Prevalence of Osteonecrosis of the Jaw in Patients With Oral Bisphosphonate Exposure

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J Oral Maxillofac Surg68:243-253, 2010

Prevalence of Osteonecrosisof the Jaw in Patients With Oral

Bisphosphonate ExposureJoan C. Lo, MD,* Felice S. O’Ryan, DDS,† Nancy P. Gordon, ScD,‡

Jingrong Yang, MA,§ Rita L. Hui, PharmD, MS,¶

Daniel Martin, DDS,� Matthew Hutchinson, DDS,#

Phenius V. Lathon,** Gabriela Sanchez,†† Paula Silver,‡‡

Malini Chandra,§§ Carolyn A. McCloskey, MD,¶¶

Judy A. Staffa, PhD,�� Mary Willy, PhD,##

Joe V. Selby, MD, MPH,*** and Alan S. Go, MD†††; for the

Predicting Risk of Osteonecrosis of the Jaw with Oral

Bisphosphonate Exposure (PROBE) Investigators

*Research Scientist, Division of Research, Kaiser Permanente

orthern California, Oakland, and Associate Clinical Professor, De-

artment of Medicine, University of California, San Francisco,

chool of Medicine, San Francisco, CA.

†Director, Division of Maxillofacial Surgery, Kaiser Permanente

akland Medical Center, Oakland, CA.

‡Research Scientist, Division of Research, Kaiser Permanente

orthern California, Oakland, CA.

§Data Consultant, Division of Research, Kaiser Permanente


¶Outcomes Research Scientist, Pharmacy Outcomes Research

roup, Drug Information Services, Kaiser Permanente California,

akland, CA.

�Resident, Division of Maxillofacial Surgery, Kaiser Permanente

akland Medical Center, and Department of Oral and Maxillofacial

urgery, Highland General Hospital, Oakland, CA.

#Resident, Division of Maxillofacial Surgery, Kaiser Permanente

akland Medical Center, and Department of Oral and Maxillofacial

urgery, Highland General Hospital, Oakland, CA.

**Project Manager, Division of Research, Kaiser Permanente


††Project Manager, Division of Research, Kaiser Permanente


‡‡Project Manager, Division of Research, Kaiser Permanente


§§Senior Consulting Data Analyst, Division of Research, Kaiser

ermanente Northern California, Oakland, CA.

¶¶Epidemiologist, US Food and Drug Administration, Center for

rug Evaluation and Research, Office of Surveillance and Epidemi-

logy, Silver Spring, MD.

��Associate Director for Regulatory Research, US Food and Drug

dministration, Center for Drug Evaluation and Research, Office of

urveillance and Epidemiology, Silver Spring, MD.

##Senior Risk Analyst, US Food and Drug Administration, Center

or Drug Evaluation and Research, Office of Surveillance and Epi-

***Director, Division of Research, Kaiser Permanente Northern

California, Oakland, CA.

†††Research Scientist, Division of Research, Kaiser Permanente

Northern California, Oakland, and Associate Professor, Depart-

ments of Medicine and Epidemiology and Biostatistics, University of

California, San Francisco, School of Medicine, San Francisco, CA.

This study was funded by the US Food and Drug Administration

(HHSF223200510008C), the National Institute of Child Health and

Human Development at the National Institutes of Health (K12

HD052163), and the Kaiser Permanente Community Benefit Pro-

gram; a portion of this study was also supported by the National

Center for Research Resources at the National Institutes of Health

(UCSF-CTSI UL1 RR024131).

These data were presented in part at the 90th Annual Meeting of

the Endocrine Society, San Francisco, CA, June 15-18, 2008.

J. Lo previously received research funding from Novartis; D.

Martin previously owned stock in Merck & Company, Incorpo-

rated; a household family member of N. Gordon previously owned

stock in Novartis Pharmaceuticals; a nonhousehold family member

of F. O’Ryan is employed by Roche Laboratories; A. Go previously

received research funding from Amgen and currently receives re-

search funding from GlaxoSmithKline.

The contents of this publication are solely the responsibility of

the authors and do not represent the official views of the Food and

Drug Administration or the National Institutes of Health.

Address correspondence and reprint requests to Dr Lo: Division

of Research, Kaiser Permanente Northern California, 2000 Broad-

way, Oakland, CA 94612; e-mail: [email protected]

© 2010 American Association of Oral and Maxillofacial Surgeons

0278-2391/10/6802-0003$36.00/0

doi:10.1016/j.joms.2009.03.050

emiology, Silver Spring, MD.

243

mailto:[email protected]

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244 PREVALENCE OF ONJ AFTER ORAL BISPHOSPHONATE EXPOSURE

Purpose: Osteonecrosis of the jaw (ONJ) is a serious complication associated with bisphosphonatetherapy, but its epidemiology in the setting of oral bisphosphonate therapy is poorly understood. The presentstudy examined the prevalence of ONJ in patients receiving chronic oral bisphosphonate therapy.

