American Association of Oral and
Maxillofacial Surgeons Position Paper on
Bisphosphonate-Related Osteonecrosis of
Bisphosphonate-related osteonecrosis of the jaw Maxillofacial Surgeons (AAOMS). The Task Force (BRONJ) adversely affects the quality of life and was composed of clinicians with extensive experi- produces significant morbidity in afflicted patients.
ence in caring for these patients, clinical epidemi- Oral and maxillofacial surgeons have been respon- ologists, and basic science researchers offering a sible for counseling, managing, and treating a ma- broad range of experience and background. The jority of these patients. The strategies set forth in strategies are based on an analysis of the existing this position paper were developed by a Task Force literature and the clinical observations of the expert appointed by the American Association of Oral and Task Force members. AAOMS considers it vitallyimportant that this information be disseminated toother dental and medical specialties. It is under- Disclaimer: The AAOMS is providing this position paper on stood that the strategies and treatment algorithms Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) to in- outlined in this article are starting points based on form practitioners, patients, and other interested parties. The po- our current understanding of BRONJ. As the knowl- sition paper is based on a review of the existing literature and the edge base and experience in addressing BRONJ clinical observations of an expert Task Force composed of oral and evolves, future modifications and refinements of maxillofacial surgeons experienced in the diagnosis, surgical and the current strategies will necessarily be required.
adjunctive treatment of diseases, injuries and defects involving both the functional and esthetic aspects of the hard and soft tissues of the oral and maxillofacial regions, epidemiologists, and basic re- searchers. The position paper is informational in nature and is not The purpose of this position paper is to provide: intended to set any standards of care. AAOMS cautions all readers that the strategies described in the position paper are not practice 1. Perspectives on the risk of developing BRONJ parameters or guidelines and may not be suitable for every, or any, and the risks and benefits of bisphosphonates in purpose or application. This position paper cannot substitute for order to facilitate medical decision-making of the individual judgment brought to each clinical situation by the both the treating physician and the patient; patient’s oral and maxillofacial surgeon. As with all clinical materi- 2. Guidance to clinicians regarding the differential als, the position paper reflects the science related to BRONJ at the diagnosis of BRONJ in patients with a history of time of the paper’s development, and it should be used with the treatment with intravenous (IV) or oral bisphos- clear understanding that continued research and practice may re- sult in new knowledge or recommendations. AAOMS makes no 3. Guidance to clinicians on possible BRONJ pre- express or implied warranty regarding the accuracy, content, com- vention measures and management of patients pleteness, reliability, operability, or legality of information con- with BRONJ based on the presenting stage of tained within the position paper, including, without limitation, the warranties of merchantability, fitness for a particular purpose, and noninfringement of proprietary rights. In no event shall the AAOMS be liable to the user of the position paper or anyone else for any Background
decision made or action taken by him or her in reliance on such Address correspondence and reprint requests to: AAOMS, 9700 Intravenous bisphosphonates are primarily used W Bryn Mawr Ave, Rosemont, IL 60018.
and effective in the treatment and management of 2007 American Association of Oral and Maxillofacial Surgeons cancer-related conditions. These include hypercalce- mia of malignancy, skeletal-related events associated with bone metastases in the context of solid tumors such as breast cancer, prostate cancer, and lung can- or previous treatment with a bisphosphonate; 2) ex- cer, and in the management of lytic lesions in the posed, necrotic bone in the maxillofacial region that has persisted for more than 8 weeks; and 3) no history nates are effective in preventing and reducing hyper- of radiation therapy to the jaws. It is important to calcemia, stabilizing bony pathology, and preventing understand that patients at risk for BRONJ or with fractures in the context of skeletal involvement.
established BRONJ can also present with other com- While they have not been shown to improve cancer- mon clinical conditions not to be confused as specific survival, they have had a significant impact on BRONJ. Commonly misdiagnosed conditions may in- the quality of life for patients with advanced cancer clude, but are not limited to, alveolar osteitis, sinus- that involves the skeletal system. Before 2001, pam- itis, gingivitis/periodontitis, caries, periapical pathol- idronate (Aredia; Novartis, East Hanover, NJ) was the ogy, and temporomandibular joint disorders.
