UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Medication-related osteonecrosis of the jaw in patients with cancer

Authors
James R Berenson, MD
Alison T Stopeck, MD
Section Editors
Robert A Kyle, MD
Reed E Drews, MD
Deputy Editor
Diane MF Savarese, MD

INTRODUCTION

Osteonecrosis of the jaw (ONJ), which was first described in 2002 [1], is a relatively uncommon but potentially serious side effect of treatment with antiresorptive agents such as intravenous (IV) high potency bisphosphonates (image 1) and denosumab, which decrease the risk of skeletal-related events (SREs) in patients with cancer and metastatic bone disease. The increased dose intensity of anti-resorptive therapy typically prescribed for cancer indications places cancer patients at a substantially higher risk for ONJ than are patients who receive them for other conditions such as osteoporosis and Paget's disease [2-5].

ONJ has also been described as a complication of cancer therapies that target angiogenesis; however, this association is more controversial with little confirmatory prospective trial data available in the setting of monotherapy with an antiangiogenic agent alone. Use of antiangiogenic agents as a risk factor for medication-related ONJ (MRONJ) among patients receiving antiresorptive agents for cancer is more clearly established. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Osteonecrosis of the jaw'.)

This topic review will describe the incidence, risk factors, staging, clinical course, prevention strategies, and management of MRONJ in patients with cancer who are receiving antiresorptive agents. The incidence, risk factors, and management strategies for MRONJ in patients receiving antiresorptive therapy for osteoporosis and other side effects associated with bisphosphonates and denosumab in patients with cancer are addressed elsewhere. (See "Denosumab for osteoporosis", section on 'Oversuppression of bone remodeling' and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

NOMENCLATURE AND DEFINITION

ONJ associated with bisphosphonate treatment has been referred to by several acronyms including BRONJ (bisphosphonate-related ONJ), BRON (bisphosphonate-related osteonecrosis), BON (bisphosphonate osteonecrosis), BAONJ (bisphosphonate-associated ONJ), and simply ONJ. The recognition of jaw necrosis as a complication of other drugs, including the RANK (receptor activator of nuclear factor kappa B) ligand inhibitor denosumab and antiangiogenic agents prompted a special committee of the American Association of Oral and Maxillofacial Surgeons (AAOMS) to recommend the term medication-related osteonecrosis of the jaw as preferred [6].

Definition — Two working definitions of MRONJ have been proposed:

                              

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Aug 2017. | This topic last updated: Feb 03, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Edwards BJ, Gounder M, McKoy JM, et al. Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw. Lancet Oncol 2008; 9:1166.
  2. Khosla S, Burr D, Cauley J, 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 2007; 22:1479.
  3. Hoff AO, Toth BB, Altundag K, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008; 23:826.
  4. Zervas K, Verrou E, Teleioudis Z, 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 2006; 134:620.
  5. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007; 65:415.
  6. Medication-Related Osteonecrosis of the Jaw - 2014 Update. American Association of Oral and Maxillofacial Surgeons. http://www.aaoms.org/docs/position_papers/mronj_position_paper.pdf?pdf=MRONJ-Position-Paper (Accessed on September 04, 2014).
  7. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015; 30:3.
  8. Allen MR, Burr DB. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 2009; 67:61.
  9. Katsarelis H, Shah NP, Dhariwal DK, Pazianas M. Infection and medication-related osteonecrosis of the jaw. J Dent Res 2015; 94:534.
  10. Allen MR, Kubek DJ, Burr DB. Cancer treatment dosing regimens of zoledronic acid result in near-complete suppression of mandible intracortical bone remodeling in beagle dogs. J Bone Miner Res 2010; 25:98.
  11. Ristow O, Gerngroß C, Schwaiger M, et al. Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in pathogenesis of bisphosphonate-related osteonecrosis? J Oral Maxillofac Surg 2014; 72:903.
  12. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002; 302:1055.
  13. Santini D, Vincenzi B, Dicuonzo G, et al. Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 2003; 9:2893.
  14. Hansen T, Kunkel M, Weber A, James Kirkpatrick C. Osteonecrosis of the jaws in patients treated with bisphosphonates - histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 2006; 35:155.