Materials and Methods: We mailed a survey to 13,946 members who had received chronic oralbisphosphonate therapy as of 2006 within a large integrated health care delivery system in NorthernCalifornia. Respondents who reported ONJ, exposed bone or gingival sores, moderate periodontaldisease, persistent symptoms, or complications after dental procedures were invited for examination orto have their dental records reviewed. ONJ was defined as exposed bone (of �8 weeks’ duration) in themaxillofacial region in the absence of previous radiotherapy.

Results: Of the 8,572 survey respondents (71 � 9 years, 93% women), 2,159 (25%) reported pertinentdental symptoms. Of these 2,159 patients, 1,005 were examined and an additional 536 provided dentalrecords. Nine ONJ cases were identified, representing a prevalence of 0.10% (95% confidence interval0.05% to 0.20%) among the survey respondents. Of the 9 cases, 5 had occurred spontaneously (3 inpalatal tori) and 4 occurred in previous extraction sites. An additional 3 patients had mandibularosteomyelitis (2 after extraction and 1 with implant failure) but without exposed bone. Finally, 7 otherpatients had bone exposure that did not fulfill the criteria for ONJ.

Conclusions: ONJ occurred in 1 of 952 survey respondents with oral bisphosphonate exposure (minimumprevalence of 1 in 1,537 of the entire mailed cohort). A similar number had select features concerning for ONJthat did not meet the criteria. The results of the present study provide important data on the spectrum of jawcomplications among patients with oral bisphosphonate exposure.© 2010 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 68:243-253, 2010
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isphosphonate-related osteonecrosis of the jawONJ), a rare condition characterized by exposed ne-rotic bone in the maxillofacial region of patientsith bisphosphonate exposure,1 has received increas-

ng attention since early reports were published in003.2,3 Most affected patients have presented after

nvasive dental procedures that involved dentoalveo-ar bone manipulation, although spontaneous expo-ure of bone has also been observed.4-11 The exacttiologic mechanisms remain unclear but might re-ate, in part, to altered bone remodeling or local tissueffects in susceptible patients.12,13 More than 90% ofeported cases to date have occurred with intrave-ous bisphosphonate therapy for which the preva-

ence has been estimated in the range of 1% to 5%,epending on the treatment duration.7-11,14 Early caseeries also identified approximately 5% of reportedases occurring in patients receiving oral nitrogen-ontaining bisphosphonate drugs,5,6 one of the pri-ary therapies for the prevention of osteoporotic

ractures.Limited data exist about the ONJ risk with the oral

itrogen-containing bisphosphonates: alendronate,isedronate, and ibandronate.5,6,15-17 The largest se-ies of oral bisphosphonate-related ONJ described 27ases with a minimum of 3 years of treatment, withne half presenting without a recognized incitingvent.16 Two smaller series identified 20 cases com-ined, including 13 after invasive dental proceduresnd 7 from denture trauma.18,19 The current estimates
f ONJ prevalence have ranged from 0.001% to 0.01% i
mong oral bisphosphonate-treated populations,argely from data from Australia and Germany.8,20-22

ystematic data from the United States are lacking.iven the increasing numbers of persons taking oralisphosphonate drugs (�5.4 million for the Unitedtates in 2007),23 a better understanding of the epi-emiology of ONJ and oral bisphosphonate therapy isritical. The Kaiser Permanente Predicting Risk ofsteonecrosis with Bisphosphonate Exposure

PROBE) study was conducted to determine the prev-lence of, and predictors for, ONJ among a largeommunity-based population with chronic oralisphosphonate exposure. The present report fo-uses on our initial prevalence findings from a largeross-sectional survey with targeted examinations.

aterials and Methods

SOURCE POPULATION

Kaiser Permanente of Northern California is a largentegrated health care delivery system that providesomprehensive care to 3.3 million members, repre-enting more than one third of insured adults in thereater San Francisco Bay Area. Its diverse member-hip is generally representative of the surroundingocal and statewide population, except for a some-

hat lower representation of the extremes of age andncome.

The institutional review boards of the Kaiser Founda-ion Research Institute and the Food and Drug Admin-
stration approved the study. Additional informed con-

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ent was obtained from participants in the examinationomponent of the study.

