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Bisphosphonates and jaw osteonecrosis: The UAMS experience

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Bisphosphonates and jaw osteonecrosis: The UAMS experience
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  ORIGINAL RESEARCH Bisphosphonates and jaw osteonecrosis:The UAMS experience Brett M. Clarke, MD, Jennings Boyette, BA, Emre Vural, MD,James Y. Suen, MD, Elias J. Anaissie, MD,  and  Brendan C. Stack, Jr, MD, Little Rock, AR BACKGROUND:  Over the past year at least 10 case series andseveral case reports on osteonecrosis of the jaw (ONJ) have beenpublished with most found in the oral surgery literature. Thisclinical entity is largely unknown to head and neck surgeons. METHODS:  Retrospective chart review. RESULTS:  A total of 479 charts were reviewed, identifying 25individuals meeting inclusion criteria. Mean age was 63.4 (stan-dard deviation, 9.9) years; 40% were female. Multiple myelomawas the most common comorbidity. Twenty-five patients weretreated with bisphosphonates for 4.4 years (range, 1 to 8 years);most commonly pamidronate before ONJ diagnosis. Forty-twopercent (10) took steroids within the month before diagnosis.Fifty-two percent (11) underwent dental work before developingONJ. CONCLUSION:  These data reflect the importance of awarenessof the possibility of ONJ with bisphosphonate therapy.© 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved. O ver the past few years, at least 368 cases of bisphos-phonate-related osteonecrosis of the mandible andmaxilla have been reported. 1  Bisphosphonates function asbone resorption inhibitors and have been used to treat pa-tients with hypercalcemia and bone loss as in the case of osteoporosis and multiple myeloma and other cancers. 2 Bisphosphonates are also known to have antitumor andantiangiogenic properties. 3  In some patients with long-termbisphosphonate use, osteonecrosis of the jaws (ONJ) oc-curs; oral surgery patients on bisphosphonates are at partic-ularly high risk. 2,4  The mechanism of action for this processis unclear. In the past several months, the otolaryngology–head and neck surgery clinics at UAMS have seen severalsuch patients. UAMS is in an unusual position to evaluatethe occurrence and treatment of this process because it isone of the busiest multiple myeloma treatment centers in thecountry. Bisphosphonate use in the patient population ishighly prevalent. The focus of this study is to retrospec-tively evaluate and discuss our experience with this rela-tively newly recognized disease process. METHODS According to UAMS institutional review policy, IRB ex-emption was obtained. We then performed a retrospectivechart review of all of the individuals who had been referredthe Department of Otolaryngology–Head and Neck Surgeryat the University of Arkansas for Medical Sciences for jaw-related disease since 1998. In addition, we reviewed alarge database of individuals who had received intravenous(IV) bisphosphonate therapy since 2000 as well as list of patients tracked by the UAMS Myeloma Institute for Re-search and Therapy.ONJ was defined as spontaneously exposed bone or non-healing, enlarging dental extraction wounds that may or maynot involve infection, fistulization, and/or fracture. This defi-nition is consistent with that found in the literature. 1  All pa-tients who received bisphosphonate therapy (at least one dose)within 1 year before they developed ONJ were included. Pa- From the Department of Otolaryngology–Head and Neck Surgery (DrsClarke, Vural, Suen, and Stack and Mr Boyette), and the Myeloma Institutefor Research and Therapy (Dr Anaissie), University of Arkansas for Med-ical Sciences (Dr Stack).Reprint requests: Brendan C. Stack, Jr, MD, Department of Otolaryn-gology–Head and Neck Surgery, UAMS, 4301 W. Markham St, No 543,Little Rock, AR 72205.E-mail address: bstack@uams.edu. Otolaryngology–Head and Neck Surgery (2007) 136, 396-400 0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.doi:10.1016/j.otohns.2006.11.008  tients were excluded if they had had radiation to the jaw(s)before ONJ developed. Steroid use was defined as havingtakensteroidswithin1monthofONJdiagnosis.Relateddentalwork was defined as dental work plausibly