InTech uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Immunology, Allergology and Rheumatology » "Immunopathology and Immunomodulation", book edited by Krassimir Metodiev, ISBN 978-953-51-2210-4, Published: November 18, 2015 under CC BY 3.0 license. © The Author(s).

Chapter 7

Biological Concepts on Bisphosphonate Treated Patients in the Context of Increasing Patient Life Quality and the Need for Oral Surgical Procedures

By Metodi Abadzhiev
DOI: 10.5772/61731

  1. Alberto Bedogni, Stefano Fadele, Georgio Bedogni, Matteo Scoletta, Gianfranco Favia, Giordana Bettini, Olga Di Feda, Giacomo Oleri, Stephen Porter, M. Petrizzi, P. Arduino, S. DAmatoDamato, C. Ungari, P-L Fung Polly, G. Saia, et al. Standing of Osteonecrosisosteonecrosis of the jaw requires computed tomography for accurate definition of the extent of bony disease. British J Oral Maxillofac Surg, 52(7):603–608, 2014.

  2. Raj B. Lotwala, Geoffrey M. Greenlee, Susan M. Ott, Stanton H. Hall, Greg J. Huang. Bisphosphonates as a risk factor for adverse orthodontic outcomes; a retrospective cohort study Original Research Article. American J Orthodontics and Dentofacial Orthopedics, 142(5):625–634, e3, 2012.

  3. Ines Losada, Leonardo Sartoni, Elena di Gianantonio, Margherita Zen, Maurizio Clementi, Andrea Doria. Bisphosphonates in Patients with autoimmune rheumatic diseases: Can they be used in women of childbearing age? Review Article Autoimmunity Reviews, 9(8):547–552, 2010.

  4. Carlos Pigrau–Serrallach, Evelyn Carbal–Galeano, Benito Almirante-Gragera, Roger Sorde–Masip, Dolors Rodrigues–Pardo, Nuria Fernandez–Hidalgo, Niaves Larossa, Soccoro Bescos–Atin, Albert Pahissa–Berga. Long–term follow-up of jaw osteomyelitis associated with Bisphosphonatebisphosphonate use in a tertiary-care center. originalOriginal Research Article Entermadades infecciosas y Microbiologia Clinica, 32(1):128–22, 2014.

  5. Atalay B, Yalcin S, Emes Y, et al: Bisphosphonate-related osteonecrosis: laser-assisted surgical treatment or conventional surgery? Lasers Med Sci 26:815, 2011.

  6. Ayllon J, Launay-Vacher V, Medioni J, et al: Osteonecrosis of the jaw under bisphosphonate and antiangiogenic therapies: cumulative toxicity profile? Ann Oncol 20:600, 2009.

  7. Ali-Erdem M, Burak-Cankaya A, Cemil-Isler S, et al: Extraction socket healing in rats treated with bisphosphonate: animal model for bisphosphonate related osteonecrosis of jaws in multiple myeloma patients. Med Oral Patol Oral Cir Bucal 16:e879, 2011.

  8. Aguirre JI, Akhter MP, Kimmel DB, et al: Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis. J Bone Miner Res 27:2130, 2012.

  9. Aghaloo TL, Felsenfeld AL, Tetradis S: Osteonecrosis of the jaw in a patient on denosumab. J Oral Maxillofac Surg 68:959, 2010.

  10. Abu-Id MH, Warnke PH, Gottschalk J, et al: “Bis-phossy jaws” -high and low risk factors for bisphosphonate-induced osteonecro-sis of the jaw. J Craniomaxillofac Surg 36:95, 2008.

  11. Aghaloo TL, Kang B, Sung EC, et al: Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat. J Bone Miner Res 26:1871, 2011.

  12. Allen MR, Burr DB: The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 67:61, 2009.

  13. Allen MR, Burr DB: Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J Oral Maxillofac Surg 66:987, 2008.

  14. Aapro M, Saad F, Costa L: Optimizing clinical benefits of bisphosphonates in cancer patients with bone metastases. Oncologist 15:1147, 2010.