IDENTIFICATION OF TARGET POPULATION

Using retrospective pharmacy data, we initially iden-ified all members aged �21 years who had receivedecent chronic oral nitrogen-containing bisphospho-ates, defined as �4 prescriptions in the health planharmacy for alendronate, risedronate, or oral iban-ronate, with �1 prescription in 2006, and a total esti-ated treatment exposure period spanning �1 year.

ersons with human immunodeficiency virus infection,revious known intravenous bisphosphonate ther-py, oral cavity neoplasm using 2005 Cancer Reg-stry data,24,25 diagnosed dementia, or an inabilityo understand English were excluded. Eligible indi-iduals included those who were health plan mem-ers in January 2007 with continuous membershipuring the previous 2 years (allowing �3-monthembership gap), lived within 40 miles of 1 of the 3

xamination centers (Kaiser Permanente Oakland,anta Clara or South Sacramento Medical Centers),ere �90 years old, and had not died or been admit-

ed to hospice care. Survey mailings were conductedetween April and June 2007 and included a secondailing sent to the initial nonrespondents. The mailed

uestionnaire focused on demographic information,linical history, dental symptoms, and oral and boneealth. The survey was administered by telephone onequest.

SUBJECT RECRUITMENT, CLINICAL EXAMINATION,AND ORAL HEALTH RECORD RETRIEVAL

The study cohort included all persons who com-leted the mailed questionnaire. As the surveys wereeturned, we identified respondents reporting any ofhe following oral problems (collectively referred tos “dental symptoms”) for telephone interview: ex-osed bone, ONJ, denture discomfort, moderate toevere periodontal disease, persistent gingival or pal-tal sores, complications after invasive dental proce-ures after the initiation of bisphosphonate therapyimplant loosening or exposure, infection, persistentain, or delayed healing after tooth extraction or rootanal), pain, swelling, numbness or bleeding of theingival tissues or jaws, or loosening of teeth that wasurrent or had lasted for �1 month in the previousear. Symptoms localizing only to the temporoman-ibular joint were not considered a pertinent dentalymptom. The reported dental symptoms were veri-ed by telephone interview, and participants werehen given the option to come in for a clinical exam-nation or to give signed permission for review ofheir dental records. Hence, a low threshold was used
o identify patients for examination or dental record C
eview to increase the likelihood of finding cases ofNJ.All clinical examinations included inspection of the

ral cavity by trained dentists, including the teeth,ingiva, palate, maxilla and mandible for bone expo-ure, gingival sores, fistulas, nonhealing extractionites, visibly mobile or exposed dental implants, andnfection or persistent pain. A dental history was ob-ained, and all findings concerning for ONJ were eval-ated by 1 maxillofacial surgeon (F.O.). Patients withxposed bone, concerning clinical findings, or focalersistent pain after invasive dental procedures werelso referred for evaluation and necessary treatmentithin the health plan.Staging for bisphosphonate-related ONJ was done

sing the 2006 American Association of Oral andaxillofacial Surgeons criteria, which required treat-ent with a bisphosphonate, exposed bone in theaxillofacial region lasting �8 weeks (documented

uring clinical follow-up and/or review of oral healthecords), and no radiotherapy involving the jaw.1

tage 1 was characterized by exposed/necrotic boneith no symptoms or infection; stage 2 by exposed/ecrotic bone with pain and infection; and stage 3 byvidence of stage 2 disease plus pathologic fracture,xtraoral fistula, or osteolysis extending to the infe-ior border of the mandible. Patients who had under-one previous radiotherapy involving the jaw wereonsidered to have osteoradionecrosis of the jaw.The dental records were reviewed for the eligible

ersons who were not examined, and the hospitaliza-ion and ambulatory care databases were searchedetween January 2006 and August 2008 for cases andotentially concerning diagnoses (ONJ, osteonecro-is, osteoradionecrosis, osteomyelitis of the jaw, oralavity lesion, and jaw pain). Although a specific Inter-ational Classification of Disease, revision 9, code forNJ was not available until late 2007, the centraliza-

ion of oral surgery care and liaison with the head andeck surgery departments across the health plan med-

cal centers facilitated systematic ascertainment ofew ONJ cases within our health plan. Patients werelso mailed a study letter 1 year later (Fall of 2008)hat provided a telephone number to call if theyanted to report osteonecrosis of the jaw, severe jaw

nfection, or nonhealing after tooth extraction or den-al implant to capture any missed cases.

BISPHOSPHONATE EXPOSURE

Oral bisphosphonate exposure was determined us-ng the health plan pharmacy databases, with pre-cription records available from 1994 to 2008. Theength of each prescription (pills dispensed and dos-ng interval) and exposure timeline were calculatedor each participant, similar to previous methods.26

onsecutive prescriptions were counted within the

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ame continuous treatment interval if the gap be-ween the end date of the first and the dispenseate of the second was �60 days. If the gap was60 days, the second prescription was considered

he start of a new treatment interval. For eachatient, we combined the continuous treatment

ntervals to calculate the total duration and alsoetermined the total bisphosphonate supply inays. Most bisphosphonate prescriptions (85%)rovided a 3-month drug supply.

