Bisphosphonates are a class of agents used to treat osteoporosis and malignant bone metastases. The efficacy of these agents in treating and preventing the significant skeletal complications associated with these conditions has had a major positive impact for patients and is responsible for their widespread use in medicine. Despite these benefits, osteonecrosis of the jaws has recently emerged as a significant complication in a subset of patients receiving these drugs. Based on a growing number of case reports and institutional reviews, bisphosphonate therapy may cause exposed and necrotic bone that is isolated to the jaw. This complication usually presents following simple dento-alveolar surgery, and can cause a significant adverse effect on the quality of life for most patients. The pathogenesis for this complication appears to be related to the profound inhibition of osteoclast function and bone remodeling.
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References
1.
Abrams HL, Spiro R, Goldstein N -1950-. Metastases in carcinoma. Analysis of 1000 autopsied cases. Cancer3:74–85.
2.
ADA -2006-. Report of the Council of Scientific Affairs. Expert panel recommendations: dental management of patients on oral bisphosphonate therapy. American Dental Association. June 2006. http://www.ada.org/prof/resources/topics/osteonecrosis.asp
3.
American Association of Endodontists -2005-. Position statement on endodontic implications of bisphosphonate-associated osteonecrosis of the jaws. http://www.aae.org/dentalpro/guidelines.htm.
4.
American Association of Oral and Maxillofacial Surgeons -2007-. Position paper on bisphosphonate-related osteonecrosis of the jaw. J Oral Maxillofac Surg65:369–376.
5.
Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, et al. -2006-. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol24:945–952.
6.
Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. -1996-. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl J Med334:484–493.
7.
Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. -1998-. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol16:593–602.
8.
Berenson JR, Hillner BE, Kyle RA, Anderson K, Lipton A, Yee GC, et al. -2002-. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol20:3719–3736.
9.
Bilezikian JP -2006-. Osteonecrosis of the jaw—Do bisphosphonates pose a risk? N Engl J Med355:2278–2281.
10.
Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al. -1996-. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet348:1535–1541.
11.
Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA, et al. -2006-. Effects of continuing or stopping alendronate after 5 years of treatment. The Fracture Intervention Trial Long-term Extension -FLEX-: a randomized trial. J Am Med Assoc296:2927–2938.
12.
Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, et al. -2004-. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med350:1189–1199.
13.
Cafro AM, Barbarano LA, Andriani A, D’Avanzo G, Nichelatti M, Gaglioti D, et al. -2005-. Osteonecrosis of the jaw associated with chronic bisphosphonate therapy: an Italian experience -AAOMS abstract-. Blood106:5152.
14.
Cheng A, Mavrokokki A, Carter G, Stein B, Fazzalari NL, Wilson DF, et al. -2005-. The dental implications of bisphosphonates and bone disease. Aust Dent J Med50-Suppl-:S4–S13.
15.
Chesnut C, Majumdar S, Gardner J, Shields A, Newitt DC, Erickson E, et al. -2001-. Assessment of bone quality, quantity and turnover with multiple methodologies at multiple skeletal sites. Adv Exp Med Biol496:95–97.
16.
Clain A -1985-. Secondary malignant disease of bone. Br J Cancer19:15–29.
17.
Coleman RE, Rubens RD -1987-. The clinical course of bone metastases from breast cancer. Br J Cancer55:61–66.
18.
Colon-Emeric CS -2006-. Ten vs five years of bisphosphonate treatment for postmenopausal osteoporosis: enough of a good thing -editorial-. J Am Med Assoc296:2968–2969.
19.
Conte P, Coleman R -2004-. Bisphosphonates in the treatment of skeletal metastases. Semin Oncol31:59–63.
20.
Deftos LJ -2005-. Treatment of Paget’s disease—taming the wild osteoclast. N Engl J Med353:872–875.
21.