  15. Bagan JV, Jimenez Y, Gomez 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 44:1088, 2008.

  16. Black DM, Reid IR, Boonen S, et al: The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 27:243, 2012.

  17. Bedogni A, Fusco V, Agrillo A, et al: Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ). Oral Dis 18:621, 2012.

  18. Balmor GR, Yarom N, Weitzen R: Drug-induced palate osteonecrosis following nasal surgery. Isr Med Assoc J 14:193, 2012.

  19. Bonacina R, Mariani U, Villa F, et al: Preventive strategies and clinical implications for bisphosphonate-related osteonecrosis of the jaw: a review of 282 patients. J Can Dent Assoc 77:b147, 2011.

  20. Badros A, Weikel D, Salama A, et al: Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24:945, 2006.

  21. Brown JJ, Ramalingam L, Zacharin MR: Bisphosphonate-associated osteonecrosis of the jaw: does it occur in children? Clin Endocrinol (Oxf) 68:863, 2008.

  22. Bozas G, Roy A, Ramasamy V, et al: Osteonecrosis of the jaw after a single bisphosphonate infusion in a patient with metastatic renal cancer treated with sunitinib. Onkologie 33:321, 2010.

  23. 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 44:857, 2008.

  24. Bi Y, Gao Y, Ehirchiou D, et al: Bisphosphonates cause osteonecrosis of the jaw-like disease in mice. Am J Pathol 177:280, 2010.

  25. Briefing Information for the September 9, 2011 Joint Meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. Septemer 9, 2011;

  26. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/ucm270957.htm. Accessed April 7, 2014.

  27. Bashutski JD, Eber RM, Kinney JS, et al: Teriparatide and osseous regeneration in the oral cavity. N Engl J Med 363:2396, 2010.

  28. 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 44:173, 2009.

  29. Bagan, J.V., Jimenez, Y., Murillo, J., Jaw osteonecrosis associated with bisphosphonates: Multiple exposed areas and its relationship to teeth extractions — Study of 20 cases, Oral Oncol, 42: 327–329, 2011.

  30. 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;

  31. Baron R, Ferrari S, Russell RG: Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 48:677, 2011.

  32. 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 107:1665, 2012.

  33. Carlson ER, Basile JD: The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:85, 2009.

  34. 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 76:209, 2009.

  35. Cummings SR, San Martin J, McClung MR, et al: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756, 2009.

  36. Carlson ER, Fleisher KE, Ruggiero SL: Metastatic cancer identified in osteonecrosis specimens of the jaws in patients receiving intravenous bisphosphonate medications. J Oral Maxillofac Surg 71:2077, 2013.

  37. 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 127:429, 2011.

  38. Dickinson M, Prince HM, Kirsa S, et al: Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment. Intern Med J 39:304, 2009.

  39. Damm DD, Jones DM: Bisphosphonate-related osteonecrosis of the jaws: a potential alternative to drug holidays. Gen Dent 61:33, 2013.

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

  41. Endodontic Implications of Bisphosphonate-Associated Osteonecrosis of the Jaws. Chicago, IL: American Association of Endodontists; 2010:4.

  42. Epstein MS, Epstein JB, Ephros HD: The effects of osteoclast modifiers on the oral cavity: a review for prescribers. Curr Opin Support Palliat Care 6:337, 2012.

  43. Eckardt AM, Lemound J, Lindhorst D, et al: Surgical management of bisphosphonate-related osteonecrosis of the jaw in oncologic patients: a challenging problem. Anticancer Res 31:2313, 2011.

  44. Edwards BJ, Hellstein JW, Jacobsen PL, et al: Updated recommendations for managing the care of patients receiving oral bisphosphonate therapy: an advisory statement from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 139:1674, 2008.

