Osteonecrosis of the jaws is a recently described adverse side effect of bisphosphonate therapy. Patients with multiple myeloma and metastatic carcinoma to the skeleton who are receiving intravenous, nitrogen-containing bisphosphonates are at greatest risk for osteonecrosis of the jaws; these patients represent 94% of published cases. The mandible is more commonly affected than the maxilla (2:1 ratio), and 60% of cases are preceded by a dental surgical procedure. Oversuppression of bone turnover is probably the primary mechanism for the development of this condition, although there may be contributing comorbid factors. All sites of potential jaw infection should be eliminated before bisphosphonate therapy is initiated in these patients to reduce the necessity of subsequent dentoalveolar surgery. Conservative débridement of necrotic bone, pain control, infection management, use of antimicrobial oral rinses, and withdrawal of bisphosphonates are preferable to aggressive surgical measures for treating this condition. The degree of risk for osteonecrosis in patients taking oral bisphosphonates, such as alendronate, for osteoporosis is uncertain and warrants careful monitoring.
References
- 1.
Fleisch H . Bisphosphonates: mechanisms of action. Endocr Rev. 1998;19:80-100. [PMID: 9494781] CrossrefMedlineGoogle Scholar - 2.
Russell RG ,Croucher PI ,Rogers MJ . Bisphosphonates: pharmacology, mechanisms of action and clinical uses. Osteoporos Int. 1999;9Suppl 2 S66-80. [PMID: 10525729] CrossrefMedlineGoogle Scholar - 3.
Lin JH ,Russell G ,Gertz B . Pharmacokinetics of alendronate: an overview. Int J Clin Pract.Suppl 1999;101:18-26. [PMID: 12669737] MedlineGoogle Scholar - 4.
Green JR . Bisphosphonates: preclinical review. Oncologist. 2004;9Suppl 4 3-13. [PMID: 12584689] CrossrefMedlineGoogle Scholar - 5.
Hughes DE ,MacDonald BR ,Russell RG ,Gowen M . Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow. J Clin Invest. 1989;83:1930-5. [PMID: 2524504] CrossrefMedlineGoogle Scholar - 6.
Vitté C ,Fleisch H ,Guenther HL . Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology. 1996;137:2324-33. [PMID: 8641182] CrossrefMedlineGoogle Scholar - 7.
Santini D ,Vespasiani Gentilucci U ,Vincenzi B ,Picardi A ,Vasaturo F ,La Cesa A ,et al . The antineoplastic role of bisphosphonates: from basic research to clinical evidence. Ann Oncol. 2003;14:1468-76. [PMID: 14504045] CrossrefMedlineGoogle Scholar - 8.
Wood J ,Bonjean K ,Ruetz S ,Bellahcène A ,Devy L ,Foidart JM ,et al . Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302:1055-61. [PMID: 12183663] CrossrefMedlineGoogle Scholar - 9.
Vincenzi B ,Santini D ,Dicuonzo G ,Battistoni F ,Gavasci M ,La Cesa A ,et al . Zoledronic acid-related angiogenesis modifications and survival in advanced breast cancer patients. J Interferon Cytokine Res. 2005;25:144-51. [PMID: 15767788] CrossrefMedlineGoogle Scholar - 10.
Kunzmann V ,Bauer E ,Feurle J ,Weissinger F ,Tony HP ,Wilhelm M . Stimulation of gammadelta T cells by aminobisphosphonates and induction of antiplasma cell activity in multiple myeloma. Blood. 2000;96:384-92. [PMID: 10887096] CrossrefMedlineGoogle Scholar - 11.
Mariani S ,Muraro M ,Pantaleoni F ,Fiore F ,Nuschak B ,Peola S ,et al . Effector gammadelta T cells and tumor cells as immune targets of zoledronic acid in multiple myeloma. Leukemia. 2005;19:664-70. [PMID: 15744346] CrossrefMedlineGoogle Scholar - 12.
