ETIOLOGY/OTHER

ARTICLE ANALYSIS & EVALUATION

ARTICLE TITLE ANDBIBLIOGRAPHICINFORMATION

Risk factors for osteonecrosis of thejaws: a case-control study from theCONDOR dental PBRN.

Barasch A, Cunha-Cruz J, Curro FA,Hujoel P, Sung AH, Vena D, Voinea-GriffinAE; CONDOR Collaborative Group,Beadnell S, et al.

J Dent Res 2011;90(4):439-44.

REVIEWERS

Sunday O. Akintoye, BDS, DDS, MS,Elliot V. Hersh, DMD, MS, PhD

PURPOSE/QUESTION

To determine risks associated withbisphosphonate therapy and identifyother risk factors for osteonecrosisof the jaw (ONJ)

SOURCE OF FUNDING

National Institute of Dental andCraniofacial Research grantsU01DE016747, U01DE016755,U01DE016750, U01DE016746,U01DE016754, and U01DE016752

TYPE OF STUDY/DESIGN

Multicenter case-control study

LEVEL OF EVIDENCE

Level 2: Limited-quality, patient-oriented evidence

STRENGTH OFRECOMMENDATION GRADE

Not applicable

J Evid Base Dent Pract 2012;12:116-1181532-3382/$36.00� 2012 Elsevier Inc. All rights reserved.doi:10.1016/j.jebdp.2012.03.003

Risks for Jaw Osteonecrosis DrasticallyIncreases After 2 Years of BisphosphonateTherapy

SUMMARY

SubjectsThis study consisted of 191 patients older than 40 years with osteonecrosisof the jaw (ONJ) drawn from dental practices in the geographic locationsof 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 casesoriginated from primary, secondary, and tertiary care centers. For eachONJ case diagnosed at a primary care center, the 3 matched controlswere selected from the same primary care center. However, controls forcases obtained from secondary or tertiary care centers were selectedwhen possible from the general dental practice that referred the case orfrom another practice in the same geographic area.

Key Risk/Study FactorThe key risk factor in this study was bisphosphonate therapy.

Main Outcome MeasureThe main outcome measure was ONJ. The definition of ONJ was maxillaryor mandibular exposed bone of any size that clinically appeared necrotic,without regard for duration or cause. Therefore, all types of jaw osteone-crotic lesions were included in this study; but patients were limited to thosediagnosed with onset of ONJ after January 1, 2003, without prior history offacial trauma or sickle cell disease.

Main ResultsThe results indicate that 83% of cases and 15% of controls received bi-sphosphonate therapy for a mean duration (standard error) of 5.6 (0.7)and 4.2 (0.6) years, respectively. Therapy with either intravenous or oral bi-sphosphonates was highly predictive of ONJ; however, intravenous bi-sphosphonates (odds ratio [OR] = 299.5; 95% confidence interval [CI] =70.0-1282.7) were more associated with ONJ than oral bisphosphonates(OR = 9.8; 95% CI = 5.3-18.1). Risk of developing ONJ existed within thefirst 2 years and increased fourfold after 2 years of bisphosphonate use(P < .0001).

ConclusionsThe authors concluded that ONJ is causally linked to both intravenous andoral bisphosphonate use, and risk of ONJ escalates tremendously after2 years of bisphosphonate therapy. The authors also concluded that oralsuppuration and dental extractions are independent ONJ risk factors.

COMMENTARYANDANALYSIS

ONJ has captured the attention of the health care community in the past 8years since several case series of bisphosphonate-related ONJ (BRONJ)

JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE

were published.1-4 However, the susceptibility of the jaw tonecrosis is not new. Jaw necrosis in response to irradiation,referred to as osteoradionecrosis (ORN), became a majorcomplication of cancer radiotherapy in the mid 1950s,5,6

many years after radiation-induced bone necrosis was ini-tially reported in 1926.7,8 Other forms of necrosis causedby infection (osteomyelitis), corticosteroid therapy, andalcohol abuse have also been previously described.9,10

Therefore, BRONJ is a type of drug-induced osteonecrosisspecific to the jaw, unlike other types of osteonecrosis thataffect both oral and nonoral skeletal sites.

The incidence of BRONJ ranges from 0.04% to 18.00%depending on the type of bisphosphonate, the underlyingsystemic diseases, and presence of other risk factors.11-13

As bisphosphonates are highly efficacious in the controlof skeletal events of cancer metastasis and osteoporosis,it is essential to gain insights into the pathophysiology ofBRONJ and identify associated risk factors rather thanlimit or abandon their use. Reports on different types ofONJ indicate the existence of several risk factors thatpromote jaw susceptibility to necrosis.

The authors should be commended for their work onrisk factors related to ONJ, because skeletal site specificityof BRONJ suggests that risk factors peculiar to the jawmight precipitate BRONJ. The authors assessed risk fac-tors associated with BRONJ in patients on oral and intrave-nous bisphosphonates. They identified oral suppuration,dental extractions, and bisphosphonate treatment formore than 2 years as major risk factors. Other than ane-mia, the authors also reported that the systemic diseasesassociated with BRONJ were the common indications forbisphosphonate use. The working definition for BRONJin this study, however, was expanded to include all typesof clinical necrosis in the maxilla and mandible withoutregard for duration or etiological agent. Hence, clinicalconditions such as ORN and osteomyelitis were includedin the case definition. This is clearly different from thepreviously proposed working definition of BRONJ thatincludes the fact that the necrotic lesion must be presentfor at least 8 weeks, and patients must not have undergonehead and neck radiotherapy.12,14