  15. Allen MR, Burr DB. Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J Oral Maxillofac Surg 2008; 66:987.
  16. 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 2010; 14:271.
  17. Pazianas M. Osteonecrosis of the jaw and the role of macrophages. J Natl Cancer Inst 2011; 103:232.
  18. Kos M, Junka A, Smutnicka D, et al. Pamidronate enhances bacterial adhesion to bone hydroxyapatite. Another puzzle in the pathology of bisphosphonate-related osteonecrosis of the jaw? J Oral Maxillofac Surg 2013; 71:1010.
  19. Sedghizadeh PP, Kumar SK, Gorur A, et al. Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaw secondary to bisphosphonate therapy. J Am Dent Assoc 2009; 140:1259.
  20. Wanger G, Gorby Y, El-Naggar MY, et al. Electrically conductive bacterial nanowires in bisphosphonate-related osteonecrosis of the jaw biofilms. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 115:71.
  21. Estilo CL, Van Poznak CH, Wiliams T, et al. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. Oncologist 2008; 13:911.
  22. Saussez S, Javadian R, Hupin C, et al. Bisphosphonate-related osteonecrosis of the jaw and its associated risk factors: a Belgian case series. Laryngoscope 2009; 119:323.
  23. Naik NH, Russo TA. Bisphosphonate-related osteonecrosis of the jaw: the role of actinomyces. Clin Infect Dis 2009; 49:1729.
  24. Sedghizadeh PP, Kumar SK, Gorur A, et al. Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg 2008; 66:767.
  25. Reid IR, Bolland MJ, Grey AB. Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 2007; 41:318.
  26. Scheper MA, Badros A, Chaisuparat R, et al. Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis. Br J Haematol 2009; 144:667.
  27. Geissmann F, Manz MG, Jung S, et al. Development of monocytes, macrophages, and dendritic cells. Science 2010; 327:656.
  28. Roelofs AJ, Coxon FP, Ebetino FH, et al. Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo. J Bone Miner Res 2010; 25:606.
  29. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 2006; 24:945.
  30. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 2008; 83:1032.
  31. Bertoldo F, Santini D, Lo Cascio V. Bisphosphonates and osteomyelitis of the jaw: a pathogenic puzzle. Nat Clin Pract Oncol 2007; 4:711.
  32. Raje N, Woo SB, Hande K, et al. Clinical, radiographic, and biochemical characterization of multiple myeloma patients with osteonecrosis of the jaw. Clin Cancer Res 2008; 14:2387.
  33. Van den Wyngaert T, Huizing MT, Fossion E, Vermorken JB. Bisphosphonates in oncology: rising stars or fallen heroes. Oncologist 2009; 14:181.
  34. Pozzi S, Vallet S, Mukherjee S, et al. High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties. Clin Cancer Res 2009; 15:5829.
  35. Allegra A, Oteri G, Nastro E, et al. Patients with bisphosphonates-associated osteonecrosis of the jaw have reduced circulating endothelial cells. Hematol Oncol 2007; 25:164.
  36. Allen MR, Ruggiero SL. A review of pharmaceutical agents and oral bone health: how osteonecrosis of the jaw has affected the field. Int J Oral Maxillofac Implants 2014; 29:e45.
  37. Fedele S, Porter SR, D'Aiuto F, et al. Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 2010; 123:1060.
  38. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006; 144:753.
  39. Saad F, Brown JE, Van Poznak C, et al. Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 2012; 23:1341.
  40. Ruggiero SL, 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 2006; 102:433.
  41. Treister NS, Friedland B, Woo SB. Use of cone-beam computerized tomography for evaluation of bisphosphonate-associated osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109:753.
  42. Arce K, Assael LA, Weissman JL, Markiewicz MR. Imaging findings in bisphosphonate-related osteonecrosis of jaws. J Oral Maxillofac Surg 2009; 67:75.
  43. Vescovi P, Nammour S. Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) therapy. A critical review. Minerva Stomatol 2010; 59:181.
  44. Chiandussi S, Biasotto M, Dore F, et al. Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws. Dentomaxillofac Radiol 2006; 35:236.
  45. O'Ryan FS, Khoury S, Liao W, et al. Intravenous bisphosphonate-related osteonecrosis of the jaw: bone scintigraphy as an early indicator. J Oral Maxillofac Surg 2009; 67:1363.