associated withONJ diagnosis (weeks to months). Medical treatment wasdefined as any nonsurgical treatment (primarily IV and oralantibiotics). Treatment success was defined as a documented res-olution of complaints such as drainage, pain, or exposed bone. RESULTS A total of 479 charts were reviewed from between 1998 and2005 (Fig 1); 102 patients were referred to the Department of Otolaryngology for jaw-related complaints or diseases inthis time period. In addition, charts from the pharmacydatabase were reviewed of 365 patients who receivedbisphosphonates. Also, 12 charts were provided from a listof patients tracked by the UAMS Myeloma Institute forResearch and Therapy. Twenty-five patients were found tohave been diagnosed with osteonecrosis of the mandible ormaxilla without having had radiation (Table 1). Three ad- ditional patients (not included) had chronic facial pain of unknown cause while taking bisphosphonates. All 25 pa-tients received bisphosphonates within 1 year of the diag-nosis of ONJ. Eighty percent (20) patients were multiplemyeloma patients. A frequent protocol for maintaining re-mission of myeloma at our institution involves the use of thalidomide and/or dexamethasone. Most myeloma patientswere maintained on thalidomide. Mean age was 63.4 (stan-dard deviation [SD], 9.9) years; 40% were female. All 25patients were treated with bisphosphonates for an average4.4 years (range, 1 to 8 yrs; SD, 2.6). Pamidronate (Aredia,Novartis International AG, Basel, Switzerland) use ex-ceeded other bisphosphonates (40%), however, both pam-idronate and zoledronate (Zometa, Novartis) were used overthe years in eight (32%) of patients. Ten (42%) patients took steroids within the month before ONJ diagnosis. Eleven(52%) patients underwent dental work before developingONJ. Only four patients (24%) smoked tobacco at the timeof ONJ diagnosis.A spectrum of treatment was provided that ranged fromlimited medical therapy to surgical segmental mandibulec-tomy with fibular free flap or plate reconstruction. Treat-ment was offered to all but one patient. One patient withterminal breast cancer had no further records after diagnosisand therefore was thought to have received no treatment.Twelve (50%) patients received medical treatment that in allcases consisted of antibiotics and in three cases hyperbaricoxygen. Surgical treatment in addition to medical therapywas provided in 10 (45%) cases. Usually after attemptingantibiotic regimens and oral rinses for several months orhyperbaric oxygen, simple surgical procedures such as cu-rettage and closure were performed for smaller cases. Inmore advanced cases with draining fistulas or pathologicfractures, aggressive, more complicated surgeries like seg-mental mandibulectomy with or without reconstruction wereperformed. Culture results showed a mixture of organismsincluding  Actinomycoses, Streptococcus, Candida, Entero-coccus,  and  Staphylococcus . Evaluation of treatment suc-cess was limited by the transient nature of patients whofrequent a large tertiary care center. Nine of 14 patientswere cured of their ONJ in short-term follow-up of 12months or less. Four were cured with medical therapy alonewhereas another four required additional surgical treatmentfor cure (Table 1). Twenty-five percent of patients under-went hyperbaric oxygen treatment with no noted benefit.Forty-four percent (11) of cases in this study had no decidedoutcome or treatment endpoint. DISCUSSION Postmarketing analysis by Novartis (producer of Arediaand Zometa) linked a new clinical entity, ONJ, to intra-venous bisphosphonate use. The FDA has produced sev-eral warnings in conjunction with labeling changes byNovartis for health care providers to alert them to the risk of ONJ with the use of pamidronate (Aredia) and zole-dronate (Zometa). 5  Other case reports suggest that ONJcan also occur with the oral bisphosphonates such as alendronate (Fosamax, Merck). 6  Woo et al 1  performed aliterature review that identified multiple reports of bisphosphonate-related ONJ. Survey results of bisphos-phonate recipients by Durie et al 7  indicated that 10% of patients who received zoledronate and 4% of patientswho received pamidronate developed ONJ by 36 monthsof therapy.Bisphosphonates are synthetic analogs of naturallyoccurring pyrophosphate. They tend to concentrate inlocations of active bone remodeling and, through modu-lation of osteoblast-osteoclast signaling, decrease oste-oclast bone resorption. 