Journal of Bone and Mineral Metabolism

, Volume 27, Issue 4, pp 435–443 | Cite as

Osteonecrosis of the jaw in patients with multiple myeloma treated with zoledronic acid

  • Sedat Cetiner
  • Gulsan Turkoz Sucak
  • Sevil Altundag Kahraman
  • Sahika Zeynep Akı
  • Benay Kocakahyaoglu
  • Sibel Elif Gultekin
  • Mustafa Cetiner
  • Rauf Haznedar
Original Article

Abstract

Intravenous bisphosphonates—the potent inhibitors of osteoclast-mediated bone resorption are among the most commonly prescribed drugs in the management of multiple myeloma (MM). Zoledronic acid (ZA) is a new generation potent intravenous bisphosphonate that has been approved for the treatment and prevention of bone lesions, and/or hypercalcemia associated with MM. Osteonecrosis of the jaw (ONJ) is an emerging serious side effect of the new generation bisphosphonates with a growing number of reports related to this pathological entity. ONJ usually appears following oral surgical and dental procedures but sometimes occur spontaneously. These cases are mostly seen and treated by dentists and oral surgeons. The aim of this study was to discuss the frequency, characteristics, risk factors, management and histopathological features of ZA induced ONJ based on the literature and illustrated with five own cases. Thirty-two patients with MM who received ZA for a median period of 26.5 ± 18.7 months (min: 5 months, max: 76 months) were evaluated. ONJ was detected in five patients and mean drug duration time was 34 months. The frequency was 15% and the patients were usually symptomatic. There was no significant difference in terms of the duration of ZA in patients with and without ONJ. Management of these established cases were performed with medical treatment, minor debridement, sequestrectomy, and combining bone resection with autologous platelet rich plasma. Our data indicate that ZA therapy has a major role in the development of ONJ a fact that should be considered by physicians treating MM patients.

