Mayo Clinic Consensus Statement for the Use of Bisphosphonates in Multiple Myeloma
2006; Elsevier BV; Volume: 81; Issue: 8 Linguagem: Inglês
10.4065/81.8.1047
ISSN1942-5546
AutoresMartha Q. Lacy, Angela Dispenzieri, Morie A. Gertz, Philip R. Greipp, Kimberly L. Gollbach, Suzanne R. Hayman, Shaji Kumar, John A. Lust, S. Vincent Rajkumar, Stephen J. Russell, Thomas E. Witzig, Steven R. Zeldenrust, David Dingli, P. Lief Bergsagel, Rafaël Fonseca, Craig B. Reeder, A. Keith Stewart, Vivek Roy, Robert J. Dalton, Alan B. Carr, Deepak Kademani, Eugene E. Keller, Christopher F. Viozzi, Robert A. Kyle,
Tópico(s)Oral and gingival health research
ResumoBisphosphonates are effective in the prevention and treatment of bone disease in multiple myeloma (MM). Osteonecrosis of the jaw is increasingly recognized as a serious complication of long-term bisphosphonate therapy. Issues such as the choice of bisphosphonate and duration of therapy have become the subject of intense debate given patient safety concerns. We reviewed available data concerning the use of bisphosphonates in MM. Guidelines for the use of bisphosphonates in MM were developed by a multidisciplinary panel consisting of hematologists, dental specialists, and nurses specializing in the treatment of MM. We conclude that intravenous pamidronate and intravenous zoledronic acid are equally effective and superior to placebo in reducing skeletal complications. Pamidronate is favored over zoledronic acid until more data are available on the risk of complications (osteonecrosis of the jaw). We recommend discontinuing bisphosphonates after 2 years of therapy for patients who achieve complete response and/or plateau phase. For patients whose disease is active, who have not achieved a response, or who have threatening bone disease beyond 2 years, therapy can be decreased to every 3 months. These guidelines were developed in the interest of patient safety and will be reexamined as new data emerge regarding risks and benefits. Bisphosphonates are effective in the prevention and treatment of bone disease in multiple myeloma (MM). Osteonecrosis of the jaw is increasingly recognized as a serious complication of long-term bisphosphonate therapy. Issues such as the choice of bisphosphonate and duration of therapy have become the subject of intense debate given patient safety concerns. We reviewed available data concerning the use of bisphosphonates in MM. Guidelines for the use of bisphosphonates in MM were developed by a multidisciplinary panel consisting of hematologists, dental specialists, and nurses specializing in the treatment of MM. We conclude that intravenous pamidronate and intravenous zoledronic acid are equally effective and superior to placebo in reducing skeletal complications. Pamidronate is favored over zoledronic acid until more data are available on the risk of complications (osteonecrosis of the jaw). We recommend discontinuing bisphosphonates after 2 years of therapy for patients who achieve complete response and/or plateau phase. For patients whose disease is active, who have not achieved a response, or who have threatening bone disease beyond 2 years, therapy can be decreased to every 3 months. These guidelines were developed in the interest of patient safety and will be reexamined as new data emerge regarding risks and benefits. Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for more than 15,000 new cases annually in the United States and more than 11,000 deaths per year.1Dispenzieri A Kyle RA Multiple myeloma: clinical features and indications for therapy.Best Pract Res Clin Haematol. 2005; 18: 553-568Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The introduction of new pharmacological agents such as bortezomib,2Richardson PG Barlogie B Berenson J et al.Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial.Cancer. 2006; 106: 1316-1319Crossref PubMed Scopus (139) Google Scholar thalidomide,3Rajkumar SV Blood E Vesole D Fonseca R Greipp PR Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group.J Clin Oncol. 2006 Jan 20; 24 (Epub 2005 Dec 19.): 431-436Crossref PubMed Scopus (807) Google Scholar, 4Weber DM Rankin K Gavino M Delasalle K Alexanian R Thalidomide with dexamethasone for resistant multiple myeloma [abstract].Blood. 