STATISTICAL APPROACH

All analyses were conducted using Statistical Anal-sis Systems statistical software, version 9.1.3 (SASnstitute, Cary, NC). A 2-sided P value of less than .05as considered significant. Continuous variablesere compared between subgroups using Student’s t

est or Wilcoxon’s rank sum test; categorical variablesere compared using the chi-square test or Fisher’s

xact test. The prevalence of ONJ was reported as aoint estimate, with the 95% confidence interval (CI),mong respondents and stratified by the duration ofisphosphonate therapy. We also calculated the fre-uency per 100,000 person-years of treatment withhe 95% CI. In a sensitivity analysis, we estimated theinimal prevalence of ONJ among patients with oral

isphosphonate exposure using the larger populationenominator of all individuals (n � 13,835) who re-eived the mailed survey.

esults

We initially identified 31,680 eligible persons whoet the minimal treatment criteria, including �1

FIGURE 1. Recruitment and e

o et al. Prevalence of ONJ After Oral Bisphosphonate Exposure.

isphosphonate prescription in 2006. We excluded e

,108 patients because of intravenous bisphospho-ate treatment (n � 98), oral cavity neoplasm (n �1), no written or spoken English (n � 2,185), diag-osed dementia (n � 1,185), human immunodefi-iency virus infection (n � 36), not meeting member-hip criteria (n � 1,759), and death or admission toospice care (n � 650). Of the remaining 26,572ligible patients, 13,946 lived within 40 miles of anxamination center and were 21 to 90 years old.Of the questionnaires mailed to 13,946 members,

11 surveys were undeliverable, resulting in 13,835urvey recipients. Overall, 8,572 (62%) respondedFig 1). For the 2,400 respondents with dental symp-oms, 2,354 (98%) telephone interviews were con-ucted, after which 241 patients were reclassified asaving no concerning symptoms. Clinical examina-ions were conducted in 1,005 symptomatic partici-ants, and an additional 536 provided permission toxamine their dental records (96% underwent a den-al assessment after January 2006). Of the 618 withoutental records or study examination who had re-orted symptoms, 476 indicated on their survey thathey had seen a dentist within the past year and 418ad evidence of continued oral BP therapy in 2008,uggesting a lower probability of bisphosphonate-elated jaw issues.

IDENTIFICATION OF ONJ AND ONJ-LIKE CASES

We identified 9 cases of ONJ diagnosed in 2006 to008 (Table 1), with ONJ severity stages 1-2. All visi-le lesions were �1 cm. Of the 9 cases, 2 wereonfirmed by detailed examination of the oral andaxillofacial surgery records because healing had oc-

urred before the survey mailing, and 6 patients were

ation of PROBE study cohort.

Maxillofac Surg 2010.

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LO ET AL 247

axillofacial Surgery Clinics. A final patient devel-ped spontaneous ONJ with documented bone expo-ure 8 months after the initial study examination. Ofhe 9 patients, 5 had developed ONJ spontaneouslyithout a known antecedent. Of these 5 patients, 3ad exposed bone on palatal tori and 2 developedpontaneous exposure of bone in the lingual mandi-le in areas without tori. Eventual healing occurred inpatients with palatal ONJ after spontaneous exfoli-

tion of the necrotic bone and in 1 patient withpontaneous mandible ONJ with conservative man-gement after cessation of bisphosphonate therapy.our patients developed ONJ after tooth extraction (2andibular, 2 maxillary) despite the initial superficialealing of the extraction site in 2 patients. Of theseatients, those with maxillary ONJ demonstratedmall (�5 mm) lesions that improved with oral anti-iotics, chlorhexidine rinses, and discontinuation ofisphosphonate therapy. One patient also had re-

Table 1. IDENTIFIED CASES OF OSTEONECROSIS OF JAW

Pt No. Location StageSize of ExposedBone, Symptoms

1 Maxillary palataltorus

1 2 � 2 mm,painless

Pal


2 4 � 6 mm,focal pain

Pal



Pal

4 Posterior lingualmandible

1 12 mm (R), 3 mm(L), painless

No

5 Lingual mandible,mid-body


No

6 Posterior lingualMandible

2 5 � 7 mm,swelling andpurulence

Extwr

7 Posterior lateralmaxilla

2 3 � 3 mm,focal pain anderythema

Extwrcthnfr

8 Lateral maxilla 1 3 � 2 mm,painless

Exth

9 Lateral mandible,parasymphysis

2 5 � 5 � 16-mmfistula to bonewith pain,swelling,purulence, andparesthesia V3

Extp

OTE. Patients 3 and 4 had healed by the time they receivAll patients met criteria of maxillofacial bone exposure

roviders.*None continued BP therapy.†Required long-term antibiotics (�3 months) and, ultimaAbbreviations: Pt No., patient number; BP, bisphosphona


eived chronic glucocorticoid therapy and had avas- c

ular necrosis of the hip after initial hip fractureepair. In contrast, the 2 patients with postextractionandibular ONJ did not respond to chlorhexidine

inses, local wound care, or multiple courses of long-erm oral and/or intravenous antibiotics. Both pa-ients ultimately required surgical debridement andequestrectomy, at which time Actinomyces wasound on histopathologic examination. Radiographicndings of the 4 extraction-related cases were typicalf ONJ, including sequestra, osteosclerosis, and/orocal osteolysis with cortical disruption (Fig 2).