Dimopoulos M, Kastritis E, Moulopoulos LA, Melakopoulos I, Anagnostopoulos A, Gika D, et al. -2005-. The incidence of osteonecrosis of the jaw in patients with multiple myeloma who receive bisphosphonates depends on the type of bisphosphonate -abstract-. Blood106:637.
22.
Durie BGM, Katz M, Crowley J -2005-. Osteonecrosis of the jaw and bisphosphonates -Letter-. N Engl J Med353:99–102.
23.
Gabriel SE, Tosteson AN, Leibson CL, Crowson CS, Pond GR, Hammond CS -2002-. Direct medical costs attributable to osteoporotic fractures. Osteoporos Int13:323–330.
24.
Gallucci C, Agrillo A, Iannetti G, Foà R, Petrucci M -2005-. Possible role of ozone therapy in the treatment of osteonecrosis of the jaw in multiple myeloma patients -abstract-. Blood106:3460.
25.
Gibbs SD, O’Grady J, Seymour JF, Prince HM -2005-. Bisphosphonate-induced osteonecrosis of the jaws requires early detection and intervention. Med J Aust183:549–550.
26.
Glass DA II, Patel MS, Karsenty G -2003-. A new insight into the formation of osteolytic lesions in multiple myeloma. N Engl J Med349:2479–2480.
27.
Greenberg MS -2004-. Intravenous bisphosphonates and osteonecrosis -editorial-. Oral Surg Oral Med Oral Pathol Oral Radiol Endod93:259–260.
28.
Guyatt GH, Cranney A, Griffith L, Walter S, Krolicki N, Favus M, et al. -2002-. Summary of meta-analyses of therapies for postmenopausal osteoporosis and the relationship between bone density and fractures. Endocrinol Metab Clin North Am31:659–679.
29.
Hillner BE, Ingle JN, Berenson JR, Janjan NA, Albain KS, Lipton A, et al. -2000-. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. J Clin Oncol18:1378–1391.
30.
Hoff AO, Toth BB, Altundag K, Guarnieri V, Adamus A, Nooka AK, et al. -2006-. Osteonecrosis of the jaw in patients receiving intravenous bisphosphonate therapy -abstract-. J Clin Oncol24:8528. http://meeting.jco.org/cgi/content/abstract/24/18_suppl/8528
31.
Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, et al. -1996-. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastasis. N Engl J Med335:1785–1792.
32.
Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D, Sinoff C, et al. -1998-. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol16:2038–2044.
33.
Hosking D, Chilvers CED, Christiansen C, Ravn P, Wasnich MD, Ross P, et al. -1998-. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med338:485–492.
34.
Kanis JA -1995-. Bone and cancer: pathophysiology and treatment of metastases. Bone17-Suppl-:101S–105S.
35.
Katz H -2005-. Endodontic implications of bisphosphonate-associated osteonecrosis of the jaws: a report of three cases. J Endod31:831–834.
36.
Lacy MQ, Dispenzieri A, Gertz MA, Greipp PR, Golbach KL, Hayman SR, et al. -2006-. Mayo Clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc81:1047–1053.
37.
Lerner UH -2006-. Bone remodeling in post-menopausal osteoporosis. J Dent Res85:584–595.
38.
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 Surg63:1567–1575.
39.
Mavrokokki T, Cheng A, Stein B, Goss A -2007-. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg3:415–423.
40.
McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, et al. -2001-. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med344:333–340.
41.
Mehrotra B, Ruggiero SL -2005-. Bisphosphonate related osteonecrosis -BRON- of the jaw: single institutional update -abstract-. Blood106:291.
42.
Mehrotra B, Nissel-Horowitz S, Ruggiero SL, Sheth M, Vinarsky M, et al. -2003-. Osteonecrosis of the maxilla: an unusual complication of prolonged bisphosphonate therapy. A case report -abstract-. Proc Am Soc Clin Oncol22:795.
43.
Melo MD, Obeid G -2005-. Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy. J Am Dent Assoc136:1675–1681.
44.