only drug approved in the United States for treatmentof metastatic bone disease. In 2002, zoledronic acid(Zometa; Novartis) was approved for this indication Estimated Incidence and Factors
Associated With Development of
Oral bisphosphonates are approved to treat osteo- porosis and are frequently used to treat osteopenia as IV BISPHOSPHONATES AND INCIDENCE OF BRONJ They are also used for a variety of less com-mon conditions such as Paget’s disease of bone, and The clinical efficacy of IV bisphosphonates for the treatment of hypercalcemia and bone metastases is most prevalent and common indication, however, is cidence data for BRONJ are limited to retrospective text of other diseases such as inflammatory bowel studies with limited sample sizes. Based on these disease or primary biliary cirrhosis, as the result of studies, estimates of the cumulative incidence of medications, most commonly steroids, or as a conse- recognition, duration of exposure, and follow-up, it is underlying etiology of the osteoporosis, bisphospho- likely that the incidence will rise.
nates may play a role, perhaps in conjunction withcalcium and vitamin D, in its management.
ORAL BISPHOSPHONATES AND INCIDENCE OFBRONJ The clinical efficacy of oral bisphosphonates for the In 2003 and 2004, oral and maxillofacial surgeons treatment of osteopenia/osteoporosis is well established were the first clinicians to recognize and report cases and is reflected in the fact that over 190 million oral of nonhealing exposed, necrotic bone in the maxillo- bisphosphonate prescriptions have been dispensed facial region in patients treated with IV bisphospho- The specialty’s experiences have identi- Since these initial reports, several case se- fied several BRONJ cases related to oral bisphospho- Patients under treatment with oral bisphos- September 2004, Novartis, the manufacturer of the phonate therapy are at a considerably lower risk for BRONJ than patients treated with IV bisphosphonates.
zoledronic acid (Zometa), notified healthcare profes- Based on data from the manufacturer of alendronate sionals of additions to the labeling of these products, (Merck, Whitehouse Station, NJ), the incidence of which provided cautionary language related to the BRONJ was calculated to be 0.7/100,000 person/years development of osteonecrosis of the This was followed in 2005 by a broader drug class warning of reported (not confirmed) cases that were deemed to this complication for all bisphosphonates, including likely represent BRONJ divided by the number of alen- dronate pills prescribed since approval of the drug, and bisphosphonate medications that are currently avail- converted to number of patient years. Although these are the best available data to date, there may be seriousunder-reporting and, as noted above, none confirmed.
BRONJ Case Definition
Correspondence with Alastair Goss, DDSc (September2006) reported that the estimated incidence of BRONJ To distinguish BRONJ from other delayed healing for patients treated weekly with alendronate is 0.01% to conditions, the following working definition of 0.04%, based on prescription data in Australia. After extractions, this rate increased to 0.09% to 0.34%.
Patients may be considered to have BRONJ if all of Based on the above cited data, the risk of BRONJ for the following 3 characteristics are present: 1) current patients receiving IV bisphosphonates appears to be significantly greater than the risk for patients receiv- abscesses, are at a 7-fold increased risk for ing oral bisphosphonates. Regardless, given the large number of patients receiving oral bisphosphonatesfor the treatment of osteoporosis/osteopenia, it is likely that most practitioners may encounter some A. Age: With each passing decade, there is a 9% patients with BRONJ. It is important to accurately increased risk for BRONJ in multiple myeloma determine the incidence of BRONJ in this population patients treated with IV bisphosphonates.
and to assess the risk associated with long-term use, ie, more than 3 years, of oral bisphosphonates. The C. Cancer diagnosis: Risk is greater for patients effect of certain comorbidities, eg, chronic corticoste- roid use, also requires further study.
with breast cancer; and those with breastcancer have a greater risk than those with Risk factors for the development of BRONJ can be D. Osteopenia/osteoporosis diagnosis concur- grouped as drug-related, local risk factors, and demo- The following factors are thought to be risk factors A. Potency of the particular bisphosphonate: bisphosphonates; the IV route of adminis- tration results in a greater drug exposure B. Duration of therapy: longer duration appears Further studies are required to accurately determine ifthese factors are associated with BRONJ risk.