Keywords

Multiple myeloma Jaw osteonecrosis Zoledronic acid Bisphosphonates Thalidomide 

References

  1. 1.
    Dunstan CR, Felsenberg D, Seibel MJ (2007) Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor-induced bone disease. Nat Clin Pract Oncol 4:42–55PubMedCrossRefGoogle Scholar
  2. 2.
    Melo MD, Obeid G (2005) Osteonecrosis of the maxilla in a patient with a history of bisphosphonate therapy. J Can Dent Assoc 71:111–113PubMedGoogle Scholar
  3. 3.
    Robinson NA, Yeo JF (2004) Bisphosphonates—a word of caution. Ann Acad Med Singap 33:48–49PubMedGoogle Scholar
  4. 4.
    Diego R, D’Orto O, Pagani D, Agazzi A, Marzano U, Derada Troletti G, Fontanella W, Pignataro L (2007) Bisphosphonate-associated osteonecrosis of the jaws—a therapeutic dilemma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103:e1–e5PubMedCrossRefGoogle Scholar
  5. 5.
    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 62:527–534PubMedCrossRefGoogle Scholar
  6. 6.
    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 83:1930–1935PubMedCrossRefGoogle Scholar
  7. 7.
    Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC (2000) Cellular and molecular mechanisms of action of bisphosphonates. Cancer 15(88):2961–2978CrossRefGoogle Scholar
  8. 8.
    Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, Mundy GR, Boyce BF (1995) Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 10:1478–1487PubMedCrossRefGoogle Scholar
  9. 9.
    Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117PubMedCrossRefGoogle Scholar
  10. 10.
    Zervas K, Verrou E, Teleioudis Z, Vahysevanos K, Banti A, Mihou D, Krikelis D, Terpos E (2006) 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 134:620–623PubMedCrossRefGoogle Scholar
  11. 11.
    Prophet EB, Mills B, Arrington JB, Sobin LH (1992) Laboratory methods in histotechnology. Armed Forces Institute of Pathology. AM Registry of Pathology Washington DCGoogle Scholar
  12. 12.
    Bagan JV, Murillo J, Jimenez Y, Poveda R, Milian MA, Sanchis JM, Silvestre FJ, Scully C (2005) Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med 34:120–123PubMedCrossRefGoogle Scholar
  13. 13.
    Melo MD, Obeid G (2005) Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy: strategies for prevention and early recognition. J Am Dent Assoc 136:1675–1681PubMedGoogle Scholar
  14. 14.
    Pogrel MA, Miller CE (2003) A case of maxillary necrosis. J Oral Maxillofac Surg 61:489–493PubMedCrossRefGoogle Scholar
  15. 15.
    Reuther T, Schuster T, Mende U, Kubler A (2003) Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients—a report of a thirty year retrospective review. Int J Oral Maxillofac Surg 32:289–295PubMedCrossRefGoogle Scholar
  16. 16.
    Ruggiero SL, Fantasia J, Carlson E (2006) Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:433–441PubMedCrossRefGoogle Scholar
  17. 17.
    Vannucchi AM, Ficarra G, Antonioli E, Bosi A (2005) Osteonecrosis of the jaw associated with zoledronate therapy in a patient with multiple myeloma. Br J Haematol 128:738PubMedCrossRefGoogle Scholar
  18. 18.
    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 35:155–160PubMedCrossRefGoogle Scholar
  19. 19.
    Hansen T, Kunkel M, Springer E, Walter C, Weber A, Siegel E, Kirkpatrick CJ (2007) Actinomycosis of the jaws-histopathological study of 45 patients shows significant involvement in bisphosphonate-associated osteonecrosis and infected osteoradionecrosis. Virchows Arch 451:1009–1017PubMedCrossRefGoogle Scholar
  20. 20.
    Font Gomez R, Garcia MLM, Martinez JMO (2008) Osteochemonecrosis of the jaws due to bisphosphonate treatments. Update. Med Oral Patol Oral Cir Bucal 13:318–324Google Scholar
  21. 21.
    Sarin J, DeRossi SS, Akintoye SO (2008) Updates on bisphosphonates and potential pathobiology of bisphosphonate-induced jaw osteonecrosis. Oral Dis 14:277–285PubMedCrossRefGoogle Scholar
  22. 22.
    Woo SB, Hellstein JW, Kalmar JR (2006) Narrative review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144:753–761PubMedGoogle Scholar
  23. 23.
    Ardine M, Generali D, Donadio M et al (2006) 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 17:1336–1337PubMedCrossRefGoogle Scholar
  24. 24.
    Suda K, Udugawa N, Sato N (2004) Suppression of osteoprotegrin expression by prostaglandin E2 crucially involved in lipopolysaccharide-induced osteoclast formation. J Immunol 172:2504–2508PubMedGoogle Scholar
  25. 25.
    Li EC, Davis LE (2003) Zoledronic acid: a new parenteral bisphosphonate. Clin Ther 25:2669–2708PubMedCrossRefGoogle Scholar
  26. 26.
    Durie BG, Katz M, Crowley J (2005) Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 353:99–102PubMedCrossRefGoogle Scholar
  27. 27.
    Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel RF, Hortobagyi GN (2008) Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23:826–836PubMedCrossRefGoogle Scholar
  28. 28.
    Van Poznak C, Estilo C (2006) Osteonecrosis of the jaw in cancer patients receiving IV bisphosphonates. Oncology (Williston Park) 20:1053–1065Google Scholar
  29. 29.
    Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, Dimopoulos MA (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23:8580–8587PubMedCrossRefGoogle Scholar
  30. 30.
    Moehler TM, Hillengass J, Glasmacher A, Goldschmidt H (2006) Thalidomide in multiple myeloma. Curr Pharm Biotechnol 7:431–440PubMedCrossRefGoogle Scholar
  31. 31.
    Tosi P, Zamagni E, Cangini D, Tacchetti P, Di Raimondo F, Catalano L, D’Arco A, Ronconi S, Cellini C, Offidani M, Perrone G, Ceccolini M, Brioli A, Tura S, Baccarani M, Cavo M (2006) Osteonecrosis of the jaws in newly diagnosed multiple myeloma patients treated with zoledronic acid and thalidomide-dexamethasone. Blood 108:3951–3952PubMedCrossRefGoogle Scholar
  32. 32.
    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 63:1567–1575PubMedCrossRefGoogle Scholar
  33. 33.
    Woeller A, Gering A, Brix M, Bettega G, Lebeau J (2006) Bone necrosis of the jaws in five patients taking bisphosphonates. Rev Stomatol Chir Maxillofac 107:417–422PubMedCrossRefGoogle Scholar
  34. 34.
    Farrugia MC, Summerlin DJ, Krowiak E, Huntley T, Freeman S, Borrowdale R, Tomich C (2006) Osteonecrosis of the mandible or maxilla associated with the use of new generation bisphosphonates. Laryngoscope 116:115–120PubMedCrossRefGoogle Scholar
  35. 35.
    American Dental Association Council on Scientific Affairs (2006) Dental management of patients receiving oral bisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 137:1144–1150Google Scholar
  36. 36.
    Katz H (2005) Endodontic implications of bisphosphonate-associated osteonecrosis of the jaws: a report of three cases. J Endod 31:831–834PubMedCrossRefGoogle Scholar
  37. 37.
    Curi MM, Cossolin GS, Koga DH, Araujo SR, Feher O, Dos Santos MO, Zardetto C (2007) Treatment of avascular osteonecrosis of the mandible in cancer patients with a history of bisphosphonate therapy by combining bone resection and autologous platelet-rich plasma: report of 3 cases. J Oral Maxillofac Surg 65:349–355PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2009

Authors and Affiliations

  • Sedat Cetiner
    • 1
  • Gulsan Turkoz Sucak
    • 2
  • Sevil Altundag Kahraman
    • 1
    • 5
  • Sahika Zeynep Akı
    • 2
  • Benay Kocakahyaoglu
    • 1
  • Sibel Elif Gultekin
    • 3
  • Mustafa Cetiner
    • 4
  • Rauf Haznedar
    • 2
  1. 1.Department of Oral and Maxillofacial Surgery, Faculty of DentistryGazi UniversityAnkaraTurkey
  2. 2.Department of Hematology, Faculty of MedicineGazi UniversityAnkaraTurkey
  3. 3.Department of Oral Pathology, Faculty of DentistryGazi UniversityAnkaraTurkey
  4. 4.Department of Hematology, Faculty of MedicineMarmara UniversityIstanbulTurkey
  5. 5.Emek, AnkaraTurkey

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