8  Bisphosphonates appear to beincorporated into the bony matrix where they have a highaffinity for hydroxyapatite crystals. Because of this as-sociation, they degrade slowly, some having a half-life upto 12 years. Further research has suggested that bisphos-phonates have antitumor properties including antiangio-genesis. 8,9 Both intravenous (IV) and oral bisphosphonate forms areavailable. IV forms are FDA-approved for treatment of  Figure 1  Description of patients reviewed for this study. 397Clarke et al Bisphosphonates and jaw osteonecrosis . . .  hypercalcemia associated with multiple myeloma and solidtumors that metastasize to bone such as breast and prostatecancer. Oral forms have been successfully used to treatosteoporosis-related bone resorption. In the past few years,however, this new clinical entity of ONJ has appeared. Thesepatients often present with pain, draining fistulas, pathologicfracture of mandible, or simply exposed bone. 1-4,6,10-16 There is no good data to date to identify the pathophys-iology of this disease process. Hellstein and Marek  3  com-pared this disease process to one that was recognized in theearly 20th century in match makers and other people ex-posed to white phosphorus. According to Hellstein andMarek, 3  white phosphorus had a propensity to accumulatein the jaws. After an extended period of exposure, patientswould develop intraoral bony necrosis. In a bisphosphonate“primed” oral cavity, local trauma from dental work or, inspontaneous cases, alimentaria to osteophytic prominencesmay promote initial bony exposure. 1,12,13 Though no exact mechanism has been elucidated yet,ONJ seems to correlate with bisphosphonate therapy. Co-morbid systemic disease states, most commonly multiplemyeloma, breast, and prostate cancers, play no conclusiverole. 1  In our study, multiple myeloma predominated as aprimary reason for bisphosphonate use. Just over half of patients in our study underwent dental procedures beforedeveloping ONJ. This is in line with percentages reported in Table 1Demographic and data of 25 patients found to have osteonecrosis (ONJ) with no radiation history to the maxillaor mandible Age SexReason forBisphos UseBisphosDuration(yrs) Bisphos Used SteroidDentalWorkConcurrentTobaccoUse ONJ SiteTreatmentModTreatmentSuccess65 F Met lymphoma 7 Pamidronate No Yes No Mandible Medical No data72 F Mult myeloma 7 Pamidronate No Yes Yes Mandible Medical No data69 M Mult myeloma 3 Zoledronate Yes No No Maxilla Medical No80 F Mult myeloma 8 Pamidronate/ zoledronateYes No No Mandible Both No75 F Osteoporosis 1 Alendronate No Yes Yes Mandible Both No62 M Mult myeloma 1 Pamidronate Yes No No Mandible Medical No data80 M Prostate ca No data Pamidronate No No No data Mandible Both Yes54 M Mult myeloma No data Pamidronate Yes No No Mandible Medical No data54 M Mult myeloma 7 Pamidronate Yes Yes No Maxilla Both Yes50 F Mult myeloma 6 Pamidronate/ zoledronateNo Yes No Mandible Both Yes41 F Met breast ca 1 Pamidronate No No No Maxilla None No data68 M Mult myeloma 6 Pamidronate Yes Yes Yes Mandible Medical Yes77 F Breast ca/ osteoporosisNo data Alendronate No Yes No Mandible Both Yes63 M Mult myeloma 2 Zoledronate No Yes No data Mandible Medical Yes69 M Mult myeloma 7 Pamidronate/ zoledronateNo Yes Yes Mandible Both No data61 M Mult myeloma 1 Zoledronate No No Data No data Mandible Both No74 M Mult myeloma 2 Zoledronate No Data No Data No Mandible No data No67 M Mult myeloma 1 Zoledronate No No Data No Mandible No data Yes52 F Mult myeloma 3 Pamidronate/ zoledronateYes No Data No data Maxilla Both No data61 F Mult myeloma 6 Pamidronate/ zoledronateYes No No data Maxilla Medical Yes59 M Mult myeloma 5 Pamidronate/ zoledronateYes Yes No Mandible Medical No data59 M Mult myeloma 8 Pamidronate/ zoledronateYes No No Mandible Medical Yes53 M Mult myeloma 4 Pamidronate/ zoledronateNo No No data Maxilla Medical No data55 M Mult myeloma 3 Pamidronate No No No data Mandible Both No data64 F Mult myeloma 7 Pamidronate No Yes No data Mandible Medical No data Reason used, primary diagnosis for which bisphosphates were started. Bisphos, bisphosphonate used within 1 year of ONJdiagnosis. Steroid, steroid use within 1 month of ONJ diagnosis. Dental work, dental work plausibly associated with ONJ diagnosis(weeks to months). Concurrent tobacco use, at time of ONJ diagnosis. ONJ site, which jaw. Treatment modality, medical, surgical,or both. Treatment success: yes, cure; no, persistent problems despite treatment; no data, ongoing treatment with endpoint notreached or patient lost to follow-up. 398 Otolaryngology–Head and Neck Surgery, Vol 136, No 3, March 2007  the literature of 33% to 86%. 