We also identified 10 patients with ONJ-like fea-ures that did not meet the ONJ criteria, many withbnormal radiographic findings (Table 2). Of these 10atients, 2 had purulent osteomyelitis and intraoralstulas that had developed 5 to 10 months after man-ibular molar extraction and a third patient had lateailure (�4 years) of 4 anterior mandibular implantsith associated osteomyelitis and extensive bone ne-

D PREDISPOSING FACTORS

l History and/orsposing Factors

BP Duration(yr) 1-yr Outcome*

rus 4.9 Healed after exfoliationof exposed bone

rus 3.0 Nearly healed

rus 4.4 Healed after exfoliationof necrotic torus

4.1 Healed

4.3 Not healed

17 mo previouslyparent healing;toid arthritis

4.8 Not healed†

11 mo previouslyparent healing;toid arthritis,glucocorticoid

, avasculars of hip after hip

2.6 Not healed

8 mo previously,status unclear

6.0 Not healed

14 mosly, never healed

5.6 Not healed andworsening†

survey.sting �8 weeks with documentation by oral health care

urgical debridement.right; L, left.


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ransient, atypical, or related to bony sequestra, in-luding 2 with contributory dental factors (dentureear and periodontal abscess), 3 with a previous

xtraction (3 to 14 months previously), and 1 afterhronic glucocorticoid therapy. The final patient hadecurrent bony spicule formation and spontaneousooth loss in a focal region that was found to have ansteolytic defect on panoramic radiography (Fig 3).hree participants whom we diagnosed with osteora-ionecrosis were not included in these cases.

PATIENT CHARACTERISTICS

Among survey respondents, we examined charac-eristics by symptom status and evidence of ONJ or

IGURE 2. Radiographic findings in ONJ after dental extraction., Patient 7: Axial computed tomography scan showing irregularrea of bony sclerosis (12.5 � 9.3 mm) corresponding to extrac-

ion site (maxillary molar extraction occurred 11 months beforecan date). B, Patient 9: Axial computed tomography scan showingclerosis with areas of lucency proximal to extraction site (mandib-lar bicuspid extraction occurred 14 months before scan date).amina dura is thickened and sclerotic, and the extraction socket istill visible radiographically.

o et al. Prevalence of ONJ After Oral Bisphosphonate Exposure.Oral Maxillofac Surg 2010.

NJ-like findings (Table 3). The mean age was 71 m

ears, 93% were women, and 71% were white. Theedian duration of oral nitrogen-containing bisphos-honate exposure was 3.5 years (interquartile range.5 to 4.7), with a median total days supply of 3.3ears (interquartile range 2.4 to 4.5). The cumulativexposure was 32,678 person-years of treatment.early all respondents (99.7%) had health plan phar-acy benefits in 2006, and �85% of the cohort had

een continuous members for the past 7 years (77%ad been members since 1995). No significant differ-nces were found in gender or bisphosphonate expo-ure by symptom status, although age and race/thnicity varied. As a group, patients with ONJ orNJ-like findings were older and had a longer treat-ent duration (Table 3).A systematic search of the ambulatory and hospital-

zation databases for known ONJ cases and potentiallyoncerning diagnoses (eg, oral cavity lesion, jaw pain,steoradionecrosis, osteomyelitis of the jaw, or osteo-ecrosis) did not identify additional cases among allhe survey respondents. These efforts, coupled withhe patient interviews and follow-up mailing to cohortembers 1 year after the mailed survey, reduced the

ikelihood of missed ONJ cases among symptomaticarticipants for whom we did not have dentalecords. Also, no cases of ONJ or concerning findingsere found among the 37 patients who self-reportedr had received intravenous bisphosphonate therapyfter the cohort exclusion date.