The authors also reported that specific information ondental diseases and procedures pertaining to the caseswere presented elsewhere. Therefore, the influence ofa patient’s dental status on the outcome measures is un-clear. This also heightens the possibility that osteomyelitismay have been included in the cases assessed. To appro-priately define BRONJ risk factors, it is vital to excludeONJ caused by radiation (ORN) as well as infection (oste-omyelitis); however, this may be impractical in patientswho have received both radiotherapy and bisphospho-nates. As ORN may not develop for many years afterhead and neck radiotherapy, it is possible that patientswho received radiotherapy may have developed ONJcaused by synergistic effects of radiation and bisphospho-nate. The authors also reported that cases of ONJ

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escalated after 2 years, so it is equally unclear if thesewere outcomes of bisphosphonate therapy, delayed ef-fects of radiotherapy, or a combination of both.

The pathophysiology of BRONJ is still unclear, so studiesthat provide details on associated risk factors can providea road map for understanding the pathophysiologic mech-anisms of BRONJ.15 Bisphosphonates act by suppressingosteoclast activity, so recent reports that BRONJ is equallyassociated with denosumab, another inhibitor of osteo-clasts, point to the hypothesis that BRONJ pathophysiologymay be attributable to dysfunctional bone remodeling.16,17

As bisphosphonates also have antiangiogenic properties, itis fitting that antiangiogenic drugs, such as bevacizumaband sunitinib, are also associated with ONJ.18-20 If drug-induced ONJ continues to be a recalcitrant complicationof therapy, delineating the risk factors is vital because itwill enhance development of evidence-based preventiveguidelines aimed at reducing ONJ cases.

In summary, the authors presented data that suggestBRONJ can develop at any time during bisphosphonatetherapy, and that risks for BRONJ escalate significantlyafter 2 years.

REFERENCES

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2. Migliorati CA. Bisphosphanates and oral cavity avascular bone necro-sis. J Clin Oncol 2003;21(22):4253-4.

3. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associ-ated with cancer chemotherapy. J Oral Maxillofac Surg2003;61(9):1104-7.

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5. Kaplan H. Osteoradionecrosis and the dentist. US Armed ForcesMed J 1955;6(10):1452-8.

6. McLennan W. Some aspects of the problems of radionecrosis of thejaws. Proc R Soc Med 1955;48:1017-21.

7. Ewing J. Radiation osteitis. Acta Radiol 1926;6:339-412.8. Phemister DB. Radium necrosis of bone. Am J Roentgenol

1926;16:340-8.9. Chiu CT, Chiang WF, Chuang CY, Chang SW. Resolution of oral bi-

sphosphonate and steroid-related osteonecrosis of the jaw—a serialcase analysis. J Oral Maxillofac Surg 2010;68(5):1055-63.

10. Fusco V, Galassi C, Berruti A, Ciuffreda L, Ortega C, Ciccone G, et al.Osteonecrosis of the jaw after zoledronic acid and denosumab treat-ment. J Clin Oncol 2011;29(17):e521-2. author reply e3-4.

11. Aragon-Ching JB, Ning YM, Chen CC, Latham L, Guadagnini JP,Gulley JL, et al. Higher incidence of osteonecrosis of the jaw (ONJ)in patients withmetastatic castration resistant prostate cancer treatedwith anti-angiogenic agents. Cancer Invest 2009;27(2):221-6.

12. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE,Mehrotra B. American Association of Oral and MaxillofacialSurgeons position paper on bisphosphonate-related osteonecrosisof the jaws—2009 update. J Oral Maxillofac Surg 2009;67(5Suppl):2-12.

13. Van Poznak C, Estilo C. Osteonecrosis of the jaw in cancer patientsreceiving IV bisphosphonates. Oncology 2006;20(9):1053-62. discus-sion 65-6.

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14. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D,

et al. Bisphosphonate-associated osteonecrosis of the jaw: report of

a task force of the American Society for Bone and Mineral Research.

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potential pathobiology of bisphosphonate-induced jaw osteonecro-

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induced by anti-RANK ligand therapy. Brit J Oral Maxillofac Surg

2010;48(3):221-3.17. Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in

a patient on denosumab. J Oral Maxillofac Surg 2010;68(5):959-63.18. Christodoulou C, Pervena A, Klouvas G, Galani E, Falagas ME,

Tsakalos G, et al. Combination of bisphosphonates and antiangio-

genic factors induces osteonecrosis of the jaw more frequently

than bisphosphonates alone. Oncology 2009;76(3):209-11.19. Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G 3rd, Huryn JM.

Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol

2008;26(24):4037-8.

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20. Greuter S, Schmid F, Ruhstaller T, Thuerlimann B. Bevacizumab-associated osteonecrosis of the jaw. Ann Oncol 2008;19(12):2091-2.

REVIEWERS

Sunday O. Akintoye, BDS, DDS, MSAssistant Professor of Oral Medicine, University of PennsylvaniaSchool of Dental Medicine, Department of Oral Medicine, RobertSchattner Room 211, 240 S. 40th Street, Philadelphia,PA 19104, Phone: 215-898-9932, Fax: 215-573-7835akintoye@dental.upenn.eduElliot V. Hersh, DMD, MS, PhDProfessor of Pharmacology, University of Pennsylvania Schoolof Dental Medicine, Chair IRB #3 – University of PennsylvaniaOffice of Regulatory Affairs, 240 South 40th Street, Philadelphia,PA 19104-6030, Phone: 215-898-9686, Fax: 215-746-8891evhersh@pobox.upenn.edu

June 2012