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ETIOLOGY/OTHER ARTICLE ANALYSIS & EVALUATIONARTICLE TITLE AND Risks for Jaw Osteonecrosis DrasticallyBIBLIOGRAPHICINFORMATION Increases After 2 Years of BisphosphonateRisk factors for osteonecrosis of the Therapyjaws: a case-control study from theCONDOR dental PBRN. SUMMARYBarasch A, Cunha-Cruz J, Curro FA,Hujoel P, Sung AH, Vena D, Voinea-Griffin SubjectsAE; CONDOR Collaborative Group, This study consisted of 191 patients older than 40 years with osteonecrosisBeadnell S, et al. of the jaw (ONJ) drawn from dental practices in the geographic locationsJ Dent Res 2011;90(4):439-44. of 3 practice-based research networks (PBRNs). Control patients (n = 573) enrolled were individuals older than 40 years without prior history of ONJ. Three control patients were matched with each ONJ case. The ONJ casesREVIEWERS originated from primary, secondary, and tertiary care centers. For eachSunday O. Akintoye, BDS, DDS, MS, ONJ case diagnosed at a primary care center, the 3 matched controlsElliot V. Hersh, DMD, MS, PhD were selected from the same primary care center. However, controls for cases obtained from secondary or tertiary care centers were selected when possible from the general dental practice that referred the case orPURPOSE/QUESTION from another practice in the same geographic area.To determine risks associated withbisphosphonate therapy and identify Key Risk/Study Factorother risk factors for osteonecrosis The key risk factor in this study was bisphosphonate therapy.of the jaw (ONJ) Main Outcome MeasureSOURCE OF FUNDING The main outcome measure was ONJ. The definition of ONJ was maxillary or mandibular exposed bone of any size that clinically appeared necrotic,National Institute of Dental and without regard for duration or cause. Therefore, all types of jaw osteone-Craniofacial Research grants crotic lesions were included in this study; but patients were limited to thoseU01DE016747, U01DE016755, diagnosed with onset of ONJ after January 1, 2003, without prior history ofU01DE016750, U01DE016746, facial trauma or sickle cell disease.U01DE016754, and U01DE016752 Main ResultsTYPE OF STUDY/DESIGN The results indicate that 83% of cases and 15% of controls received bisphosphonate therapy for a mean duration (standard error) of 5.6 (0.7)Multicenter case-control study and 4.2 (0.6) years, respectively. Therapy with either intravenous or oral bisphosphonates was highly predictive of ONJ; however, intravenous bisphosphonates (odds ratio [OR] = 299.5; 95% confidence interval [CI] =LEVEL OF EVIDENCE 70.0-1282.7) were more associated with ONJ than oral bisphosphonatesLevel 2: Limited-quality, patient- (OR = 9.8; 95% CI = 5.3-18.1). Risk of developing ONJ existed within theoriented evidence first 2 years and increased fourfold after 2 years of bisphosphonate use (P < .0001).STRENGTH OF ConclusionsRECOMMENDATION GRADE The authors concluded that ONJ is causally linked to both intravenous andNot applicable oral bisphosphonate use, and risk of ONJ escalates tremendously after 2 years of bisphosphonate therapy. The authors also concluded that oral suppuration and dental extractions are independent ONJ risk factors.J Evid Base Dent Pract 2012;12:116-118 COMMENTARY AND ANALYSIS1532-3382/$36.00Ó 2012 Elsevier Inc. All rights reserved. ONJ has captured the attention of the health care community in the past 8doi:10.1016/j.jebdp.2012.03.003 years since several case series of bisphosphonate-related ONJ (BRONJ)