PREVALENCE OF ONJ AMONG ORALBISPHOSPHONATE-TREATED PATIENTS

Among the 8,572 survey respondents, the preva-ence of ONJ was 0.10% (95% CI 0.05% to 0.20%),

ith a frequency of 28 (95% CI 14 to 53) per 100,000erson-years of oral bisphosphonate treatment. Theinimal prevalence of ONJ among the larger popula-

ion denominator of 13,835 individuals who receivedhe mailed survey was 0.07% (95% CI 0.03% to 0.12%),ssuming hypothetically that no cases were presentmong the nonrespondents. When stratified by treat-ent duration (Fig 4), the prevalence of ONJ was

reater among respondents with �4 years of expo-ure compared with those with �4 years of exposure0.21% vs 0.04%, respectively, P � .03). No casesere reported among the 2,191 cohort members with2.5 years of treatment.

iscussion

Among the nearly 14,000 patients who had re-eived chronic oral bisphosphonate therapy, we iden-ified 9 cases of ONJ, for a minimum prevalence of 10.10%) in 952 survey respondents or 1 (0.07%) in,537 in the target population who received the
ailed survey. Among the survey respondents, we

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LO ET AL 249

stimated a frequency of ONJ of 28 per 100,000 per-on-years of treatment. These estimates might be con-ervative because they did not include 3 cases ofsteomyelitis without bone exposure. However, theyo provide reassurance that the prevalence of oralisphosphonate-related ONJ appears to be low, albeitreater than initially estimated.20,21

Few studies have investigated the prevalence ofNJ in persons receiving exclusive oral bisphospho-

Table 2. OSTEONECROSIS OF JAW-LIKE CASES THAT D

Pt No. Location Description Radiograp

10 Mandible Pain and paresthesia V3,nonhealing extractionsite with multiplefistulas andosteomyelitis

Focal osteon pano

11 Mandible Intermittent dull ache,purulence, fistula, andosteomyelitis atprevious extractionsite

Osteosclefocal raon CT

12 Mandible Purulence, exposureand mobility ofimplants,osteomyelitis, andextensive necrosis

Osteolysisnecrosis

13 Mandible 4-mm exposed bone�6 wk

Osteoscle

14 Mandible 3-mm exposed bone(�2.5 mo) adjacent tomolar root

CT of manunrema

15 Mandible 4 mm sequestrum� 4 wk at previousextraction site

Normal px-ray

16 Mandible Pain and 3 mmsequestrum inprevious extractionsite

Osteoscle

17 Maxilla 3 � 2-mm exposedbone � 1 yrassociated withperiodontal abscess

Periodont

18 Mandible Pain with focalrecurrent bonyspicules for 1 yrfollowed byspontaneous loss ofadjacent tooth

Focal osteon pano

19 Mandible Pain with fistula (3 molater), erythema, andbony spicule (7 molater) in previousextraction site

Osteoscleand inteuptakescintigr

OTE. Imaging studies included panoramic radiography (x-r1, 12, 13, 14, 16, and 19), with the exception of patient 17f exposed bone; patients 15 and 17 had healed by the timAbbreviations: AAOMS, American Association of Oral a

one-beam CT; ONJ, osteonecrosis of the jaw; other abbrev


ate therapy. Merck reported no cases of ONJ among m

linical trials involving �17,000 patients (including,000 patients with 3 to 5 years of exposure and 800atients with 8 to 10 years of exposure) and estimatedhe worldwide reporting rate of ONJ to be �3/100,000atient years of treatment, regardless of etiology.27 How-ver, nonsystematic ascertainment of adverse dental out-omes during these clinical trials and the shortcomingsf current postmarketing surveillance methods28,29 have

imited the accuracy and generalizability of these esti-

T MEET 2006 AAOMS CRITERIA FOR ONJ

ndings Predisposing Factors BP Duration (yr)

regionx-ray

Extraction 5 mo previously 2.7

ndency

Extraction 10 mo previously 3.9

oneBCT

Late failure of implantsplaced �4 yr previously

4.6

n CT Partial denture 4.4

, Prednisone, azathioprine 9.4

ic Extraction 14 mo previously 4.3

n CT Extraction 4 mo previously 11.1

e loss Periodontal abscess 4.7

regionx-ray

Tooth extraction �10 yrpreviously

3.0

n CTcale

Extraction 3 mo beforeinitial presentation,diabetes mellitus

3.8

ients 10, 13, 15, and 18), CBCT (patient 12), or CT (patientshom only periapical radiographs were available at the timereceived the survey.

axillofacial Surgeons; CT, computed tomography; CBCT,s as in Table 1.


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NJ prevalence among patients receiving oral bisphos-honates for osteoporosis was 1 in 260,000, as deter-ined by cases captured by a German Central Reg-

stry,20,22 with follow-up data from that registryuggesting an increase in ONJ cases in this patientubset.30 These estimates contrast with those from anustralian study that identified ONJ cases through aationwide maxillofacial surgeon survey (using pre-cription count to estimate the denominator ofreated patients) and found that oral bisphosphonate-elated ONJ had occurred in 1 in 2,260 to 8,470ersons, depending on the subregion.8 The Southustralian subregion, which prospectively capturedll cases through a single center, had the greatestrevalence of ONJ.8 Our results extend these findingsy conducting both systematic case surveillance andscertainment of cumulative bisphosphonate expo-ure. Using this approach, we found a slightly greaterrevalence of ONJ among a contemporary, chronicral bisphosphonate-treated population in the Unitedtates.