1  The type of bisphosphonateand length of exposure to bisphosphonates increases the risk of ONJ. 11  In our study, pamidronate use was predominant.In 8 cases, bisphosphonate treatment was initiated with oneIV form, then switched to another several years later.Zoledronate was used singly in five cases; alendronate wasused in two cases. Ninety-four percent of cases previouslyreported received pamidronate or zoledronate. Nonaminobisphosphonates (clodronate, etidronate, and tiludronate)may not be associated with ONJ. 1  Exposure time as short as4 months with a median time of 1.8 to 3.3 years has beenreported. 1 Our study found a mean of 4.4 years (median, 4.5yrs) with a range of 1 to 8 years exposure before ONJdevelopment. Bamias et al 11  reported that patients whoreceived fewer than 12 IV infusions did not developONJ. Oral alendronate use for 1 year by one patient in ourstudy was associated with ONJ. In contrast, Jeffcoat, 17  in aprospective randomized double-blinded, placebo-controlledstudy of 335 patients, found no increased risk of ONJ withoral alendronate use with a 3-year follow-up. Apart frombisphosphonate therapy, steroid use and chemotherapy havebeen associated with ONJ previously. 18-21  In our study,42% of patients received corticosteroids within 1 month of developing ONJ.Treatment regimens in the literature have a mixed ap-proach with treatment recommendations commonly alignedwith the treating physician’s expertise, ie, surgeons performsurgery, nonsurgeons provide various medical regimens. Inour study, medical treatments were most common. Often(45%) a surgical therapy was added. The initial expert panelrecommendations 22  suggested the use of antibiotics for in-fected wounds, but recommended against the use of surgerybecause it would further traumatize the bone and worsen thecondition. Ruggiero et al 4  suggested that surgery shouldonly be offered to patients who were symptomatic fromtheir osteonecrosis. Migliorati et al 13 demonstrated worsen-ing conditions in surgical patients with more aggressivesurgery. For small involved areas, conservative manage-ment of irrigations and antibiotic therapy have been mosteffective. 1,4,11,13  More conservative regimens have been ef-fective at decreasing pain that may be associated with ONJ. 1 Almost universally, hyperbaric oxygen treatments havedemonstrated little benefit and are not recommended. 1,4,22 Given the potential half-life of bisphosphonates, cessationof bisphosphonate use may offer little benefit to treatment. 23 Our study adds a new series of multiple myeloma patientstreated with bisphosphonates that developed OJN and weremanaged by an otolaryngology–head and neck surgery ser-vice. The strength of this study is that it is a large singleinstitution report from a center that has one of the largestmultiple myeloma patient volumes where experience withbisphosphonates is extensive. The limit of this study isprimarily its retrospective design. Additionally, confound-ing variables include thalidomide and corticosteroid use,both factors which could aggrevate jaw bone infectionand/or death. This study should serve as an alert for otolar-yngologists that this population of bisphosphonate-treatedpatients exists and they might present with OJN. Futureresearch should focus on elucidation of the mechanism bywhich OJN develops. CONCLUSION Bisphosphonate-related osteonecrosis of the jaw is a rela-tively new clinical entity. The pathophysiology remainsunelucidated but may be related to poor bone and bloodvessel remodeling coinciding with local trauma to the max-illa or mandible. The greatest risk is associated