A. Dentoalveolar surgery, including, but not Management Strategies for Patients
Treated With Bisphosphonates
Prior to treatment with an IV bisphosphonate, the patient should have a thorough oral examination, any unsalvageable teeth should be removed, all invasive and undergoing dentoalveolar surgery are atleast 7 times more likely to develop BRONJ dental procedures should be completed, and optimal than patients who are not having dentoal- periodontal health should be achieved.
Based on the experience of 2 Task Force members with approximately 50 patients, the risk of develop- ing BRONJ associated with oral bisphosphonates, al- though exceedingly small, appears to increase when the duration of therapy exceeds 3 years. This time frame may be shortened in the presence of certain comorbidities, such as chronic corticosteroid use. If systemic conditions permit, it has been proposed that discontinuation of oral bisphosphonates for a than the maxilla (2:1 ratio) and more com- period of 3 months prior to and 3 months after elec- monly in areas with thin mucosa overlying tive invasive dental surgery may lower the risk of bony prominences such as tori, bony exos- BRONJ. The risk reduction may vary depending on the duration of bisphosphonate exposure. Modifica- tion or cessation of oral bisphosphonate therapy should be done in consultation with the treating phy- dental disease, eg, periodontal and dental crosis prevention protocols are guidelines that are The major goals of treatment for patients at risk of familiar to most oncologists and general dentists.
Asymptomatic Patients Receiving IntravenousBisphosphonates ● Prioritization and support of continued onco- Maintaining good oral hygiene and dental care is of logic treatment in patients receiving IV bisphos- paramount importance in preventing dental disease that may require dentoalveolar surgery. Procedures ● Oncology patients can benefit greatly from the that involve direct osseous injury should be avoided.
therapeutic effect of bisphosphonates by con- Nonrestorable teeth may be treated by removal of the trolling bone pain and reducing the incidence crown and endodontic treatment of the remaining Placement of dental implants should beavoided in the oncology patient who was exposed to ● Preservation of quality of life through: the more potent intravenous bisphosphonate medica- tions (zoledronic acid and pamidronate) on a frequent dosing schedule (4 –12 times per year).
There has been limited information on IV bisphos- ● Prevention of extension of lesion and develop- phonate use for osteoporosis, as this indication is an off-label use. However, the dosing schedule for osteo-porosis is far less frequent than for adjunct treatment of oncology patients. A September 16, 2006, mediarelease from Novartis provided information on Phase Patients About to Initiate Intravenous III trials of a once-yearly infusion of zoledronic acid for the treatment of postmenopausal osteoporosis, The treatment objective for this group of patients is to which is currently under review by the Based minimize the risk of developing BRONJ. Although a on the decreased frequency/dosage for this indica- small percentage of patients receiving bisphosphonates tion, the Task Force believes the risk of developing develop osteonecrosis of the jaw spontaneously, the BRONJ may be equivalent to or possibly less than that majority of affected patients experience this complica- tion after dentoalveolar Therefore, if sys-temic conditions permit, initiation of bisphosphonate Asymptomatic Patients Receiving Oral therapy should be delayed until dental health is opti- mized. This decision must be made in conjunction with Patients receiving oral bisphosphonates are also at the treating physician and dentist and other specialists risk for developing BRONJ, but to a much lesser involved in the care of the patient.