  46. Goodwin JS, Zhou J, Kuo YF, Baillargeon J. Risk of Jaw Osteonecrosis After Intravenous Bisphosphonates in Cancer Patients and Patients Without Cancer. Mayo Clin Proc 2017; 92:106.
  47. lipton A, Saad F, Van Poznak CH, et al. Incidence of osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases from solid tumors or multiple myeloma: Results from three phase III trials (abstract). J Clin Oncol 31, 2013 (suppl; abstr 9640). Abstract aviailable online at http://meetinglibrary.asco.org/content/117414-132 (Accessed on September 08, 2014).
  48. Ruggiero SL, Dodson TB, Assael LA, et al. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws--2009 update. J Oral Maxillofac Surg 2009; 67:2.
  49. Qi WX, Tang LN, He AN, et al. Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol 2014; 19:403.
  50. Mauri D, Valachis A, Polyzos IP, et al. Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis. Breast Cancer Res Treat 2009; 116:433.
  51. Coleman R, Woodward E, Brown J, et al. Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01-04) for women with stage II/III breast cancer. Breast Cancer Res Treat 2011; 127:429.
  52. Palaska PK, Cartsos V, Zavras AI. Bisphosphonates and time to osteonecrosis development. Oncologist 2009; 14:1154.
  53. King AE, Umland EM. Osteonecrosis of the jaw in patients receiving intravenous or oral bisphosphonates. Pharmacotherapy 2008; 28:667.
  54. Jackson GH, Morgan GJ, Davies FE, et al. Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results. Br J Haematol 2014; 166:109.
  55. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005; 23:8580.
  56. Background document for meeting of advisory committee for reproductive health drugs and drug safety and risk management advisory committee. United States Food and Drug Administration. September 9, 2011. Available online at http://www.fda.gov/downloads/Advisory-Committees/CommitteesMeetingMaterials/drugs/DrugSafetyandRiskManagementAdvisoryCommittee/ucm270958.pdf (Accessed on September 11, 2014).
  57. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005; 353:99.
  58. Filleul O, Crompot E, Saussez S. Bisphosphonate-induced osteonecrosis of the jaw: a review of 2,400 patient cases. J Cancer Res Clin Oncol 2010; 136:1117.
  59. Dimopoulos MA, Kastritis E, Anagnostopoulos 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 2006; 91:968.
  60. Boonyapakorn T, Schirmer I, Reichart PA, et al. Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008; 44:857.
  61. Corso A, Varettoni M, Zappasodi P, et al. A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma. Leukemia 2007; 21:1545.
  62. Gralow J, Barlow WE, Paterson AHG, et al. SWOG S0307 phase III trial of bisphosphonates as adjuvant therapy ini primary breast cancer: Comparison of toxicities and patient-stated preference for oral versus intravenous therapy (abstract). J Clin Oncol 32:5s, 2014 (suppl; abstr 558). Abstract avaiolable online at http://meetinglibrary.asco.org/content/129741-144.
  63. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011; 29:1125.
  64. Guarneri V, Miles D, Robert N, et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 2010; 122:181.
  65. Christodoulou C, Pervena A, Klouvas G, et al. Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone. Oncology 2009; 76:209.
  66. Aragon-Ching JB, Dahut WL. Osteonecrosis of the jaw and the use of antiangiogenic agents: just an association? Oncologist 2008; 13:1314; author reply 1315.
  67. Brunello A, Saia G, Bedogni A, et al. Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 2009; 44:173.
  68. Aragon-Ching JB, Ning YM, Chen CC, et al. Higher incidence of Osteonecrosis of the Jaw (ONJ) in patients with metastatic castration resistant prostate cancer treated with anti-angiogenic agents. Cancer Invest 2009; 27:221.
  69. Beuselinck B, Wolter P, Karadimou A, et al. Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. Br J Cancer 2012; 107:1665.
  70. Hoefert S, Eufinger H. Sunitinib may raise the risk of bisphosphonate-related osteonecrosis of the jaw: presentation of three cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 110:463.