  45. Fleissig Y, Regev E, Lehman H: Sunitinib related osteonecrosis of jaw: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol 113:e1, 2012.

  46. Ferrari S, Bianchi B, Savi A, et al: Fibula free flap with endosseous implants for reconstructing a resected mandible in bisphosphonate osteonecrosis. J Oral Maxillofac Surg 66:999, 2008

  47. Fedele S, S. Porter, F. Daiuto, N. Donos, H. Ireland, S. Humphries. P1.41. the GEN-VA-BO study (GENetic VAriants in Bisphosphonate–related Ostenecrosis of the jaws). A cooperation proposal. Oral Oncology Supplement, vol. 3. Issue 1. July 2009, p. 136.

  48. Ferlito S, Puzzo S, Palermo F, et al: 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 50:425, 2012.

  49. Fehm T, Felsenberg D, Krimmel M, et al: Bisphosphonate-associated osteonecrosis of the jaw in breast cancer patients: recommendations for prevention and treatment. Breast 18:213, 2009.

  50. Freiberger JJ: Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:96, 2009.

  51. Fizazi K, Carducci M, Smith M, et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813, 2011.

  52. Fleisher KE, Welch G, Kottal S, et al: Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 110:509, 2010.

  53. 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 70:1573, 2012.

  54. 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 112:605, 2009.

  55. Fedele S, Porter SR, D'Aiuto F, et al: Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 123:1060, 2010.

  56. 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 122:181, 2010.

  57. Gerard DA, Carlson ER, Gotcher JE, et al: Early inhibitory effects of zoledronic acid in tooth extraction sockets in dogs are negated by recombinant human bone morphogenetic protein. J Oral Maxillofac Surg 72:61, 2014.

  58. Grbic JT, Black DM, Lyles KW, et al: The incidence of osteonecrosis of the jaw in patients receiving 5 milligrams of zoledronic acid: data from the health outcomes and reduced incidence with zoledronic acid once yearly clinical trials program. J Am Dent Assoc 141:1365, 2010.

  59. Graziani F, Vescovi P, Campisi G, et al: Resective surgical approach shows a high performance in the management of advanced cases of bisphosphonate-related osteonecrosis of the jaws: a retrospective survey of 347 cases. J Oral Maxillofac Surg 70:2501, 2012.

  60. 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 29:1125, 2011.

  61. Hellstein JW, Adler RA, Edwards B, et al: Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 142:1243, 2011.

  62. 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 23:826, 2008.

  63. 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 110:463, 2010.

  64. Hokugo A, Christensen R, Chung EM, et al: Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats. J Bone Miner Res 25:1337, 2010.

  65. Hinchy NV, Jayaprakash V, Rossitto RA, et al: Osteonecrosis of the jaw-prevention and treatment strategies for oral health professionals. Oral Oncol 49:878, 2013.

  66. John W. Hellstein, Robert A. Adier, Beatrice Edwards, Peter L. Jacobsen, John R. Kalman, Sreenivas Koka, Cesar A. Migliorati, Helen Ristic. Managing the care of patients receiving antiresorptive for prevention and treatment of osteoporosis: Executive summery of recommendations from the American Dental Association Council on Scientific Affairs. J American Dent Assoc, vol. 142, issue 11, Nov.2011, p. 1243–1251.

  67. Khan AA, Sandor GK, Dore E, et al: Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 36:478, 2009.

  68. Kim I, Ki H, Lee W, et al: The effect of systemically administered bisphosphonates on bony healing after tooth extraction and osseointegration of dental implants in the rabbit maxilla. Int J Oral Maxillofac Implants 28:1194, 2013.

  69. 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 40:605, 2011.

  70. Koch FP, Walter C, Hansen T, et al: Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg 15:63, 2011.

  71. 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 71:1010, 2013.

  72. Kumar SK, Gorur A, Schaudinn C, et al: The role of microbial biofilms in osteonecrosis of the jaw associated with bisphosphonate therapy. Curr Osteoporos Rep 8:40, 2010.