Michaelson MD, Smith MR -2005-. Bisphosphonates for the treatment and prevention of bone metastases. J Clin Oncol23:8219–8224.
45.
Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB -2005a-. Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am Dent Assoc136:1658–1668.
46.
Migliorati CA, Schubert MM, Peterson DE, Seneda LM -2005b-. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone. An emerging oral complication of supportive cancer therapy. Cancer104:83–93.
47.
Miller P, Roux C, McClung M, Watts N, Genant H, Adami S, et al. -1999-. Risedronate reduces hip fractures in patients with low femoral neck bone mineral density. Arthritis Rheum42-Suppl 9-:S287–S295.
48.
Mundy GR -1987-. Bone resorption and turnover in health and disease. Bone8-Suppl 1-:S9–S16.
49.
Odvina CV, Zerwekh JE, Rao DS, Mahlouf N, Gottschalk FA, Pak CY -2005-. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab90:1294–1301.
50.
Office of the Surgeon General -2004-. Bone health and osteoporosis: a report of the Surgeon General. Rockville, MD: Department of Health and Human Services.
51.
Ott SM -2005-. Long-term safety of bisphosphonates -editorial-. J Clin Endocrinol Metab90:1897–1899.
52.
Pozzi S, Marcheselli R, Sacchi S, Quarta G, Musto P, Caparrotti G, et al. -2005-. Analysis of frequency and risk factors for developing bisphosphonate associated necrosis of the jaw -abstract-. Blood106:5057.
53.
Purcell PM, Boyd IW -2005-. Bisphosphonates and osteonecrosis of the jaw. Med J Aust182:417–418.
54.
Ravn P, Bidstrup M, Wasnick RD, Davis JW, McClung MR, Balske A, et al. -1999-. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med131:935–942.
55.
Rosenberg TJ, Ruggiero S, Mehrotra O, Engroff SL -2003-. Osteonecrosis of the jaws associated with the use of bisphosphonates. J Oral Maxillofac Surg61-Suppl 1-:60.
56.
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 Surg62:527–534.
57.
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 Endod102:433–441.
58.
Santini D, Vincenzi B, Avvisati G, Dicuonzo G, Battistoni F, Gavasci M, et al. -2002-. Pamidronate induces modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res8:1080–1084.
59.
Sarathy AP, Bourgeois SL, Goodell GG -2005-. Bisphosphonate-associated osteonecrosis of the jaws and endodontic treatment: two case reports. J Endod31:759–763; erratum in J Endod 31:835–836, 2005.
60.
Theriault RL, Lipton A, Hortobagyi GN, Leff R, Gluck S, Stewart JF, et al. -1999-. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic lesions: a randomized placebo-controlled trial. J Clin Oncol17:846–854.
61.
Tosi P, Zamagni E, Cangini D, Tacchetti P, Offidari M, Ronconi S, et al. -2005-. Bisphosphonates and osteonecrosis of the jaws: incidence in a homogeneous series of patients with newly diagnosed multiple myeloma treated with zolendronic acid -abstract-. Blood106:3461.
van Holten-Verzantvoort ATM, Kroon HM, Bijvoet OLM, Cleton FS, Beex LV, Blijham G, et al. -1993-. Palliative pamidronate treatment in patients with bone metastases from breast cancer. J Clin Oncol11:491–498.
64.
Van Poznak C, Ward B -2006-. Osteonecrosis of the jaw. Curr Opin Orthop17:462–468.
65.
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 Haematol128:738–740.
66.
Woo SB, Hellstein JW, Kalmar JR -2006-. Narrative corrected review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med144:753–761; erratum in Ann Intern Med 145:235, 2006.
67.
Wood J, Bonjean K, Ruetz S, Bellahcène A, Devy L, Foidart JM, et al. -2002-. Novel antiangiogenic effects of the bisphosphonate compound zolendronic acid. J Pharmacol Exp Ther302:1055–1061.