2000; 96 (Abstract 719.): 167aGoogle Scholar, 5Raza SN Veksler Y Sabir T Li Z Anderson L Jagannath S Durable response to thalidomide in relapsed/refractory multiple myeloma (MM).Blood. 2000; 96 (Abstract 726.): 168aGoogle Scholar and other immunomodulatory drugs6Rajkumar SV Hayman SR Lacy MQ et al.Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma.Blood. 2005 Dec 15; 106 (Epub 2005 Aug 23): 4050-4053Crossref PubMed Scopus (575) Google Scholar has improved treatment options for patients with MM. However, MM is still thought to be incurable with current therapies. Therefore, emphasis must be placed on quality-of-life considerations when selecting treatment options. Bone destruction is a significant cause of morbidity in patients with MM. Multiple myeloma cells and stromal cells of the bone marrow secrete cytokines that increase osteoclast activity, including interleukin 1,7Lacy MQ Donovan KA Heimbach JK Ahmann GJ Lust JA Comparison of interleukin-1 beta expression by in situ hybridization in monoclonal gammopathy of undetermined significance and multiple myeloma.Blood. 1999; 93: 300-305PubMed Google Scholar, 8Lust JA Donovan KA The role of interleukin-1 beta in the pathogenesis of multiple myeloma.Hemat Oncol Clin North Am. 1999; 13: 1117-1125Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar interleukin 6,8Lust JA Donovan KA The role of interleukin-1 beta in the pathogenesis of multiple myeloma.Hemat Oncol Clin North Am. 1999; 13: 1117-1125Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 9Klein B Zhang XG Lu ZY Bataille R Interleukin-6 in human multiple myeloma.Blood. 1995; 85: 863-872Crossref PubMed Google Scholar and tumor necrosis factor,10Callander NS Roodman GD Myeloma bone disease.Semin Hematol. 2001; 38: 276-285Abstract Full Text PDF PubMed Scopus (134) Google Scholar, 11Carter A Merchav S Silvian-Draxler I Tatarsky I The role of interleukin-1 and tumour necrosis factor-alpha in human multiple myeloma.Br J Haematol. 1990; 74: 424-431Crossref PubMed Scopus (138) Google Scholar resulting in osteoporosis, lytic bone disease, and skeletal fractures. The most frequent sites of bony involvement include the vertebrae, calvarium, sternum, ribs, pelvis, and proximal humeri and femurs. Pathologic fractures are a devastating cause of morbidity and pain. Bisphosphonates are synthetic analogues of the naturally occurring pyrophosphate. They have an affinity for bone and are preferentially delivered to sites of increased bone formation or resorption.12Fleisch H Bisphosphonates in osteoporosis.Eur Spine J. 2003; 12: S142-S146Crossref PubMed Scopus (73) Google Scholar Once deposited, bisphosphonates are internalized by osteoclasts that are engaged in bone resorption and modulate signaling from osteoblasts to osteoclasts. They are potent inhibitors of osteoclast-induced bone resorption and are effective in treating cancer-induced hypercalcemia malignancy and osteoporosis.12Fleisch H Bisphosphonates in osteoporosis.Eur Spine J. 2003; 12: S142-S146Crossref PubMed Scopus (73) Google Scholar Bisphosphonates have been shown to reduce bony complications associated with MM13Berenson JR Rosen LS Howell A et al.Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases [published correction appears in Cancer. 2001;91:1956].Cancer. 2001; 91: 1191-1200Crossref PubMed Scopus (493) Google Scholar, 14Berenson JR Lichtenstein A Porter L Myeloma Aredia Study Group et al.Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma.N Engl J Med. 1996; 334: 488-493Crossref PubMed Scopus (992) Google Scholar, 15Berenson JR Vescio RA Rosen LS et al.A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases.Clin Cancer Res. 2001; 7: 478-485PubMed Google Scholar, 16Rosen LS Gordon D Kaminski M et al.Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.Cancer J. 2001; 7: 377-387Crossref PubMed Scopus (305) Google Scholar, 17Ruggiero 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: 527-534Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar, 18Lahtinen R Laakso M Palva I Virkkunen P Elomaa I Finnish Leukaemia Group Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma [published correction appears in Lancet. 1992;340:1420].Lancet. 