Lipton A ,Theriault RL ,Hortobagyi GN ,Simeone J ,Knight RD ,Mellars K ,et al . Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000;88:1082-90. [PMID: 10699899] CrossrefMedlineGoogle Scholar - 13.
Berenson JR ,Rosen LS ,Howell A ,Porter L ,Coleman RE ,Morley W ,et al . Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer. 2001;91:1191-200. [PMID: 11283917] CrossrefMedlineGoogle Scholar - 14.
Saad F . Clinical benefit of zoledronic acid for the prevention of skeletal complications in advanced prostate cancer. Clin Prostate Cancer. 2005;4:31-7. [PMID: 15992459] CrossrefMedlineGoogle Scholar - 15.
Mashiba T ,Mori S ,Burr DB ,Komatsubara S ,Cao Y ,Manabe T ,et al . The effects of suppressed bone remodeling by bisphosphonates on microdamage accumulation and degree of mineralization in the cortical bone of dog rib. J Bone Miner Metab. 2005;23Suppl 36-42. [PMID: 15984412] CrossrefMedlineGoogle Scholar - 16.
Weinstein RS . True strength. J Bone Miner Res. 2000;15:621-5. [PMID: 10780853] CrossrefMedlineGoogle Scholar - 17.
Whyte MP ,Wenkert D ,Clements KL ,McAlister WH ,Mumm S . Bisphosphonate-induced osteopetrosis. N Engl J Med. 2003;349:457-63. [PMID: 12890844] CrossrefMedlineGoogle Scholar - 18.
Odvina CV ,Zerwekh JE ,Rao DS ,Maalouf N ,Gottschalk FA ,Pak CY . Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab. 2005;90:1294-301. [PMID: 15598694] CrossrefMedlineGoogle Scholar - 19.
Ott SM . Fractures after long-term alendronate therapy [Letter]. J Clin Endocrinol Metab. 2001;86:1835-6. [PMID: 11297626] CrossrefMedlineGoogle Scholar - 20.
Ott SM . Long-term safety of bisphosphonates. J Clin Endocrinol Metab. 2005;90:1897-9. [PMID: 15758064] CrossrefMedlineGoogle Scholar - 21.
Goodship AE ,Walker PC ,McNally D ,Chambers T ,Green JR . Use of a bisphosphonate (pamidronate) to modulate fracture repair in ovine bone. Ann Oncol. 1994;5Suppl 7 S53-5. [PMID: 7873463] MedlineGoogle Scholar - 22.
Li C ,Mori S ,Li J ,Kaji Y ,Akiyama T ,Kawanishi J ,et al . Long-term effect of incadronate disodium (YM-175) on fracture healing of femoral shaft in growing rats. J Bone Miner Res. 2001;16:429-36. [PMID: 11277259] CrossrefMedlineGoogle Scholar - 23.
Gonzalez-Moles MA ,Bagan-Sebastian JV . Alendronate-related oral mucosa ulcerations. J Oral Pathol Med. 2000;29:514-8. [PMID: 11048968] CrossrefMedlineGoogle Scholar - 24.
Demerjian N ,Bolla G ,Spreux A . Severe oral ulcerations induced by alendronate. Clin Rheumatol. 1999;18:349-50. [PMID: 10468180] CrossrefMedlineGoogle Scholar - 25.
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;62:527-34. [PMID: 15122554] CrossrefMedlineGoogle Scholar - 26.
Estilo CS ,Van Poznak CH ,Williams T ,Evtimovska E ,Tkach L ,Halpern JL ,et al . Osteonecrosis of the maxilla and mandible in patients treated with bisphosphonates: a retrospective study [Abstract]. Proc Am Soc Clin Oncol. 2004;22:750. MedlineGoogle Scholar - 27.
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. [PMID: 16243172] CrossrefMedlineGoogle Scholar - 28.
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;104:83-93. [PMID: 15929121] CrossrefMedlineGoogle Scholar - 29.