degree than those treated with intravenous bisphos- Nonrestorable teeth and those with a poor progno- sis should be extracted. Other necessary elective den- ously or after minor trauma. In general, these patients toalveolar surgery should also be completed at this seem to have less severe manifestations of necrosis time. Based on experience with osteoradionecrosis, it and respond more readily to stage-specific treatment appears advisable that bisphosphonate therapy should be delayed, if systemic conditions permit, until the does not appear to be contraindicated in this group. It extraction site has mucosalized (14 –21 days) or until is recommended that patients be adequately informed there is adequate osseous healing. Dental prophylaxis, of the small risk of compromised bone healing. The caries control, and conservative restorative dentistry are risk of BRONJ may be associated with increased du- critical to maintaining functionally sound teeth. This ration of treatment with oral bisphosphonates, ie, 3 level of care must be continued indefinitely.
years or more, based on experience with 50 such Patients with full or partial dentures should be patients by 2 Task Force members. The risk of long- examined for areas of mucosal trauma, especially term oral bisphosphonate therapy clearly requires fur- along the lingual flange region. It is critical that pa- tients be educated as to the importance of dentalhygiene and regular dental evaluations, and specifi- cally instructed to report any pain, swelling, or ex- Sound recommendations for patients taking oral bisphosphonates that are based on strong clinical Medical oncologists should evaluate and manage research designs are lacking. The Task Force strate- patients scheduled to receive IV bisphosphonates gies outlined below are based on clinical experience similarly to those patients scheduled to initiate radia- of clinicians involved in caring for these patients, in tion therapy to the head and neck. The osteoradione- which it appears that the risk of developing BRONJ Table 1. STAGING AND TREATMENT STRATEGIES
At risk category: No apparent exposed/necrotic bone in patients who have been treated with either oral Stage 1: Exposed/necrotic bone in patients who are asymptomatic and have no evidence of infection ● Clinical follow-up on a quarterly basis● Patient education and review of indications for continued Stage 2: Exposed/necrotic bone associated with ● Symptomatic treatment with broad-spectrum oral infection as evidenced by pain and erythema in antibiotics, eg, penicillin, cephalexin, clindamycin, or first- the region of the exposed bone with or without ● Oral antibacterial mouth rinse● Pain control● Only superficial debridements to relieve soft tissue irritation Stage 3: Exposed/necrotic bone in patients with pain, infection, and one or more of the following: pathologic fracture, extraoral fistula, or osteolysis ● Surgical debridement/resection for longer term palliation of *Exposed, necrotic bone in the maxillofacial region without resolution in 8 to 12 weeks in persons treated with a bisphosphonate who have not received radiation therapy to the jaws.
†Regardless of the disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. The extraction of symptomatic teeth within exposed, necrotic bone should be considered because it is unlikely that the extraction will exacerbatethe established necrotic process.
‡Discontinuation of the IV bisphosphonates shows no short-term benefit. However, if systemic conditions permit, long-term discontinu- ation may be beneficial in stabilizing established sites of BRONJ, reducing the risk of new site development, and reducing clinical symptoms.
The risks and benefits of continuing bisphosphonate therapy should be made only by the treating oncologist in consultation with the OMSand the patient.
§Discontinuation of oral bisphosphonate therapy in patients with BRONJ has been associated with gradual improvement in clinical disease.
Based on the experience of 2 Task Force members managing 50 BRONJ patients who were treated with oral bisphosphonates, discontinuationof oral bisphosphonates for 6 to 12 months may result in either spontaneous sequestration or resolution following debridement surgery. Ifsystemic conditions permit, modification or cessation of oral bisphosphonate therapy should be done in consultation with the treatingphysician and the patient.
associated with oral bisphosphonates increased when taken corticosteroids concomitantly, the prescribing duration of therapy exceeded 3 years. As more data provider should be contacted to consider discontinu- become available, these strategies will be updated and ation of the oral bisphosphonate (drug holiday) for at least 3 months prior to oral surgery, if systemic con- For individuals who have taken an oral bisphos- ditions permit. The bisphosphonate should not be phonate for less than 3 years and have no clinical restarted until osseous healing has occurred. These risk factors, no alteration or delay in the planned strategies are based on the hypothesis that concomi- surgery is necessary. This includes any and all surger- tant treatment with corticosteroids may increase the ies common to oral and maxillofacial surgeons, peri- risk of developing BRONJ and that a “drug holiday” odontists, and other dental providers.