1992; 340: 1049-1052Abstract PubMed Scopus (380) Google Scholar, 19McCloskey EV MacLennan IC Drayson MT Chapman C Dunn J Kanis JA MRC Working Party on Leukaemia in Adults A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma.Br J Haematol. 1998; 100: 317-325Crossref PubMed Scopus (318) Google Scholar in a variety of studies. On the basis of this finding, in 2002 the American Society of Clinical Oncology (ASCO) issued clinical practice guidelines regarding the role of bisphosphonates in MM.20Berenson JR Hillner BE Kyle RA American Society of Clinical Oncology Bisphosphonates Expert Panel et al.American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma.J Clin Oncol. 2002; 20: 3719-3736Crossref PubMed Scopus (420) Google Scholar Adverse effects associated with the use of bisphosphonates are usually mild and consist of fever, renal function impairment, myalgias and hypocalcemia.12Fleisch H Bisphosphonates in osteoporosis.Eur Spine J. 2003; 12: S142-S146Crossref PubMed Scopus (73) Google Scholar Renal complications are rare but include renal insufficiency and proteinuria.21Guarneri V Donati S Nicolini M Giovannelli S D'Amico R Conte PF Renal safety and efficacy of i.v. bisphosphonates in patients with skeletal metastases treated for up to 10 years.Oncologist. 2005; 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62: 527-534Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar, 32Marx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic [letter].J Oral Maxillofac Surg. 2003; 61: 1115-1117Abstract Full Text Full Text PDF PubMed Scopus (2145) Google Scholar, 33Durie BG Katz M Crowley J Osteonecrosis of the jaw and bisphosphonates [letter].N Engl J Med. 2005; 353: 99-100Crossref PubMed Scopus (660) Google Scholar, 34Bagan JV Murillo J Jimenez Y et al.Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases.J Oral Pathol Med. 2005; 34: 120-123Crossref PubMed Scopus (233) Google Scholar, 35Melo 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: 1675-1681Crossref PubMed Scopus (133) Google Scholar, 36Vannucchi 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: 738Crossref PubMed Scopus (100) Google Scholar, 37Migliorati 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: 83-93Crossref PubMed Scopus (443) Google Scholar, 38Migliorati CA Casiglia J Epstein J Jacobsen PL Siegel MA Woo SB Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper [published correction appears in J Am Dent Assoc. 2006;137:26].J Am Dent Assoc. 2005; 136: 1658-1668Crossref PubMed Scopus (356) Google Scholar, 39Badros 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: 945-952Crossref PubMed Scopus (494) Google Scholar, 40Bamias 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: 8580-8587Crossref PubMed Scopus (979) Google Scholar, 41Ficarra G Beninati F Rubino I et al.Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment.J Clin Periodontol. 2005; 32: 1123-1128Crossref PubMed Scopus (160) Google Scholar, 42Woo SB Hellstein JW Kalmar JR Systematic review: bisphosphonates and osteonecrosis of the jaws.Ann Intern Med. 2006; 144: 753-761Crossref PubMed Scopus (1065) Google Scholar Bisphosphonate-associated ONJ has been described in various malignancies, including MM, breast cancer, and prostate cancer, and can be a debilitating problem associated with significant morbidity (a photograph showing ONJ involving the mandible of a patient with MM can be found in the case report by Kademani et al43Kademani D Koka S Lacy MQ Rajkumar SV Primary surgical therapy for osteonecrosis of the jaw secondary to bisphosphonate therapy.Mayo Clin Proc. 2006; 81: 1100-1103Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar in this issue of Mayo Clinic Proceedings). The underlying pathophysiologic mechanisms have not yet been clarified.38Migliorati CA Casiglia J Epstein J Jacobsen PL Siegel MA Woo SB Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper [published correction appears in J Am Dent Assoc. 2006;137:26].J Am Dent Assoc. 