Purcell PM ,Boyd IW . Bisphosphonates and osteonecrosis of the jaw. Med J Aust. 2005;182:417-8. [PMID: 15850440] CrossrefMedlineGoogle Scholar - 30.
Bagan JV ,Jimenez Y ,Murillo J ,Hernandez S ,Poveda R ,Sanchis JM ,et al . Jaw osteonecrosis associated with bisphosphonates: multiple exposed areas and its relationship to teeth extractions. Study of 20 cases [Letter]. Oral Oncol. 2006;42:327-9. [PMID: 16275156] CrossrefMedlineGoogle Scholar - 31.
Pires FR ,Miranda A ,Cardoso ES ,Cardoso AS ,Fregnani ER ,Pereira CM ,et al . Oral avascular bone necrosis associated with chemotherapy and biphosphonate therapy. Oral Dis. 2005;11:365-9. [PMID: 16269027] CrossrefMedlineGoogle Scholar - 32.
Bamias A ,Kastritis E ,Bamia C ,Moulopoulos LA ,Melakopoulos I ,Bozas G ,et al . Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol. 2005;23:8580-7. [PMID: 16314620] CrossrefMedlineGoogle Scholar - 33.
Melo MD ,Obeid G . Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy: strategies for prevention and early recognition. J Am Dent Assoc. 2005;136:1675-81. [PMID: 16383049] CrossrefMedlineGoogle Scholar - 34.
Zarychanski R ,Elphee E ,Walton P ,Johnston J . Osteonecrosis of the jaw associated with pamidronate therapy. Am J Hematol. 2006;81:73-5. [PMID: 16369966] CrossrefMedlineGoogle Scholar - 35.
Wang J ,Goodger NM ,Pogrel MA . Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg. 2003;61:1104-7. [PMID: 12966490] CrossrefMedlineGoogle Scholar - 36.
Lugassy G ,Shaham R ,Nemets A ,Ben-Dor D ,Nahlieli O . Severe osteomyelitis of the jaw in long-term survivors of multiple myeloma: a new clinical entity [Letter]. Am J Med. 2004;117:440-1. [PMID: 15380503] CrossrefMedlineGoogle Scholar - 37.
Vannucchi AM ,Ficarra G ,Antonioli E ,Bosi A . Osteonecrosis of the jaw associated with zoledronate therapy in a patient with multiple myeloma. Br J Haematol. 2005;128:738. [PMID: 15755276] CrossrefMedlineGoogle Scholar - 38.
Maerevoet M ,Martin C ,Duck L . Osteonecrosis of the jaw and bisphosphonates [Letter]. N Engl J Med. 2005;353:99-102. [PMID: 16003838] CrossrefMedlineGoogle Scholar - 39.
Viale PH ,Lin A . Exposed bone in oral cavities. Clin J Oncol Nurs. 2005;9:355-7. [PMID: 15973847] CrossrefMedlineGoogle Scholar - 40.
Carter G ,Goss AN ,Doecke C . Bisphosphonates and avascular necrosis of the jaw: a possible association. Med J Aust. 2005;182:413-5. [PMID: 15850439] CrossrefMedlineGoogle Scholar - 41.
Philipone E . Nonhealing extraction site. Gen Dent. 2005;53:161, 163. [PMID: 15833019] MedlineGoogle Scholar - 42.
Throndson RR ,Healy SM ,Zwickey MR . Bisphosphonate-induced osteonecrosis of the jaws. Tex Dent J. 2005;122:960-5. [PMID: 16320503] MedlineGoogle Scholar - 43.
Markiewicz MR ,Margarone JE ,Campbell JH ,Aguirre A . Bisphosphonate-associated osteonecrosis of the jaws: a review of current knowledge. J Am Dent Assoc. 2005;136:1669-74. [PMID: 16383048] CrossrefMedlineGoogle Scholar - 44.
Polizzotto MN ,Cousins V ,Schwarer AP . Bisphosphonate-associated osteonecrosis of the auditory canal [Letter]. Br J Haematol. 2006;132:114. [PMID: 16371027] CrossrefMedlineGoogle Scholar - 45.