However, it is suggested that if dental implants are For those patients who have taken an oral placed, informed consent should be provided related bisphosphonate for more than 3 years with or with- to possible future implant failure and possible osteo- out any concomitant prednisone or other steroid necrosis of the jaws if the patient continues to take an medication, the prescribing provider should be con- oral bisphosphonate. Such patients should be placed tacted to consider discontinuation of the oral bisphos- on a regular recall schedule. It is also advisable to phonate for 3 months prior to oral surgery, if systemic contact the provider who originally prescribed the conditions permit. The bisphosphonate should not oral bisphosphonate and suggest monitoring such pa- be restarted until osseous healing has occurred. These tients and considering either alternate dosing of the strategies are based on the experience of 2 Task Force bisphosphonate, drug holidays, or an alternative to members managing 50 BRONJ patients who had a history of oral bisphosphonate therapy for 3 or more For those patients who have taken an oral years, and the hypothesis that a “drug holiday” may bisphosphonate for less than 3 years and have also Patients With an Established Diagnosis of 1. Patients at risk: No apparent exposed/necrotic bone in patients who have been treated with The treatment objectives for patients with an estab- lished diagnosis of BRONJ are to eliminate pain, con- trol infection of the soft and hard tissue, and minimize Stage 1: Exposed/necrotic bone in patients who are the progression or occurrence of bone necrosis.
asymptomatic and have no evidence of infection.
These patients respond less predictably to the es- Stage 2: Exposed/necrotic bone in patients with tablished surgical treatment algorithms for osteomy- pain and clinical evidence of infection.
elitis or osteoradionecrosis. Surgical debridement has Stage 3: Exposed/necrotic bone in patients with been variably effective in eradicating the necrotic pain, infection, and one or more of the following:pathologic fracture, extraoral fistula, or osteolysis ex- margin with viable bleeding bone as the entire jaw-bone has been exposed to the pharmacologic influ- ence of the bisphosphonate. Therefore, surgical treat-ment should be delayed if possible. Areas of necrotic bone that are a constant source of soft tissue irritation Patients who are at risk of developing BRONJ by should be removed or recontoured without exposure virtue of the fact that they have been exposed to a of additional bone. Based on the experience of the bisphosphonate do not require any treatment. How-ever, these patients should be informed of the risks of Task Force members and case reports, loose segments developing BRONJ, as well as the signs and symptoms of bony sequestrum should be removed without ex- posing uninvolved The extraction of symp-tomatic teeth within exposed, necrotic bone should be considered because it is unlikely that the extrac- These patients benefit from the use of oral antimi- tion will exacerbate the established necrotic process.
crobial rinses, such as chlorhexidine 0.12%. No surgi- Patients with established BRONJ should avoid elec- cal treatment is indicated. Patients who present with tive dentoalveolar surgical procedures, because these Stage 1 disease have done well with this type of surgical sites may result in additional areas of exposed necrotic bone. Symptomatic patients with pathologic mandibular fractures may require segmental resection These patients benefit from the use of oral antimi- and immediate reconstruction with a reconstruction crobial rinses in combination with antibiotic therapy.