2005; 136: 1658-1668Crossref PubMed Scopus (356) Google Scholar However, the clinical similarity of ONJ to osteoradionecrosis encountered in patients after receiving head and neck irradiation is striking. Studies suggest that the incidence of ONJ is related to duration of exposure and the type of bisphosphonate used.33Durie BG Katz M Crowley J Osteonecrosis of the jaw and bisphosphonates [letter].N Engl J Med. 2005; 353: 99-100Crossref PubMed Scopus (660) Google Scholar, 39Badros 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: 945-952Crossref PubMed Scopus (494) Google Scholar, 40Bamias 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: 8580-8587Crossref PubMed Scopus (979) Google Scholar Treatment strategies used in osteoradionecrosis are often unsatisfactory when applied to ONJ because patients are left with severe morbidity, pain, and permanent disability.39Badros 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: 945-952Crossref PubMed Scopus (494) Google Scholar As a result, there is increasing concern about the indefinite use of bisphosphonates in patients with MM and remarkable interest in determining the optimal way to administer these agents that would maximize the risk-benefit ratio. In view of this, the Mayo Clinic Myeloma Group reexamined practice guidelines regarding bisphosphonate use for MM. Since pamidronate and zoledronic acid are the only bisphosphonates approved for use in MM in the United States, we chose to restrict our comments and recommendations to these 2 agents. The evidence supporting the use of bisphosphonates to prevent bony disease in MM comes from 4 randomized phase 3 clinical trials, 2 of which used oral clodronate, which is not available in the United States. The first trial evaluated the use of intravenous pamidronate in patients with MM.14Berenson JR Lichtenstein A Porter L Myeloma Aredia Study Group et al.Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma.N Engl J Med. 1996; 334: 488-493Crossref PubMed Scopus (992) Google Scholar In this randomized, placebo-controlled trial, 392 patients with stage III MM and at least 1 lytic lesion were randomized to placebo or pamidronate, 90 mg, given as a 4-hour infusion every 4 weeks for 21 cycles. All patients' chemotherapy regimens had to have been unchanged for at least 2 months before entry into the study. The primary preplanned end points were the reduction of skeletal-related events (SREs) after 9 cycles of therapy and evaluation of safety and survival after 21 cycles of randomized treatment. Patients were stratified before randomization on the basis of having received either their first anti-MM regimen (stratum 1) or their second or further anti-MM regimen (stratum 2). A total of 377 patients were assessable for the primary end point (SREs), 179 in the placebo group and 198 in the pamidronate group. Of these patients, 247 were in stratum 1. At 9 months, the number of SREs per year was 2.1 in the placebo group and 1.1 in the pamidronate group (P=.0006). At 21 months of follow-up, the number of SREs changed minimally, 2.2 per year in the placebo group and 1.3 per year in the pamidronate group (P=.008). The median time to the first SRE was 10 months in the placebo group and 21 months in the pamidronate group (P<.001). At 12 months, 28% of patients in the pamidronate group vs 44% in the placebo group had an SRE (P=.001). Other benefits in the pamidronate group included a lower percentage of patients developing pathologic fracture or requiring radiation to bone, significant decreases in pain, and no increase in analgesic drug use. The placebo group had no improvement in pain and required escalating analgesic drug use during the trial. Quality-of-life studies also favored the use of pamidronate. This prospective study subsequently led to the Food and Drug Administration approving the use of this drug for MM. In February 2002, the Food and Drug Administration approved an expanded indication for zoledronic acid for the treatment of patients with bone metastases that included its use in MM. Two randomized trials showed that zoledronic acid had similar efficacy and safety compared to 90 mg of pamidronate. The first, a randomized phase 2 study,13Berenson JR Rosen LS Howell A et al.Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases [published correction appears in Cancer. 2001;91:1956].Cancer. 