  73. Kyle RA, Yee GC, Somerfield MR, et al: American Society of Clinical Oncology Kang B, Cheong S, Chaichanasakul T, et al: Periapical disease and bisphosphonates induce osteonecrosis of the jaws in mice. J Bone Miner Res 28:1631, 2013.

  74. .Kwon YD, Kim DY, Ohe JY, et al: Correlation between serum C-terminal cross-linking telopeptide of type I collagen and staging of oral bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67:2644, 2009.

  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 26:4634, 2008.

  76. Kim HK: Introduction to osteonecrosis of the femoral head (OFH) and osteonecrosis of the jaw (ONJ). J Musculoskelet Neuronal Interact 7:350, 2007.

  77. Kikuiri T, Kim I, Yamaza 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, 2010.

  78. Kunchur R, Need A, Hughes T, et al: Clinical investigation of C-terminal cross-linking telopeptide test in prevention and management of bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 67:1167, 2009.

  79. Kuroshima S, Kovacic BL, Kozloff KM, et al: Intra-oral PTH administration promotes tooth extraction socket healing. J Dent Res 92:553, 2013.

  80. Khan AA, Morrison A, Hanley DA, et al: International Consensus on Diagnosis and Management of Osteonecrosis of the Jaw. 2013:22.

  81. Lacey DL, Boyle WJ, Simonet WS, et al: Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 11:401, 2012.

  82. Lee CY, David T, Nishime M: Use of platelet-rich plasma in the management of oral biphosphonate-associated osteonecrosis of the jaw: a report of 2 cases. J Oral Implantol 33:371, 2007.

  83. Lane, N., Armitage, G.C., Loomer, P., Bisphosphonate therapy improves the outcome of conventional periodontal treatment: Results of a 12-month, randomized, placebo-controlled study J Periodontol, 2005: 76, 1113-1122.

  84. Lopez-Jornet P, Camacho-Alonso F, Martinez-Canovas A, et al: Perioperative antibiotic regimen in rats treated with pamidronate plus dexamethasone and subjected to dental extraction: a study of the changes in the jaws. J Oral Maxillofac Surg 69:2488, 2011.

  85. Lo JC, O'Ryan F, Yang J, et al: Oral health considerations in older women receiving oral bisphosphonate therapy. J Am Geriatr Soc 59:916, 2011.

  86. 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 106:389, 2008.

  87. Landesberg R, Woo V, Cremers S, et al: Potential pathophysiological mechanisms in osteonecrosis of the jaw. Ann N Y Acad Sci 1218:62, 2011.

  88. Landesberg R, Cozin M, Cremers S, et al: Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg 66:839, 2008.

  89. Lo JC, O'Ryan FS, Gordon NP, et al: Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 68:243, 2010.

  90. Lipton A, Fizazi K, Stopeck AT, et al: Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48:3082, 2012.

  91. Marini F, Tonelli P, Cavalli L, et al: Pharmacogenetics of bisphosphonate-associated osteonecrosis of the jaw. Front Biosci (Elite Ed) 3:364, 2011.

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

  93. Marx RE, Oral and Intravenous Bisphosphonata-Indiced Osteonecrosis of the Jaws. History, Etiology, Prevention and treatment, second edition, Quintessence, 2011

  94. Mehrotra B, Fantasia J, Ruggiero SL: Outcomes of bisphosphonate related osteonecrosis of the jaw. Importance of staging and management. A large single institution update. J Clin Oncol 26:20526, 2008.

  95. Marcelo Cunio Fonseca, Gabriela Tannus Branco de Araujo, Helder Etto, Alexandre Schiola, Natalia Santoni, Marko Machado. Economic Evalution of Clodronate and Zolesronatw in Patients Diagnosed with Metastatic Bone Disease From the Perspective of Public and III-rd Party Payors in Brazil. Clinical Therapeutics, 33 (11), 1769-1780, e2.