Sarathy AP ,Bourgeois SL ,Goodell GG . Bisphosphonate-associated osteonecrosis of the jaws and endodontic treatment: two case reports. J Endod. 2005;31:759-63. [PMID: 16186759] CrossrefMedlineGoogle Scholar - 46.
Merigo E ,Manfredi M ,Meleti M ,Corradi D ,Vescovi P . Jaw bone necrosis without previous dental extractions associated with the use of bisphosphonates (pamidronate and zoledronate): a four-case report. J Oral Pathol Med. 2005;34:613-7. [PMID: 16202082] CrossrefMedlineGoogle Scholar - 47.
Katz H . Endodontic implications of bisphosphonate-associated osteonecrosis of the jaws: a report of three cases. J Endod. 2005;31:831-4. [PMID: 16249730] CrossrefMedlineGoogle Scholar - 48.
Gibbs SD ,O'Grady J ,Seymour JF ,Prince HM . Bisphosphonate-induced osteonecrosis of the jaw requires early detection and intervention [Letter]. Med J Aust. 2005;183:549-50. [PMID: 16296983] CrossrefMedlineGoogle Scholar - 49.
Lenz JH ,Steiner-Krammer B ,Schmidt W ,Fietkau R ,Mueller PC ,Gundlach KK . Does avascular necrosis of the jaws in cancer patients only occur following treatment with bisphosphonates? J Craniomaxillofac Surg. 2005;33:395-403. [PMID: 16253510] CrossrefMedlineGoogle Scholar - 50.
Yeo AC ,Lye KW ,Poon CY . Bisphosphonate-related osteonecrosis of the jaws. Singapore Dent J. 2005;27:36-40. [PMID: 16438267] MedlineGoogle Scholar - 51.
Marunick M ,Miller R ,Gordon S . Adverse oral sequelae to bisphosphonate administration. J Mich Dent Assoc. 2005;87:44-9. [PMID: 16372548] MedlineGoogle Scholar - 52.
Sitters MA ,Caldwell CS . Bisphosphonates, dental care and osteonecrosis of the jaws. Tex Dent J. 2005;122:968-72. [PMID: 16320504] MedlineGoogle Scholar - 53.
Ficarra G ,Beninati F ,Rubino I ,Vannucchi A ,Longo G ,Tonelli P ,et al . Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment. J Clin Periodontol. 2005;32:1123-8. [PMID: 16212571] CrossrefMedlineGoogle Scholar - 54.
Pastor-Zuazaga D ,Garatea-Crelgo J ,Martino-Gorbea R ,Etayo-Pérez A ,Sebastián-López C . Osteonecrosis of the jaws and bisphosphonates. Report of three cases. Med Oral Patol Oral Cir Bucal. 2006;11:76-9. [PMID: 16388300] MedlineGoogle Scholar - 55.
Starck WJ ,Epker BN . Failure of osseointegrated dental implants after diphosphonate therapy for osteoporosis: a case report. Int J Oral Maxillofac Implants. 1995;10:74-8. [PMID: 7615320] MedlineGoogle Scholar - 56.
Marx RE . Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg. 1983;41:283-8. [PMID: 6572704] CrossrefMedlineGoogle Scholar - 57.
Thorn JJ ,Hansen HS ,Specht L ,Bastholt L . Osteoradionecrosis of the jaws: clinical characteristics and relation to the field of irradiation. J Oral Maxillofac Surg. 2000;58:1088-93; discussion 1093-5. [PMID: 11021701] CrossrefMedlineGoogle Scholar - 58.
Reuther T ,Schuster T ,Mende U ,Kübler A . 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. 2003;32:289-95. [PMID: 12767877] CrossrefMedlineGoogle Scholar - 59.