2001; 91: 1191-1200Crossref PubMed Scopus (493) Google Scholar compared zoledronic acid to pamidronate in 280 patients with lytic bone metastases from either MM (n=108) or breast cancer (n=172). Patients were randomized to 9 monthly infusions of 0.4 mg, 2 mg, or 4 mg of zoledronic acid in a 5-minute infusion or to 90 mg of pamidronate as a 2-hour infusion. The primary end point was to determine the dose of zoledronic acid required to reduce the need for radiation to less than 30% of treated patients. Duration of follow-up was not reported. Radiation treatment was required in a similar proportion of patients receiving pamidronate and zoledronic acid at 2 mg or 4 mg (18% to 21%). A slightly higher number of patients receiving zoledronic acid at 0.4 mg required radiation therapy (24%). A larger phase 3 randomized trial compared 4- or 8-mg doses of zoledronic acid to 90 mg of pamidronate every 3 to 4 weeks in patients with MM or breast cancer who had lytic disease.16Rosen LS Gordon D Kaminski M et al.Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.Cancer J. 2001; 7: 377-387Crossref PubMed Scopus (305) Google Scholar The infusion time for zoledronic acid was increased from 5 minutes to 15 minutes during the trial because of an increase in creatinine that occurred more frequently among patients receiving the rapid infusion. Renal problems continued to occur more often among patients randomized to 8 mg of zoledronic acid, and their dose was subsequently reduced to 4 mg. The sample size was based on showing non-inferiority of zoledronic acid to pamidronate. The study enrolled 1648 patients in an intent-to-treat analysis; 510 had MM, and the remainder had metastatic breast cancer. The portion of patients with any SRE after 13 months did not differ among the 3 treatments and did not differ between patients with breast cancer and those with MM. Notably, none of these trials included formal quality-of-life measures or adverse event measures of oral-related conditions and pathology. Since the trials were conducted before ONJ was a known complication of bisphosphonate therapy, they did not report this long-term adverse event. These trials led the ASCO panel to advocate the use of either pamidronate or zoledronic acid monthly for patients with MM and lytic bone disease.20Berenson JR Hillner BE Kyle RA American Society of Clinical Oncology Bisphosphonates Expert Panel et al.American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma.J Clin Oncol. 2002; 20: 3719-3736Crossref PubMed Scopus (420) Google Scholar These guidelines recommended the use of pamidronate at 90 mg delivered intravenously for at least 2 hours or zoledronic acid at 4 mg intravenously for 15 minutes every 3 to 4 weeks for patients with MM and lytic bone disease. The panel also extrapolated these data and recommended use of bisphosphonates for patients with MM and osteopenia. The panel suggested that once initiated, intravenous pamidronate or zoledronic acid be continued until there was evidence of substantial decline in a patients general performance status…. Discontinuation of pamidronate or zoledronic acid, because of performance status changes, should only be considered if patients' likely palliative benefit is believed to be less than the inconvenience of receiving an intravenous infusion.20Berenson JR Hillner BE Kyle RA American Society of Clinical Oncology Bisphosphonates Expert Panel et al.American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma.J Clin Oncol. 2002; 20: 3719-3736Crossref PubMed Scopus (420) Google Scholar Of note, currently no data are available from randomized trials regarding the long-term adverse event rate associated with monthly bisphosphonates beyond 2 years of therapy. Osteonecrosis of the jaw is not a new phenomenon. Descriptions of "phossy jaw" date back to the 19th century among workers in the matchstick making industry.44Dearden WF The causation of phosphorus necrosis.BMJ. 1901; 2: 408Google Scholar, 45Dearden WF Fragilitas ossium amongst workers in Lucifer match factories.BMJ. 1899; 2: 270Crossref PubMed Scopus (18) Google Scholar High levels of phosphorus-containing products held in the oral cavity of workers often led to spontaneous jaw exposure and pain.46Miles AE Phosphorus necrosis of the jaw: 'phossy jaw'.Br Dent J. 1972; 133: 203-206Crossref PubMed Scopus (25) Google Scholar Since the initiation of routine use of radiotherapy for solid