  71. Tosi P, Zamagni E, Cangini D, et al. Osteonecrosis of the jaws in newly diagnosed multiple myeloma patients treated with zoledronic acid and thalidomide-dexamethasone. Blood 2006; 108:3951.
  72. Pozzi S, Marcheselli R, Sacchi S, et al. Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients. Leuk Lymphoma 2007; 48:56.
  73. Morgan GJ, et al. Efficacy and side-effect profile of long-term bisphosphonate therapy in patients with multiple myeloma (MM): MRC myeloma IX study results. J Clin Oncol 30, 2012 (suppl; abstr 8015). Abstract available online at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=114&abstractID=100635.
  74. Marx RE, 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 2005; 63:1567.
  75. Kyrgidis A, Vahtsevanos K, Koloutsos G, et al. Bisphosphonate-related osteonecrosis of the jaws: a case-control study of risk factors in breast cancer patients. J Clin Oncol 2008; 26:4634.
  76. Hoff AO, Toth B, Hu M, et al. Epidemiology and risk factors for osteonecrosis of the jaw in cancer patients. Ann N Y Acad Sci 2011; 1218:47.
  77. Vahtsevanos K, Kyrgidis A, Verrou E, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009; 27:5356.
  78. Fehm T, Beck V, Banys M, et al. Bisphosphonate-induced osteonecrosis of the jaw (ONJ): Incidence and risk factors in patients with breast cancer and gynecological malignancies. Gynecol Oncol 2009; 112:605.
  79. Yamazaki T, Yamori M, Ishizaki T, et al. Increased incidence of osteonecrosis of the jaw after tooth extraction in patients treated with bisphosphonates: a cohort study. Int J Oral Maxillofac Surg 2012; 41:1397.
  80. Mozzati M, Arata V, Gallesio G. Tooth extraction in patients on zoledronic acid therapy. Oral Oncol 2012; 48:817.
  81. Scoletta M, Arata V, Arduino PG, et al. Tooth extractions in intravenous bisphosphonate-treated patients: a refined protocol. J Oral Maxillofac Surg 2013; 71:994.
  82. Tsao C, Darby I, Ebeling PR, et al. Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg 2013; 71:1360.
  83. Cetiner S, Sucak GT, Kahraman SA, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with zoledronic acid. J Bone Miner Metab 2009; 27:435.
  84. Sarasquete ME, García-Sanz R, Marín L, et al. Bisphosphonate-related osteonecrosis of the jaw is associated with polymorphisms of the cytochrome P450 CYP2C8 in multiple myeloma: a genome-wide single nucleotide polymorphism analysis. Blood 2008; 112:2709.
  85. Lehrer S, Montazem A, Ramanathan L, et al. Bisphosphonate-induced osteonecrosis of the jaws, bone markers, and a hypothesized candidate gene. J Oral Maxillofac Surg 2009; 67:159.
  86. Nicoletti P, Cartsos VM, Palaska PK, et al. Genomewide pharmacogenetics of bisphosphonate-induced osteonecrosis of the jaw: the role of RBMS3. Oncologist 2012; 17:279.
  87. Katz J, Gong Y, Salmasinia D, et al. Genetic polymorphisms and other risk factors associated with bisphosphonate induced osteonecrosis of the jaw. Int J Oral Maxillofac Surg 2011; 40:605.
  88. Marini F, Tonelli P, Cavalli L, et al. Pharmacogenetics of bisphosphonate-associated osteonecrosis of the jaw. Front Biosci (Elite Ed) 2011; 3:364.
  89. Berenson JR, Yellin O, Crowley J, et al. Prognostic factors and jaw and renal complications among multiple myeloma patients treated with zoledronic acid. Am J Hematol 2011; 86:25.
  90. Jadu F, Lee L, Pharoah M, et al. A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients. Ann Oncol 2007; 18:2015.
  91. Migliorati CA, Epstein JB, Abt E, Berenson JR. Osteonecrosis of the jaw and bisphosphonates in cancer: a narrative review. Nat Rev Endocrinol 2011; 7:34.
  92. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011; 29:1221.
  93. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007; 25:2464.
  94. European Medicines Agency. CHMP Assessment Report on Bisphosphonates and Osteonecrosis of the Jaw. London: EMA/CHMP 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500051383.pdf (Accessed on October 16, 2014).