Several potential explanations exist for our greaterbserved prevalence. First, we studied persons receiv-

ng chronic oral bisphosphonate therapy becauseany discontinue treatment within the first year,26

uring which almost no reported cases have oc-urred. Second, differences may exist in bisphospho-ate prescribing, dietary patterns, and oral health caremong the different countries. Third, given that pri-ary and subspecialty physicians were only recently

ware of oral bisphosphonate-related ONJ and com-unication with dental providers was often not well

stablished, we concentrated on direct patient query,linical examination, and dental record review, ratherhan relying only on electronic data and physicianeporting for case ascertainment. Finally, we con-ucted screening examinations among the patientseporting suspicious dental issues to identify caseshat had not yet come to medical attention.

In our ONJ cases, the area of bone exposure wasenerally limited (2 to 10 mm), none were stage 3,nd some eventually healed. In general, the cases ofpontaneous ONJ were milder, and the majorityealed with conservative treatment. This contrastsith the more extensive ONJ cases reported in pa-

ients receiving chronic intravenous bisphosphonateherapy. Nearly one half of our cases were temporallyelated to previous dental extractions, and, amonghese, 2 mandibular lesions progressed, requiringong-term antibiotics and surgical debridement. All 4ases with previous extraction demonstrated radio-raphic features on computed tomography similar tohose seen with intravenous bisphosphonate-relatedNJ.31-33

In the present study, we also described 10 addi-

IGURE 3. Radiographic findings in ONJ-like cases. A, Case 12:one-beam computed tomography scan demonstrating severe osteol-sis around 3 of 4 implants with sclerosis of remaining bone to thenferior border of the mandible. B, Case 16: Axial computed tomog-aphy scan showing osteosclerosis surrounding area of lucency cor-esponding to the extraction site (mandibular molar extraction oc-urred 4 months before the scan date). C, Case 18: Panoramicadiograph demonstrating focal osteolytic defect with sclerosis of theurrounding bone and increased density of left inferior alveolar canal.atient reported distant extraction history (�10 years previously) withecurrent bony spicules and spontaneous tooth loss in this regionuring the previous year.

ional patients with selected ONJ-like features that did

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ot meet the current ONJ criteria. These included 3atients with purulent mandibular osteomyelitis—2ccurring in nonhealing or previously healed extrac-ion sites and 1 with late implant failure in whomlinical and radiographic bone necrosis and osteomy-litis supported the presumptive diagnosis of ONJ,espite the absence of bone exposure. It has beenuggested that bisphosphonate-related ONJ is moreike osteomyelitis than aseptic osteonecrosis,34 andome have grouped these conditions together for ONJase ascertainment,30,35 particularly in the setting ofone necrosis.36 Because oral bisphosphonate drugsave less effective potency than intravenous bisphos-honates at the doses used for skeletal malignancy,

Table 3. BASELINE CLINICAL CHARACTERISTICS OF PRO

CharacteristicOverall Cohort

(n � 8,572)No D

ean age � SD (yr) 71.0 � 9.3 7omen (%) 93.0

ace/ethnicity* (%)White 70.9Black 3.2Hispanic 5.2Asian 18.3Other 1.8Unknown 0.7

P duration (yr)Median 3.5IQR 2.5-4.7

P typeAlendronate 8,503Risedronate 258Ibandronate (oral) 34

*P � .01 comparing those with and without dental symp†P � .01 between those with and without ONJ or ONJ-l‡P � .05 between those with and without ONJ or ONJ-lAbbreviations: PROBE, Predicting Risk of Osteonecrosis o

f the jaw; BP, bisphosphonate.


IGURE 4. Prevalence of ONJ by duration of bisphosphonate (BP)herapy. Error bars represent 95% CIs.

ao et al. Prevalence of ONJ After Oral Bisphosphonate Exposure.Oral Maxillofac Surg 2010.

hese cases were likely recognized before progressiono overt bone exposure and are consistent with thebservation that oral bisphosphonate-related ONJ isenerally less severe and might resolve with earlyecognition and treatment.1,8 The 2006 consensusefinition of ONJ1 excludes these osteomyelitis casesnd might not address the full spectrum of jaw com-lications seen in oral bisphosphonate-treated pa-ients.