Reid IR ,Brown JP ,Burckhardt P ,Horowitz Z ,Richardson P ,Trechsel U ,et al . Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002;346:653-61. [PMID: 11870242] CrossrefMedlineGoogle Scholar - 60. Jones JR, Lehtinen T, Riphagen FE, von Roemeling R. Adverse event (AE) reporting of oral clodronate with emphasis on osteonecrosis of the jaws [Abstract]. Presented at the Annual Meeting of the American Society for Clinical Oncology, 2005. Abstract 799. Google Scholar
- 61.
Durie BG ,Katz M ,Crowley J . Osteonecrosis of the jaw and bisphosphonates [Letter]. N Engl J Med. 2005;353:99-102. [PMID: 16000365] CrossrefMedlineGoogle Scholar - 62.
Drexler HC ,Risau W ,Konerding MA . Inhibition of proteasome function induces programmed cell death in proliferating endothelial cells. FASEB J. 2000;14:65-77. [PMID: 10627281] CrossrefMedlineGoogle Scholar - 63.
Rajkumar SV ,Hayman S ,Gertz MA ,Dispenzieri A ,Lacy MQ ,Greipp PR ,et al . Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002;20:4319-23. [PMID: 12409330] CrossrefMedlineGoogle Scholar - 64.
Peters E ,Lovas GL ,Wysocki GP . Lingual mandibular sequestration and ulceration. Oral Surg Oral Med Oral Pathol. 1993;75:739-43. [PMID: 8515988] CrossrefMedlineGoogle Scholar - 65.
Ruggiero S ,Gralow J ,Marx RE ,Hoff AO ,Schubert MM ,Huryn JM ,et al . Practical guidelines for the prevention, diagnosis and treatment of osteonecrosis of the jaws in patients with cancer. Journal of Oncology Practice. 2006;2:7-14. CrossrefMedlineGoogle Scholar - 66. Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004. Professional Education Material. East Hanover, NJ: Novartis; 2004. Google Scholar
- 67.
Woo SB ,Matin K . Off-site dental evaluation program for prospective bone marrow transplant recipients. J Am Dent Assoc. 1997;128:189-93. [PMID: 9037972] CrossrefMedlineGoogle Scholar - 68.
Bishay N ,Petrikowski CG ,Maxymiw WG ,Lee L ,Wood RE . Optimum dental radiography in bone marrow transplant patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;87:375-9. [PMID: 10102604] CrossrefMedlineGoogle Scholar - 69.
Carter GD ,Goss AN . Bisphosphonates and avascular necrosis of the jaws [Letter]. Aust Dent J. 2003;48:268. [PMID: 14738134] MedlineGoogle Scholar - 70.
McCloskey EV ,Dunn JA ,Kanis JA ,MacLennan IC ,Drayson MT . Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol. 2001;113:1035-43. [PMID: 11442499] CrossrefMedlineGoogle Scholar - 71.
Pectasides D ,Nikolaou M ,Farmakis D ,Kanakis I ,Gaglia A ,Kountourakis P ,et al . Clinical value of bone remodelling markers in patients with bone metastases treated with zoledronic acid. Anticancer Res. 2005;25:1457-63. [PMID: 15865105] MedlineGoogle Scholar
Author, Article, and Disclosure Information
Affiliations:
From Brigham and Women's Hospital and Harvard School of Dental Medicine, Boston, Massachusetts; University of Iowa College of Dentistry, Iowa City, Iowa; and The Ohio State University College of Dentistry, Columbus, Ohio.
Note: This is a position paper of the American Academy of Oral and Maxillofacial Pathology.
Grant Support: None.
Disclosures: Grants received: S.-B. Woo (Novartis).
Corresponding Author: Sook-Bin Woo, DMD, Brigham and Women's Hospital, 45 Francis Street, Boston, MA 02115.
Current Author Addresses: Dr. Woo: Brigham and Women's Hospital, 45 Francis Street, Boston, MA 02115.
Dr. Hellstein: University of Iowa, 356 Dental Science South, Iowa City, IA 52246.
Dr. Kalmar: The Ohio State University, 305 West 12th Avenue, Columbus, OH 43210.
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