tumors of the head and neck, it has been well recognized that jaw "osteoradionecrosis" is frequently observed and can occur either spontaneously or secondary to dental infection or oral surgical manipulation. The use of irradiation creates hard and soft tissue hypoxia-hypocellularity and hypovascularity, and it significantly decreases the healing ability of the soft tissue and bone in the oral-facial region.47Marx RE Osteoradionecrosis: a new concept of its pathophysiology.J Oral Maxillofac Surg. 1983; 41: 283-288Abstract Full Text PDF PubMed Scopus (866) Google Scholar Osteoradionecrosis is not the same entity as ONJ but is similar pathophysiologically. In 2003, ONJ was first recognized as a complication of bisphosphonate therapy.32Marx RE Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic [letter].J Oral Maxillofac Surg. 2003; 61: 1115-1117Abstract Full Text Full Text PDF PubMed Scopus (2145) Google Scholar It has been seen with a higher frequency in the mandible (63%) than in the maxilla (38%).17Ruggiero 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: 527-534Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar The etiology of ONJ remains unclear but is likely to be multifactorial in origin. Although most patients who develop ONJ have had recent dental or oral surgical procedures (70%), a large subset (30%) develops spontaneous ONJ without a history of recent oral therapy.17Ruggiero 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: 527-534Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar In one series of 22 patients, 91% of the ONJ occurred posterior to canine teeth, and 45% of the lesions were spontaneous. The authors described the spontaneous ONJ as occurring on the lingual surface of the mandible, a region easily traumatized during normal mastication.39Badros 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: 945-952Crossref PubMed Scopus (494) Google Scholar Interestingly, this location mimics that of osteoradionecrosis in oncology patients who have received irradiation. Proposed induction mechanisms are that inhibition of osteoclast activity reduces bone turnover and remodeling and that bisphosphonates prevent release of bone-specific factors that promote bone formation.38Migliorati CA Casiglia J Epstein J Jacobsen PL Siegel MA Woo SB Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper [published correction appears in J Am Dent Assoc. 2006;137:26].J Am Dent Assoc. 2005; 136: 1658-1668Crossref PubMed Scopus (356) Google Scholar In addition, bisphosphonates, particularly zoledronic acid, may have antiangiogenic effects,48Wood J Bonjean K Ruetz S et al.Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid.J Pharmacol Exp Ther. 2002; 302: 1055-1061Crossref PubMed Scopus (712) Google Scholar, 49Santini D Vespasiani Gentilucci U Vincenzi B et al.The antineoplastic role of bisphosphonates: from basic research to clinical evidence.Ann Oncol. 2003; 14: 1468-1476Crossref PubMed Scopus (143) Google Scholar and impaired blood supply has been implicated in the development of ONJ. Finally, after dental extractions, healing of an open osseous oral wound is challenged by bacterial insult from oral microflora, especially if the protective fibrin clot does not form or is dissolved. This may explain the strong association of ONJ with dental or oral surgical procedures.38Migliorati CA Casiglia J Epstein J Jacobsen PL Siegel MA Woo SB Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper [published correction appears in J Am Dent Assoc. 2006;137:26].J Am Dent Assoc. 2005; 136: 1658-1668Crossref PubMed Scopus (356) Google Scholar Numerous reports have discussed ONJ in patients using bisphosphonates,17Ruggiero 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: 527-534Abstract Full Text Full Text PDF PubMed Scopus (1624) Google Scholar, 33Durie BG Katz M Crowley J Osteonecrosis of the jaw and bisphosphonates [letter].N Engl J Med. 2005; 353: 99-100Crossref PubMed Scopus (660) Google Scholar, 35Melo 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: 1675-1681Crossref PubMed Scopus (133) Google Scholar, 36Vannucchi 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: 738Crossref PubMed Scopus
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