plate. The potential for failure of the reconstruction It is hypothesized that the pathogenesis of BRONJ plate because of the generalized effects of the may be related to factors adversely influencing bone bisphosphonate exposure needs to be recognized by remodeling. Additionally, BRONJ is not due to a pri- the clinician and patient. Immediate reconstruction of mary infectious etiology. Most of the isolated mi- these patients with nonvascularized or vascularized crobes have been sensitive to the penicillin group of bone may be problematic as necrotic bone may de- antibiotics. Quinolones, metronidazole, clindamycin, doxycycline, and erythromycin have been used with The effectiveness of hyperbaric oxygen therapy is success in those patients who are allergic to penicil- lin. Microbial cultures should also be analyzed for the Freiberger, MD, MPH on May 17, 2006, reported that presence of actinomyces species of bacteria. If this a clinical trial has been funded to establish the effi- microbe is isolated, then the antibiotic regimen cacy of hyperbaric oxygen therapy in treating patients should be adjusted accordingly. In some refractory with BRONJ, and began enrolling patients in August cases, however, patients may require combination antibiotic therapy, long-term antibiotic maintenance,or a course of intravenous antibiotic therapy.
Staging and Treatment Strategies
These patients typically have pain that impacts the quality of life. Surgical debridement/resection in com-bination with antibiotic therapy may offer long-term palliation with resolution of acute infection and pain.
In order to direct rational treatment guidelines and Regardless of the disease stage, mobile segments of collect data to assess the prognosis in patients who have bony sequestrum should be removed without expos- used either IV or oral bisphosphonates, the AAOMS ing uninvolved bone. The extraction of symptomatic proposes use of the following staging categories: teeth within exposed, necrotic bone should be con- sidered because it is unlikely that the extraction will 3. Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pam- exacerbate the established necrotic process.
idronate in reducing skeletal complications in patients withbreast cancer and lytic bone metastases. Protocol 19 ArediaBreast Cancer Study Group. N Engl J Med 335:1785, 1996 4. Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term pre- vention of skeletal complications of metastatic breast cancerwith pamidronate. Protocol 19 Aredia Breast Cancer Study Oncology patients benefit greatly from the thera- 5. Hillner BE, Ingle JN, Chelbowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates peutic effects of bisphosphonates by controlling bone and bone health issues in women with breast cancer. J Clin pain and the incidence of pathologic fractures. Dis- continuation of IV bisphosphonates offers no short- 6. Saad F, Gleason DM, Murray R, et al: A randomized, placebo- controlled trial of zoledronic acid in patients with hormone- term benefit. However, if systemic conditions per- refractory metastatic prostate carcinoma. J Natl Cancer Inst mit, long-term discontinuation may be beneficial in stabilizing established sites of BRONJ, reducing the 7. Saad F, Gleason DM, Murray R, et al: Long-term efficacy of zoledronic acid for the prevention of skeletal complications in risk of new site development, and reducing clinical patients with metastatic hormone-refractory prostate cancer.
symptoms. The risks and benefits of continuing bisphosphonate therapy should be made only by the 8. Rosen LS, Gordon D, Tchekmedyian NS, et al: Long-term effi- cacy and safety of zoledronic acid in the treatment of skeletal treating oncologist in consultation with the OMS and metastases in patients with non-small cell lung carcinoma and other solid tumors: A randomized, Phase III, double-blind pla-cebo-controlled trial. Cancer 100:2613, 2004 9. Berenson JR, Lichtenstein A, Porter L, et al: Efficacy of pami- Discontinuation of oral bisphosphonate therapy in dronate in reducing skeletal events in patients with advancedmultiple myeloma. Myeloma Aredia Study Group. N Engl J Med patients with BRONJ has been associated with gradual improvement in clinical disease. Based on the expe- 10. Berenson JR, Lichtenstein A, Porter L, et al: Long-term pami- rience of 2 Task Force members managing 50 BRONJ dronate treatment of advanced multiple myeloma patients re-duces skeletal events. Myeloma Aredia Study Group. J Clin patients who were treated with oral bisphosphonates, discontinuation of oral bisphosphonates for 6 to 12 11. Rosen LS, Gordon D, Kaminski M, et al: Zoledronic acid versus months may result in either spontaneous sequestra- pamidronate in the treatment of skeletal metastases in patientswith breast cancer or osteolytic lesions of multiple myeloma: A tion or resolution after debridement surgery. If sys- phase III double-blind, comparative trial. Cancer J 7:377, 2002 temic conditions permit, modification or cessation of 12. Berenson JR, Hillner BE, Kyle RA, et al: American Society of oral bisphosphonate therapy should be done in con- Clinical Oncology clinical practice guidelines: The role ofbisphosphonates in multiple myeloma. J Clin Oncol 20:3719, sultation with the treating physician and the patient.