Table 2 also describes select patients without overtNJ who had localized pain, bony sequestra, or

picules in recent or distant extraction sites with focaladiographic findings similar to those seen in osteo-yelitis and ONJ (eg, osteosclerosis, osteolysis, bony

equestra). Some have speculated whether theseases represent an earlier (at risk) precursor stage (eg,tage 0) warranting close follow-up for potential pro-ression to ONJ,37-40 although the contributory role ofther dental factors cannot be excluded.The Kaiser Permanente PROBE study is the largest

ohort to date in which surveillance for ONJ has beenystematically conducted among patients with exclu-ive oral bisphosphonate exposure. Although limitedo northern California and primarily alendronate ex-osure, one of the strengths of our study was the

nclusion of a diverse community-based population ofearly 14,000 individuals who had received chronicisphosphonate therapy from which a minimal prev-

UDY COHORT

vey Response Category Patients With ONJor ONJ-Like

Features (n � 19)mptoms13)

Dental Symptoms(n � 2,159)

9.3 69.6 � 9.3* 76.0 � 6.8†2.8% 93.8 94.7%

.0 67.4 63.2

.8 4.2 5.3

.0 5.8 5.3

.0 19.1 26.3

.5 2.6 0.0

.6 1.0 0.0

.5 3.5 4.47 2.5-4.7 3.8-4.9‡

2,137 1971 1

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ged Kaiser’s multiple automated databases for drugxposure and rapid ascertainment of key variables, asell as for possible jaw-related complications or

ymptoms. This approach, along with the screeningxamination and dental record review of symptom-tic patients, allowed us to efficiently identify rarelinical outcomes when systematic examination of allatients was not feasible. Because there may haveeen inherent survey response bias and potential un-erestimation of ONJ with self-reported symptoms,e also provided the minimum prevalence of ONJithin the broader population of those who had re-

eived the mailed survey.Although bisphosphonate-naive patients were not

ncluded for comparison, the diagnosis of ONJ (inde-endent of radiotherapy, chemotherapy, or maxillo-

acial trauma) remains extremely rare. This contrastsith the growing number of bisphosphonate-relatedNJ cases reported in oral and maxillofacial surgeryenters, where it is now the major cause of diagnosedNJ.5,41 In 2004, Ruggiero et al5 reported 63 patientsith bisphosphonate-related ONJ diagnosed from

001 to 2003, including 6 receiving exclusive oralisphosphonate drugs, compared with only 4 in therevious 3 years without bisphosphonate exposure.imilarly we found no ONJ cases among the 2,191ith �2.5 years of treatment, but the prevalence

mong those with �4 years of treatment was as greats 0.21%. Although a better understanding of ONJrevalence in an unexposed population is needed,hese data and others8,16 argue against the supposi-ion that the ONJ cases observed simply reflect thexpected rate of adverse dental outcomes in patientsith dental or periodontal disease, independent ofisphosphonate treatment.ONJ occurred in 1 in 952 participants who had

eceived chronic oral bisphosphonate therapy, with ainimum prevalence of 1 in 1,537 among the targetopulation. The additional ONJ-like cases, especiallysteomyelitis, suggest that the overall prevalence of

aw-related complications could be somewhatreater, albeit still extremely low compared with theisk of osteoporotic fracture among postmenopausalomen. Hence, the net clinical benefit of oralisphosphonate therapy remains high for the majorityf patients with osteoporosis. However, these dataupport current guidelines recommending good oralygiene, regular dental care,17,21,42 and enhanced pa-ient and provider awareness for timely recognition ofarly-stage disease.18,43 For patients who developNJ, initial management should include local conser-ative therapy and consideration of a drug “holiday”ecause oral bisphosphonate cessation might be as-ociated with clinical improvement.16 The results ofhe present study also highlight the need for addi-
ional research to identify the clinical risk factors for
1

NJ, including comorbid conditions, pharmacologicxposures, and dental factors that might inform treat-ent guidelines in patients receiving oral bisphospho-ate therapy.

cknowledgments

We wish to thank the other members of the PROBE Study Teamor their support: Donald Liberty, DDS, Julia Townsend, DDS,udheer Surpure, DDS, Jeffrey Caputo, DDS, Vicente Chavez, DDS,. Thomas Indresano, DMD, David Baer, MD, Pete Bogdanos, Alicensfield, Marvella Villasenor, Beatriz Monjaras, Joelle Ebalo, Benjaminang, Virginia Browning, Colanda Grier, Teresa Lin, Maryanne Arm-

trong, Mohammad Hararah, and Joel Gonzalez. Our sincere appreci-tion to the Maxillofacial Clinics at Kaiser Permanente’s Oakland,anta Clara, and South Sacramento medical centers who facilitatedhe study visits and provided clinical evaluation of the concerningases. Finally, we are deeply grateful to the 8,572 study participantsnd their dentists whose support and contribution made this studyossible.

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http://www.merck.com/newsroom/press_releases/product/fosamax_statement.html



http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4095B2_03_04-FDA-TAB3.pdf

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Prevalence of Osteonecrosis of the Jaw in Patients With Oral Bisphosphonate Exposure

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