  96. Mucke T, Koschinski J, Deppe H, et al: Outcome of treatment and parameters influencing recurrence in patients with bisphosphonate-related osteonecrosis of the jaws. J Cancer Res Clin Oncol 137:907, 2011.

  97. 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 65:2397, 2007.

  98. Mozzati M, Arata V, Gallesio G: Tooth extraction in patients on zoledronic acid therapy. Oral Oncol 48:817, 2012.

  99. 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 116:433, 2009.

  100. Migliorati CA, Saunders D, Conlon MS, et al: Assessing the association between bisphosphonate exposure and delayed mucosal healing after tooth extraction. J Am Dent Assoc 144:406, 2013.

  101. Malden N, Lopes V: An epidemiological study of alendronate-related osteonecrosis of the jaws. A case series from the south-east of Scotland with attention given to case definition and prevalence. J Bone Miner Metab 30:171, 2012.

  102. Marx R: Oral and Intravenous Bisphosphonate Induced Osteonecrosis of the Jaws: History, etiology, prevention, and treatment. 2nd ed. Hanover Park, IL: Quintessence Publishing Co; 2011.

  103. Marx, R.E., Sawatari, Y., Fortin, M., Broumand, V., Bisphosphonate-induced exposed bone (osteonerosis/osteopetrosis) of the jaws: Risk factors, recognition, prevention, and treatment (2005) J Oral Maxillofac Surg, 63, pp. 1567-1575;

  104. Mortensen M, Lawson W, Montazem A: Osteonecrosis of the jaw associated with bisphosphonate use: Presentation of seven cases and literature review. Laryngoscope 117:30, 2007.

  105. Nicoletti P, Cartsos VM, Palaska PK, et al: Genomewide pharmacogenetics of bisphosphonate-induced osteonecrosis of the jaw: the role of RBMS3. Oncologist 17:279, 2012.

  106. Nicolatou-Galitis O, Migkou M, Psyrri A, et al: Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: report of 2 cases with clinical implications. Oral Surg Oral Med Oral Pathol Oral Radiol 113:234, 2012.

  107. 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 67:1363, 2009.

  108. 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, 2013.

  109. Patel V, McLeod NM, Rogers SN, et al: Bisphosphonate osteonecrosis of the jaw—a literature review of UK policies versus international policies on bisphosphonates, risk factors and prevention. Br J Oral Maxillofac Surg 49:251, 2011.

  110. Papapoulos S, Chapurlat R, Libanati C, et al: Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 27:694, 2012.

  111. Rosen LS, Gordon D, Tchekmedyian NS, 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, 2004.

  112. Ruggiero, S., Gralow, J., Marx, R.E., Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer (2006) J Oncol Prac, 2, pp. 7-14;

  113. 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 67:2, 2009.

  114. 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 102:433, 2006.

  115. 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 20:137, 2009.

  116. Roelofs AJ, Thompson K, Gordon S, et al: Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12:6222s, 2006.

  117. Reid IR, Cornish J: Epidemiology and pathogenesis of osteonecrosis of the jaw. Nat Rev Rheumatol 8:90, 2012.

  118. Reid IR, Bolland MJ, Grey AB: Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 41:318, 2007.

  119. Shannon J, Shannon J, Modelevsky S, et al: Bisphosphonates and osteonecrosis of the jaw. J Am Geriatr Soc 59:2350, 2011.

  120. 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 23:1341, 2012.

  121. Saussez S, Javadian R, Hupin C, et al: Bisphosphonate-related osteonecrosis of the jaw and its associated risk factors: a Belgian case series. Laryngoscope 119:323, 2009.

  122. Savoidelli C, F. le Page, J. Santini, G. Scortecci, G. Odin. Osteonecrose maxillaire sous Bisphosphonateset implants dentaires. Revue de Stomatologie et de Chirurgie Maxillo-faciale, vol. 108, issue 8, Dec. 2007, P. 555-558.