13. Physicians’ Desk Reference (ed 57). Montvale, NJ, Medical Future Research
14. Delmas PD, Meunier PJ: The management of Paget’s disease of On July 31, 2006, the National Institutes of Health 15. Letocha AD, Cintas HL, Troendle JF, et al: Controlled trial of announced funding opportunities for research on the pamidronate in children with types III and IV osteogenesisimperfecta confirms vertebral gains but not short-term func- pathophysiology of bisphosphonate-associated osteo- tional improvement. J Bone Miner Res 20:977, 2005 necrosis of the At least one grant has been 16. Watts NB: Bisphosphonate treatment of osteoporosis. Clin awarded for a project titled “Bisphosphonates and 17. Delmas PD: The use of bisphosphonates in the treatment of Oral Complications of Cancer Chemotherapy: A Pilot osteoporosis. Curr Opin Rheumatol 17:462, 2005 Study,” with Dr Regina Landesberg as the principal 18. Haderslev KV, Tjellesen L, Sorensen HA, et al: Alendronate increases lumbar spine bone mineral density in patients withCrohn’s disease. Gastroenterology 119:639, 2000 so that the present staging system can evolve into a 19. Zein CO, Jorgensen RA, Clarke B, et al: Alendronate improves more comprehensive staging system, which would bone mineral density in primary biliary cirrhosis: A randomized enable clinicians to make accurate judgments about placebo-controlled trial. Hepatology 42:762, 2005 20. Bone HG, Hosking D, Devogelaer JP, et al: Ten years’ experi- risk, prognosis, treatment selection, and outcome for ence with alendronate for osteoporosis in postmenopausal 21. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) in- duced avascular necrosis of the jaws: A growing epidemic.
22. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al: Osteonecrosis of 1. Nussbaum SR, Younger J, Vandepol CJ, et al: Single-dose intra- the jaws associated with the use of bisphosphonates: A review venous therapy with pamidronate for the treatment of hyper- of 63 cases. J Oral Maxillofac Surg 62:527, 2004 calcemia of malignancy: Comparison of 30-, 60-, and 90-mg 23. Estilo CL, Van Posnak CH, Williams T, et al: Osteonecrosis of the maxilla and mandible in patients treated with bisphospho- 2. Major P, Lortholary A, Hon J, et al: Zoledronic acid is superior nates: A retrospective study. J Clin Oncol Proc Am Soc Clin to pamidronate in the treatment of hypercalcemia of malig- nancy: A pooled analysis of two randomized, controlled, clini- 24. Marx RE, Sawatari Y, Fortin M, et al: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: Risk Italian experience. Blood (American Society of Hematology 25. Migliorati CA, Schubert MM, Peterson DE, et al: Bisphospho- 41. Zavras AI, Zhu S: Bisphosphonates are associated with in- nate-associated osteonecrosis of mandibular and maxillary creased risk for jaw surgery in medical claims data: Is it osteo- bone: An emerging oral complication of supportive cancer necrosis? J Oral Maxillofac Surg 64:917, 2006 42. Hoff AO, Toth BB, Altundag K, et al: Osteonecrosis of the jaw 26. Purcell PM, Boyd IW: Bisphosphonates and osteonecrosis of in patients receiving intravenous bisphosphonate therapy.
