the jaws: an immunohistological study. J Transl Med 9:135. http://www.translational-medicine.com/content/9/1/135

    Google Scholar 

  51. Wehrhan F, Hyckel P, Guentsch A, Nkenke E, Stockmann P, Schlegel KA, Neukam FW, Amann K (2011) Bisphosphonate-associated osteonecrosis of the jaw is linked to suppressed TGFβ1-signaling and increased Galectin-3 expression: a histological Study on biopsies. J Transl Med 9:102. http://www.translational-medicine.com/content/9/1/102

    Google Scholar 

  52. Marx RE, Cillo EJ, Ulloa JJ (2007) Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention and treatment. J Oral Maxillofac Surg 65:2397–2410

    Article  PubMed  Google Scholar 

  53. 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 

  54. Kwon YD, Kim YR, Choi BJ, Lee DW, Kim DY (2009) Oral bisphosphonate- related osteonecrosis of the jaw: favorable outcome after bisphosphonate holiday. Quintessence Int 40(4):277–278

    PubMed  Google Scholar 

  55. Carey JJ (2005) What is a failure of bisphosphonate therapy for osteoporosis? Clevel Clin J Med 72(11):1033–1039

    Article  Google Scholar 

  56. Nocini PF, Saia G, Bettini G, Ragazzo M, Balndamura S, Chiarini L (2008) Vascularized fibula flap reconstruction of the mandible in bisphosphonate related osteonecrosis. EJSO doi:10.1016/j.ejso.2008.05.002

  57. Lau AN, Adachi JD (2009) Resolution of osteonecrosis of the jaw after Teriparatide [recombinant human PTH-(1-34)] therapy. J Rheumatol 36:1835–1837

    Article  CAS  PubMed  Google Scholar 

  58. Cheng A, Mavrokokki A, Carter G, Stein B, Fazzalri NL, Wilson DF et al (2005) The dental implication of bisphosphonates and bone disease. Aust Dent J 50(Suppl 2):S4–S13

    Article  CAS  PubMed  Google Scholar 

  59. Bagan J, Blade J, Cozar JM, Constela M, Sanz RG, Veiga FG et al (2007) Recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates. Med Oral Patol Oral Cir Bucal 12:e336–e340

    PubMed  Google Scholar 

  60. Cossio PI, Macian AC, Ceballos JLP, Nicas JP, Perez JLG (2008) Bisphosphonates related osteonecrosis of the jaw in patients with multiple myeloma. Med Oral Patol Oral Cir Bucal 13(1):e52–e55

    Google Scholar 

  61. 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 

  62. Freiberger JJ, Burgos RP, Chhoeu AH, Kraft KH, Boneta O, Moon RE, Piantodosi CA (2007) Hyperbaric oxygen treatment and bisphosphonates induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg 65:1321–1327

    Article  PubMed  Google Scholar 

  63. Erkan M, Bilgi O, Mutluoglu M, Uzun G (2009) Bisphosphonates-related osteonecrosis of the jaw in cancer patients and hyperbaric oxygen therapy. J Pancreas (Online) 10(5):579–580

    Google Scholar 

  64. Shah SAA, Aslam A, Mirza AI, Ali S (2010) Bisphosphonates related osteonecrosis of the jaws. J Ayub Med Coll Abbottabad 22(3):214–217

    CAS  PubMed  Google Scholar 

  65. Engroff LS, Kim DD (2007) Treating bisphosphonate osteonecrosis of the jaws: is there a role for resection and vascularized reconstruction? J Oral Maxillofac Surg 65:2374–2385

    Google Scholar 

  66. Epstein ME, Wicknick FW, Epstein JB, Berenson JR, Gorsky M (2010) Management of bisphosphonate-associated osteonecrosis: pentoxifylline and tocopherol in addition to antimicrobial therapy. An initial case series. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110(5):593–596

    Google Scholar 

  67. Cicciu M, Herford AS, Juodžbalys G, Stoffella E (2012) Recombinant human bone morphogenetic protein type 2 application for a possible treatment of bisphosphonates-related osteonecrosis of the jaw. J Craniofac Surg 23(3):784–788

    Article  PubMed  Google Scholar 

  68. Suzuki BJB, Klemes AB (2008) Osteoporosis and osteonecrosis of the jaw. ADHA. Supplement to Access—March 2008

Download references

Author information

Authors and Affiliations

  1. R. D. Dental Hospital and Research Centre, Patna, India

    Vijay Kumar

  2. Department of Oral and Maxillofacial Pathology, Sarjug Dental College and Hospital, Darbhanga, India

    Raman Kant Sinha

Authors
  1. Vijay Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raman Kant Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vijay Kumar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumar, V., Sinha, R.K. Bisphosphonate Related Osteonecrosis of the Jaw: An Update. J. Maxillofac. Oral Surg. 13, 386–393 (2014). https://doi.org/10.1007/s12663-013-0564-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12663-013-0564-x

Keywords

Search

Navigation