JOURNAL OF EVIDENCE-BASED DENTAL PRACTICEwere published.1-4 However, the susceptibility of the jaw to escalated after 2 years, so it is equally unclear if thesenecrosis is not new. Jaw necrosis in response to irradiation, were outcomes of bisphosphonate therapy, delayed ef-referred to as osteoradionecrosis (ORN), became a major fects of radiotherapy, or a combination of both.complication of cancer radiotherapy in the mid 1950s,5,6 The pathophysiology of BRONJ is still unclear, so studiesmany years after radiation-induced bone necrosis was ini- that provide details on associated risk factors can providetially reported in 1926.7,8 Other forms of necrosis caused a road map for understanding the pathophysiologic mech-by infection (osteomyelitis), corticosteroid therapy, and anisms of BRONJ.15 Bisphosphonates act by suppressingalcohol abuse have also been previously described.9,10 osteoclast activity, so recent reports that BRONJ is equallyTherefore, BRONJ is a type of drug-induced osteonecrosis associated with denosumab, another inhibitor of osteo-specific to the jaw, unlike other types of osteonecrosis that clasts, point to the hypothesis that BRONJ pathophysiologyaffect both oral and nonoral skeletal sites. may be attributable to dysfunctional bone remodeling.16,17 The incidence of BRONJ ranges from 0.04% to 18.00% As bisphosphonates also have antiangiogenic properties, itdepending on the type of bisphosphonate, the underlying is fitting that antiangiogenic drugs, such as bevacizumabsystemic diseases, and presence of other risk factors.11-13 and sunitinib, are also associated with ONJ.18-20 If drug-As bisphosphonates are highly efficacious in the control induced ONJ continues to be a recalcitrant complicationof skeletal events of cancer metastasis and osteoporosis, of therapy, delineating the risk factors is vital because itit is essential to gain insights into the pathophysiology of will enhance development of evidence-based preventiveBRONJ and identify associated risk factors rather than guidelines aimed at reducing ONJ cases.limit or abandon their use. Reports on different types of In summary, the authors presented data that suggestONJ indicate the existence of several risk factors that BRONJ can develop at any time during bisphosphonatepromote jaw susceptibility to necrosis. therapy, and that risks for BRONJ escalate significantly The authors should be commended for their work on after 2 years.risk factors related to ONJ, because skeletal site specificityof BRONJ suggests that risk factors peculiar to the jawmight precipitate BRONJ. The authors assessed risk fac- REFERENCEStors associated with BRONJ in patients on oral and intrave- 1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) inducednous bisphosphonates. They identified oral suppuration, avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofacdental extractions, and bisphosphonate treatment for Surg 2003;61(9):1115-7.more than 2 years as major risk factors. Other than ane- 2. Migliorati CA. Bisphosphanates and oral cavity avascular bone necro-mia, the authors also reported that the systemic diseases sis. J Clin Oncol 2003;21(22):4253-4.associated with BRONJ were the common indications for 3. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surgbisphosphonate use. The working definition for BRONJ 2003;61(9):1104-7.in this study, however, was expanded to include all types 4. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosisof clinical necrosis in the maxilla and mandible without of the jaws associated with the use of bisphosphonates: a review of 63regard for duration or etiological agent. Hence, clinical cases. J Oral Maxillofac Surg 2004;62(5):527-34.conditions such as ORN and osteomyelitis were included 5. Kaplan H. Osteoradionecrosis and the dentist. US Armed Forcesin the case definition. This is clearly different from the Med J 1955;6(10):1452-8. 6. McLennan W. Some aspects of the problems of radionecrosis of thepreviously proposed working definition of BRONJ that jaws. Proc R Soc Med 1955;48:1017-21.includes the fact that the necrotic lesion must be present 7. Ewing J. Radiation osteitis. Acta Radiol 1926;6:339-412.for at least 8 weeks, and patients must not have undergone 8. Phemister DB. Radium necrosis of bone. Am J Roentgenolhead and neck radiotherapy.12,14 1926;16:340-8. The authors also reported that specific information on 9. Chiu CT, Chiang WF, Chuang CY, Chang SW. Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw—a serialdental diseases and procedures pertaining to the cases case analysis. J Oral Maxillofac Surg 2010;68(5):1055-63.were presented elsewhere. Therefore, the influence of 10. Fusco V, Galassi C, Berruti A, Ciuffreda L, Ortega C, Ciccone G, et al.a patient’s dental status on the outcome measures is un- Osteonecrosis of the jaw after zoledronic acid and denosumab treat-clear. This also heightens the possibility that osteomyelitis ment. J Clin Oncol 2011;29(17):e521-2. author reply e3-4.may have been included in the cases assessed. To appro- 11. Aragon-Ching JB, Ning YM, Chen CC, Latham L, Guadagnini JP, Gulley JL, et al. Higher incidence of osteonecrosis of the jaw (ONJ)priately define BRONJ risk factors, it is vital to exclude in patients with metastatic castration resistant prostate cancer treatedONJ caused by radiation (ORN) as well as infection (oste- with anti-angiogenic agents. Cancer Invest 2009;27(2):221-6.omyelitis); however, this may be impractical in patients 12. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE,who have received both radiotherapy and bisphospho- Mehrotra B. American Association of Oral and Maxillofacialnates. As ORN may not develop for many years after Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg 2009;67(5head and neck radiotherapy, it is possible that patients Suppl):2-12.who received radiotherapy may have developed ONJ 13. Van Poznak C, Estilo C. Osteonecrosis of the jaw in cancer patientscaused by synergistic effects of radiation and bisphospho- receiving IV bisphosphonates. Oncology 2006;20(9):1053-62. discus-nate. The authors also reported that cases of ONJ sion 65-6.Volume 12, Number 2 117

JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE14. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, 20. Greuter S, Schmid F, Ruhstaller T, Thuerlimann B. Bevacizumab- et al. Bisphosphonate-associated osteonecrosis of the jaw: report of associated osteonecrosis of the jaw. Ann Oncol 2008;19(12):2091-2. a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22(10):1479-91.15. Sarin J, Derossi SS, Akintoye SO. Updates on bisphosphonates and REVIEWERS potential pathobiology of bisphosphonate-induced jaw osteonecro- Sunday O. Akintoye, BDS, DDS, MS sis. Oral Dis 2008;14(3):277-85.16. Taylor KH, Middlefell LS, Mizen KD. Osteonecrosis of the jaws Assistant Professor of Oral Medicine, University of Pennsylvania induced by anti-RANK ligand therapy. Brit J Oral Maxillofac Surg School of Dental Medicine, Department of Oral Medicine, Robert 2010;48(3):221-3. Schattner Room 211, 240 S. 40th Street, Philadelphia,17. Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in PA 19104, Phone: 215-898-9932, Fax: 215-573-7835 a patient on denosumab. J Oral Maxillofac Surg 2010;68(5):959-63. akintoye@dental.upenn.edu18. Christodoulou C, Pervena A, Klouvas G, Galani E, Falagas ME, Elliot V. Hersh, DMD, MS, PhD Tsakalos G, et al. Combination of bisphosphonates and antiangio- Professor of Pharmacology, University of Pennsylvania School genic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone. Oncology 2009;76(3):209-11. of Dental Medicine, Chair IRB #3 – University of Pennsylvania19. Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G 3rd, Huryn JM. Ofﬁce of Regulatory Affairs, 240 South 40th Street, Philadelphia, Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol PA 19104-6030, Phone: 215-898-9686, Fax: 215-746-8891 2008;26(24):4037-8. evhersh@pobox.upenn.edu118 June 2012

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