  95. Epstein JB, Güneri P, Barasch A. Appropriate and necessary oral care for people with cancer: guidance to obtain the right oral and dental care at the right time. Support Care Cancer 2014; 22:1981.
  96. Ripamonti CI, Maniezzo M, Campa T, 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 2009; 20:137.
  97. Dimopoulos MA, Kastritis E, Bamia C, et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 2009; 20:117.
  98. Bonacina R, Mariani U, Villa F, Villa A. Preventive strategies and clinical implications for bisphosphonate-related osteonecrosis of the jaw: a review of 282 patients. J Can Dent Assoc 2011; 77:b147.
  99. Vandone AM, Donadio M, Mozzati M, et al. Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: a single-center clinical experience. Ann Oncol 2012; 23:193.
  100. Mücke T, Deppe H, Hein J, et al. Prevention of bisphosphonate-related osteonecrosis of the jaws in patients with prostate cancer treated with zoledronic acid - A prospective study over 6 years. J Craniomaxillofac Surg 2016; 44:1689.
  101. Bagan JV, Jiménez Y, Gómez D, et al. Collagen telopeptide (serum CTX) and its relationship with the size and number of lesions in osteonecrosis of the jaws in cancer patients on intravenous bisphosphonates. Oral Oncol 2008; 44:1088.
  102. Kunchur R, Need A, Hughes T, Goss A. Clinical investigation of C-terminal cross-linking telopeptide test in prevention and management of bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 2009; 67:1167.
  103. Lehrer S, Montazem A, Ramanathan L, et al. Normal serum bone markers in bisphosphonate-induced osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 106:389.
  104. Himelstein AL, Qin R, Novotny PJ, et al. CALGB 90604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dising of zoledronic acid in metastatic cancer (abstr). J Clin Oncol 33, 2015 (suppl; abstr 9501). Abstract available at http://meetinglibrary.asco.org/content/147845-156 (Accessed on July 09, 2015).
  105. Montefusco V, Gay F, Spina F, et al. Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates. Leuk Lymphoma 2008; 49:2156.
  106. Lazarovici TS, Yahalom R, Taicher S, et al. Bisphosphonate-related osteonecrosis of the jaws: a single-center study of 101 patients. J Oral Maxillofac Surg 2009; 67:850.
  107. Bilezikian JP. Osteonecrosis of the jaw--do bisphosphonates pose a risk? N Engl J Med 2006; 355:2278.
  108. Kademani D, Koka S, Lacy MQ, Rajkumar SV. Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy. Mayo Clin Proc 2006; 81:1100.
  109. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62:527.
  110. Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 2005; 104:83.
  111. Farrugia MC, Summerlin DJ, Krowiak E, et al. Osteonecrosis of the mandible or maxilla associated with the use of new generation bisphosphonates. Laryngoscope 2006; 116:115.
  112. Tirelli G, Biasotto M, Chiandussi S, et al. Bisphosphonate-associated osteonecrosis of the jaws: the limits of a conservative approach. Head Neck 2009; 31:1249.
  113. Seth R, Futran ND, Alam DS, Knott PD. Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws. Laryngoscope 2010; 120:2165.
  114. Ferlito S, Puzzo S, Palermo F, Verzì P. Treatment of bisphosphonate-related osteonecrosis of the jaws: presentation of a protocol and an observational longitudinal study of an Italian series of cases. Br J Oral Maxillofac Surg 2012; 50:425.
  115. Scoletta M, Arduino PG, Dalmasso P, et al. Treatment outcomes in patients with bisphosphonate-related osteonecrosis of the jaws: a prospective study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 110:46.
  116. Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 2006; 81:1047.
  117. Wutzl A, Pohl S, Sulzbacher I, et al. Factors influencing surgical treatment of bisphosphonate-related osteonecrosis of the jaws. Head Neck 2012; 34:194.
  118. Montebugnoli L, Felicetti L, Gissi DB, et al. Biphosphonate-associated osteonecrosis can be controlled by nonsurgical management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007; 104:473.
  119. Marx RE, Cillo JE Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007; 65:2397.
  120. Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 2009; 20:1303.