J Clin Oncol 2006 ASCO Annual Meeting Proceedings (post 27. Bagan JV, Jimenez Y, Murillo J, et al: Jaw osteonecrosis associ- ated with bisphosphonates: Multiple exposed areas and its relationship to teeth extractions. Study of 20 cases. Oral Oncol 28. Pires FR, Miranda A, Cardoso ES, et al: Oral avascular bone 44. Report of the Council of Scientific Affairs. Expert panel necrosis associated with chemotherapy and bisphosphonate recommendations: Dental management of patients on oral bisphosphonate therapy. American Dental Association. 29. Woo SB, Hellstein JW, Kalmar JR: Systematic review: Bisphospho- nates and osteonecrosis of the jaws. Ann Intern Med 144:753, 2006 30. Woo SB, Hande K, Richardson PG: Osteonecrosis of the jaws 45. Badros A, Weikel D, Salama A, et al: Osteonecrosis of the jaw in and bisphosphonates. N Engl J Med 353:100, 2005 multiple myeloma patients: Clinical features and risk factors.
31. Hohnecker JA: Novartis “Dear Doctor” precautions added to label of Aredia and Zometa. September 24, 2004 46. Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related os- 32. US Food and Drug Administration Oncologic Drugs Advisory Com- teonecrosis of the jaw: Background and guidelines for diagno- mittee: Combidex briefing information. Available at: sis, staging and management. Oral Surg Oral Med Oral Path 47. Ruggiero SL, Gralow J, Marx RE, et al: Practical guidelines for the 33. U.S. Food and Drug Administration Office of Drug Safety: Post- prevention, diagnosis and treatment of osteonecrosis of the jaw in patients with cancer. J Clin Oncol Prac 2:7, 2006 48. Migliorati CA, Casiglia J, Epstein J, et al: Managing the care of patients with bisphosphonate-associated osteonecrosis. J Am 34. Durie BGM, Katz M, Crowley J: Osteonecrosis of the jaws and bisphosphonates. N Engl J Med 353:99, 2005 49. American Association of Endodontists: Position Statement: End- 35. Bamias A, Kastritis E, Bamia C, et al: Osteonecrosis of the jaw odontic implications of bisphosphonate-associated osteonecro- in cancer after treatment with bisphosphonates: Incidence and 36. Dimopoulos MA, Kastritis E, Anagnostopoulos A, et al: Osteo- 50. Novartis Media Release. New data demonstrate benefits of once- necrosis of the jaw in patients with multiple myeloma treated yearly Aclasta in the treatment of postmenopausal osteoporosis.
with bisphosphonates: Evidence of increased risk after treat- ment with zoledronic acid. Haematologica 91, 2006 [Epub 37. Dimopoulos M, Kastritis E, Moulopoulos LA, et al: The inci- 51. Kademani D, Koka S, Lacy MQ, et al: Primary surgical therapy dence of osteonecrosis of the jaw in patients with multiple for osteonecrosis of the jaw secondary to bisphosphonate myeloma who receive bisphosphonates depends on the type of bisphosphonate. Blood (American Society of Hematology An- 52. Chhoeu AH, Siegel D. Landesberg R, et al: A case series of hyperbaric oxygen treatment for non-radiation induced osteo- 38. Tosi P, Zamagni E, Cangini D, et al: Bisphosphonates and necrosis of the jaw. J Oral Maxillofac Surg 64:80, 2006 (suppl) osteonecrosis of the jaws: Incidence in a homogeneous series 53. National Institutes of Health Program Announcement. Avail- of patients with newly diagnosed multiple myeloma treated with zoledronic acid. Blood (American Society of Hematology 54. National Institutes of Health Computer Retrieval of Information 39. Pozzi S, Marcheselli R, Sacchi S, et al: Analysis of frequency and risk factors for developing bisphosphonate associated necrosis of the jaw. Blood (American Society of Hematology Annual 40. Cafro AM, Barbarano LA, Andriani A, et al: Osteonecrosis of the jaw associated with chroninc bisphosphonates therapy: An Appendix. BISPHOSPHONATE PREPARATIONS CURRENTLY AVAILABLE IN THE UNITED STATES*
*A once-yearly infusion of zoledronic acid for the treatment of postmenopausal osteoporosis is under FDA †Relative to etidronate.


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