  123. 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 66:767, 2008.

  124. Seth R, Futran ND, Alam DS, et al: Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws. Laryngoscope 120:2165, 2010.

  125. Sinningen K, Tsourdi E, Rauner M, et al: Skeletal and extraskeletal actions of denosumab. Endocrine 42:52, 2012.

  126. 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 140:1259, 2009.

  127. 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 28:179, 2010.

  128. Scoletta M, Arata V, Arduino PG, et al: Tooth extractions in intravenous bisphosphonate-treated patients: a refined protocol. J Oral Maxillofac Surg 71:994, 2013.

  129. 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 110:46, 2010.

  130. Smidt-Hansen T, Folkmar TB, Fode K, et al: Combination of zoledronic acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma. J Oral Maxillofac Surg 71:1532, 2013.

  131. Scagliotti GV, Hirsh V, Siena S, et al: Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol 7:1823, 2012.

  132. Soydan SS, Uckan S: Management of bisphosphonate-related osteonecrosis of the jaw with a platelet-rich fibrin membrane: technical report. J Oral Maxillofac Surg 72:322, 2014.

  133. Schubert M, Klatte I, Linek W, et al: The Saxon bisphosphonate register — therapy and prevention of bisphosphonate-related osteonecrosis of the jaws. Oral Oncol 48:349, 2012.

  134. Stopeck A, Body JJ, Fujiwara Y, et al: Denosumab versus zolendronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Cancer Supplements [EJC supplements] 7:2, 2009.

  135. Sedghizadeh PP, Yooseph S, Fadrosh DW, et al: Metagenomic investigation of microbes and viruses in patients with jaw osteonecrosis associated with bisphosphonate therapy. Oral Surg Oral Med Oral Pathol Oral Radiol 114:764, 2012.

  136. Sivolella S, Lumachi F, Stellini E, et al: Denosumab and anti-angiogenetic drug-related osteonecrosis of the jaw: an uncommon but potentially severe disease. Anticancer Res 33:1793, 2013.

  137. Stockmann P, Vairaktaris E, Wehrhan F, 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, 2010.

  138. Stanton DC, Balasanian E: Outcome of surgical management of bisphosphonate-related osteonecrosis of the jaws: review of 33 surgical cases. J Oral Maxillofac Surg 67:943, 2009.

  139. Tsao C, Darby I, Ebeling PR, et al: Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg 71:1360, 2013.

  140. United States. Food and Drug Administration. Sutent (sunitinib malate) capsules Safety Information. http://www.fda.gov/safety/ medwatch/safetyinformation/ucm224050.htm. Accessed March 13, 2014.

  141. United States. Food and Drug Administration. Office of Drug Safety. Postmarketing Safety Review. Bisphosphonates. http://www. fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_03_04-FDATab3.pdf Accessed February 10, 2014.

  142. United States. Food and Drug Administration. Avastin (bevacizumab) Safety Information. http://www.fda.gov/Safety/MedWatch/ SafetyInformation/ucm275758.htm Accessed March 13, 2014.

  143. Vescovi P, Merigo E, Meleti M, et al: Bisphosphonates-related osteonecrosis of the jaws: a concise review of the literature and a report of a single-centre experience with 151 patients. J Oral Pathol Med 41:214, 2012.

  144. 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 27:5356, 2009.

  145. Van den Wyngaert T, Claeys T, Huizing MT, et al: Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome. Ann Oncol 20:331, 2009.

  146. 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 23:193, 2012.

  147. 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 115:71, 2013.

  148. Walter C, Al-Nawas B, du Bois A, et al: Incidence of bisphosphonate-associated osteonecrosis of the jaws in breast cancer patients. Cancer 115:1631, 2009.

  149. 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 41:1397, 2012.

  150. Yamashita J, McCauley LK: Antiresorptives and osteonecrosis of the jaw. J Evid Based Dent Pract 12:233, 2012.