  121. Khan AA, Sándor GK, Dore E, et al. Canadian consensus practice guidelines for bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 2008; 35:1391.
  122. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=50538 (Accessed on November 22, 2011).
  123. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=41963 (Accessed on November 22, 2011).
  124. Badros A, Terpos E, Katodritou E, et al. Natural history of osteonecrosis of the jaw in patients with multiple myeloma. J Clin Oncol 2008; 26:5904.
  125. Epstein MS, Wicknick FW, Epstein JB, et al. 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 2010; 110:593.
  126. Ripamonti CI, Cislaghi E, Mariani L, Maniezzo M. Efficacy and safety of medical ozone (O(3)) delivered in oil suspension applications for the treatment of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: Preliminary results of a phase I-II study. Oral Oncol 2011; 47:185.
  127. Agrillo A, Ungari C, Filiaci F, et al. Ozone therapy in the treatment of avascular bisphosphonate-related jaw osteonecrosis. J Craniofac Surg 2007; 18:1071.
  128. Petrucci MT, Gallucci C, Agrillo A, et al. Role of ozone therapy in the treatment of osteonecrosis of the jaws in multiple myeloma patients. Haematologica 2007; 92:1289.
  129. Freiberger JJ, Padilla-Burgos R, Chhoeu AH, et al. Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg 2007; 65:1321.
  130. Shimura K, Shimazaki C, Taniguchi K, et al. Hyperbaric oxygen in addition to antibiotic therapy is effective for bisphosphonate-induced osteonecrosis of the jaw in a patient with multiple myeloma. Int J Hematol 2006; 84:343.
  131. Erkan M, Bilgi O, Mutluoğlu M, Uzun G. Bisphosphonate-related osteonecrosis of the jaw in cancer patients and hyperbaric oxygen therapy. JOP 2009; 10:579.
  132. Freiberger JJ, Padilla-Burgos R, McGraw T, et al. What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. J Oral Maxillofac Surg 2012; 70:1573.
  133. Rollason V, Laverrière A, MacDonald LC, et al. Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ). Cochrane Database Syst Rev 2016; 2:CD008455.
  134. Vescovi P, Merigo E, Manfredi M, et al. Nd:YAG laser biostimulation in the treatment of bisphosphonate-associated osteonecrosis of the jaw: clinical experience in 28 cases. Photomed Laser Surg 2008; 26:37.
  135. Scoletta M, Arduino PG, Reggio L, et al. Effect of low-level laser irradiation on bisphosphonate-induced osteonecrosis of the jaws: preliminary results of a prospective study. Photomed Laser Surg 2010; 28:179.
  136. Atalay B, Yalcin S, Emes Y, et al. Bisphosphonate-related osteonecrosis: laser-assisted surgical treatment or conventional surgery? Lasers Med Sci 2011; 26:815.
  137. Romeo U, Galanakis A, Marias C, et al. Observation of pain control in patients with bisphosphonate-induced osteonecrosis using low level laser therapy: preliminary results. Photomed Laser Surg 2011; 29:447.
  138. Martins MA, Martins MD, Lascala CA, et al. Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: a preliminary study. Oral Oncol 2012; 48:79.
  139. Altay MA, Tasar F, Tosun E, Kan B. Low-level laser therapy supported surgical treatment of bisphosphonate related osteonecrosis of jaws: a retrospective analysis of 11 cases. Photomed Laser Surg 2014; 32:468.
  140. Weber JB, Camilotti RS, Ponte ME. Efficacy of laser therapy in the management of bisphosphonate-related osteonecrosis of the jaw (BRONJ): a systematic review. Lasers Med Sci 2016; 31:1261.
  141. Latifyan S, Genot MT, Klastersky J. Bisphosphonate-related osteonecrosis of the jaw: a review of the potential efficacy of low-level laser therapy. Support Care Cancer 2016; 24:3687.
  142. Andrews EB, Gilsenan AW, Midkiff K, et al. The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and findings from the first 7 years. J Bone Miner Res 2012; 27:2429.
  143. Del Fabbro M, Gallesio G, Mozzati M. Autologous platelet concentrates for bisphosphonate-related osteonecrosis of the jaw treatment and prevention. A systematic review of the literature. Eur J Cancer 2015; 51:62.