with dura-tion of IV bisphosphonate use, though long-term oral alen-dronate has also been implicated. No one singularlyeffective treatment exists, though results of this study sug-gest that combined medical and simple surgical treatmentmay offer the best chance for cure. Physicians and dentalcare providers alike, including otolaryngologists, need to beaware of this disease process to alert patients to the risksassociated with these medications. REFERENCES 1. Woo S-B, Hellstein J, Kalmar J. Systematic review: bisphosphonatesand osteonecrosis of the jaws. Ann Intern Med 2006;144:753–61.2. Marx R. Pamidronate (Aredia) and zoledronate (Zometa) inducedavascular necrosis of the jaws: a growing epidemic. J Oral MaxillofacSurg 2003;61:1115–7.3. Hellstein J, Marek C. Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg2005;63:682–9.4. Ruggiero S, Mehrotra B, Rosenberg T, et al. Osteonecrosis of the jawsassociated with the use of bisphosphonates: a review of 63 cases.J Oral Maxillofac Surg 2004;62:527–34.5. Package insert revisions re: Osteonecrosis of the jaw: Zometa(zoledronic acid) injection and Aredia (pamidronate disodium) injec-tion. Oncologic Drugs Advisory Committee Meeting 2005.6. Kushner G, Alpert E. Bisphosphonate induced osteonecrosis of the jaw. AO Dialogue 2005;18:27–9.7. Durie B, Katz M, Crowley J, et al. Osteonecrosis of the jaw andbisphosphonates. N Engl J Med 2005;353:99–102.8. Rogers M, Gordon S, Benford HL, et al. Cellular and molecularmechanisms of action of bisphosphonates. Cancer 2000;88:2961–78.9. Wood J, Bonjean K, Ruetz S, et al. Novel antiangiogenic effects of thebisphosphonate compound zoledronic acid. J Pharmacol Exp Ther2002;302:1055–61.10. MignognaM,LoRussoL,FedeleS,etal.CASE2.Osteonecrosisofthejawsassociated with bisphosphonate therapy. J Clin Oncol 2006;24:1475–7.11. Bamias A, Kastritis E, Bamia C, et al. Osteonecrosis of the jaw incancer after treatment with bisphosphonates: incidence and risk fac-tors. J Clin Oncol 2005;23:8580–7.12. Carneiro E, Vibhute P, Montazem A, et al. Bisphosphonate-associatedmandibular osteonecrosis. AJNR Am J Neuroradiol 2006;27:1096–7.13. Migliorati C, Schubert M, Peterson D, et al. Bisphosphonate-associ-ated osteonecrosis of mandibular and maxillary bone. Cancer 2005;104:83–93.14. Migliorati C. Bisphosphonates and oral cavity avascular bone necrosis.J Clin Oncol 2003;21:4253–4. 399Clarke et al Bisphosphonates and jaw osteonecrosis . . .  15. Farrugia MC, Summerlin DJ, Krowiak E, et al. Osteonecrosis of themandible or maxilla associated with the use of new generationbisphosphonates. Laryngoscope 2006;116(1):115–20.16. Capalbo S, Delia M, Diomede D, et al. Jaw osteonecrosis associatedwith use of bisphosphonates and chemotherapy: paradoxical compli-cation of treatment of bone lesions in multiple myeloma patients. IntJ Hematol 2006;83:439–42.17. Jeffcoat M. Safety of oral bisphosphonates: controlled studies onalveolar bone. Int J Oral Maxillofac Implants 2006;21:349–53.18. Mattano L Jr, Sather H, Trigg M, et al. Osteonecrosis as a complicationof treating acute lymphoblastic leukemia in children: a report from theChildren’s Cancer Group. J Clin Oncol 2000;18:3262–72.19. Assouline-Dayan Y, Chang C, Greenspan A, et al. Pathogenesis andnatural history of osteonecrosis. Semin Arthritis Rheum 2002;32:94–124.20. Sung E, Chan S, Sakurai K, et al. Osteonecrosis of the maxilla as acomplication to chemotherapy: a case report. Spec Care Dentist 2002;22:142–6.21. Schwartz H. Osteonecrosis of the jaws: a complication of cancerchemotherapy. Head Neck Surg 1982;4:251–3.22. Damato K, Gralow J, Hoff A, et al. Expert panel recommendation forthe prevention, diagnosis and treatment of osteonecrosis of the jaw,2005. www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_02_12-Novartis-Zometa-App-11.pdf 23. Lacy M, Dispenzieri A, Gertz M, et al. Mayo clinic consensus state-ment for the use of bisphosphonates in multiple myeloma. Mayo ClinProc 2006;81:1047–53. Did you know? The 2007 Guidelines for Authors are available online at http://journal.entnet.orgThey also appear in print in the January and July issues of this journal. 400 Otolaryngology–Head and Neck Surgery, Vol 136, No 3, March 2007
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