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J Oral Maxillofac Surg64:917-923, 2006

Bisphosphonates Are Associated WithIncreased Risk for Jaw Surgery in Medical

Claims Data: Is it Osteonecrosis?Athanasios I. Zavras, DMD, MS, DrMS,* and Shao Zhu, MD†

Purpose: Bisphosphonates (BPs) have recently been associated with increased risk of osteonecrosis ofthe jaw. Using a large automated insurance database, we searched the medical claims for commonprocedure codes (CPT codes) denoting major surgery to the mandible or the maxilla. The primary aimof this pilot study was to alert readers to clinically relevant but preliminary information regarding the riskof jaw surgery among patients who received BPs, as compared with patients who did not.

Methods: The study utilized 2001-2004 claims data from a large nationwide medical insurer. Medicalclaims from 255,757 cancer patients with breast, lung, or prostate malignancies, or multiple myelomawere analyzed for CPT codes 21015, 21025, 21026, 21034, 21040, 21045, 21046, and 21047.

Results: We identified 224 cases of jaw surgery; of those, 39 cases were found among 26,288 BP usersand 185 cases were found among 229,469 never-users. The odds ratio of jaw surgery for intravenous BPusers was 4.24 (P � .05). Breast cancer patients experienced a 6-fold increase in risk as compared withnonusers. A trend of increased risk was noted for those on orally administered BPs, but the associationwas not significant.

Conclusion: A significant association was noted between the administration of IV BPs and oral surgeryin cancer patients. More studies are needed to understand the role of BPs in bone biology and necrosisalong with the associated biologic pathways.© 2006 American Association of Oral and Maxillofacial Surgeons

J Oral Maxillofac Surg 64:917-923, 2006

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n 1968, Fleisch et al1 published their research on thenfluence of pyrophosphate analog (diphosphonates)n the precipitation and dissolution of crystals. Thisas the first published report of the effect of bisphos-honates (BPs) on bone formation.BPs are potent inhibitors of bone resorption, with

ong lasting effects. Bone is formed by osteoblasts andesorbed by osteoclasts in a delicate homeostatic bal-nce. Although there is controversy as to the role ofPs in upregulation of the osteoblast, much more isnderstood as to their role in regulating osteoclastunction. According to Little et al,2 nitrogen-contain-ng BPs inhibit farensyl disphosphate synthase which

*Assistant Professor, Department of Oral Health Policy & Epide-

iology, Harvard School of Dental Medicine, Boston, MA; Sceintific

ffairs Consultant, Ingenix, Eden Prairie, MN.

†Medical Statistician, i3 Epidemiology, Ingenix, Eden Prairie, MN.

Address correspondence and reprint requests to Dr Zavras: De-

artment of Health Policy & Epidemiology, Harvard School of

ental Medicine, 188 Longwood Ave, Boston, MA 02115; e-mail:

avras@hms.harvard.edu

2006 American Association of Oral and Maxillofacial Surgeons

278-2391/06/6406-0008$32.00/0

boi:10.1016/j.joms.2006.02.011

917

ecreases the ability of the osteoclasts to resorb bone.Ps seem to affect osteoclast recruitment and to me-iate cytokines and growth factors secreted by osteo-lasts, thus negating the signal for resorption.3-5

In addition, BPs seem to reduce the life expectancyapoptosis) of osteoclasts and thus their overall lifetimeunctional ability.6 It is the inhibition of osteolytic activ-ty that has made BPs popular treatment modalities forhe management of osteoporosis or to treat hypercalce-ia caused by bone metastasis in cancer patients.7

rally administered BPs, such as risedronate (Actonel;rocter & Gamble, Cincinnati, OH; Aventis, Bridgewa-er, NJ) and alendronate (Fosamax; Merck, Whitehousetation, NJ) are primarily used in the treatment of osteo-orosis. Intravenous (IV) BPs are mainly used in oncol-gy to treat hypercalcemia of the tumors and metastaticone disease to prevent subsequent pathologic frac-ures, spinal compression, and pain. Pamidronate (Are-ia; Novartis, East Hanover, NJ) and zoledronic acidZometa; Novartis) are the 2 available intravenous (IV)Ps on the market.Although their clinical benefits are well studied, the

ong-term risks associated with prolonged BP expo-ure are not adequately documented. One of the con-erns is the longevity of BP action after the drug has

een discontinued, and the ability of the bone to

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ecover. In a 10-year follow-up study, Bone et al8

valuated the prolonged use of alendronate in post-enopausal women and found that the therapeutic

ffects of 10 mg of alendronate are sustained even 5ears after discontinuation, attesting to the long-termetention of BPs in the osseous tissue. Questions re-ain about the long-term safety of those who re-

eived the higher dose (20 mg/day for 2 years and 5g/day years 3-5), especially in relation to bone turn-

ver capacity. The same questions apply for the00,000� patients worldwide who have received in-usions of zoledronic acid, a much more potent os-eolytic inhibitor than alendronate.

Intravenous BPs were recently associated with anncreased risk of osteonecrosis of the jaw (ONJ). Clin-cal reports of patients taking pamidronate oroledronic acid with exposed intraoral bone that doesot heal or with radiographic signs of osteomyelitisave begun to accumulate since 2003.Marx9 presented 36 cases of BP-related osteonecro-

is; the majority of patients (24/36) had been treatedith pamidronate, 6 had been treated with zoledronic

cid, and 6 had received both. In 78% of the cases, aooth extraction had proceeded the diagnosis of avas-ular necrosis.Ruggiero et al10 reported on 56 cases of oncologic

atients with a history of IV BPs and another 7 casesn patients who had received oral chronic BP treat-

ent for osteoporosis. The maxillary bone was in-olved in 38% of the cases and the mandible in 63% ofsteonecroses. Although the typical presenting symp-oms were pain and exposed bone at the site of anxtraction, 9 of 63 patients presented with spontane-us exposure and necrosis of the alveolar bone.Lugassy et al11 presented 3 cases of multiple my-

loma in patients treated with pamidronate and/oroledronic acid for approximately 5 years each; mul-iple actinomyces colonies were discovered in 2 outf the 3 cases.Bagan et al12 presented a series of 10 patients withNJ of the mandible after cancer chemotherapy. In-

erestingly, these authors documented maxillary in-olvement in 50% of their cases. Symptoms followedooth extractions in the majority of cases. The prom-nent histopathologic diagnosis was osteomyelitis

ithout evidence of metastatic disease.Migliorati et al13 presented 17 cancer patients tak-

ng pamidronate or zoledronic acid and 1 patient withsteopenia who was receiving alendronate. All pa-ients had developed osteonecrosis after a mean ex-osure time of 25 months (range, 4 to 41 months).he average age of the 14 female and 4 male patientsas 62 years. Although a local irritant or a local

ource of infection was present in the majority of theases, 2 patients appeared to develop disease sponta-

eously.

Schirmer et al14 described 6 cases of osteonecrosisn 4 men and 2 women, all cancer patients receivingrolonged BP therapy with a median age of 69 years.imilar to all previous reports, the osteonecrosis wasefractory to treatment.

Durie et al15 recently reported the results of aurvey by the International Myeloma Foundation onhe risk factors for jaw necrosis. Among the 1,203yeloma or breast cancer patients who participated

n the web-based survey, there were 62 diagnosedNJ cases and another 54 suspicious findings. Osteo-ecrosis developed in 10% of patients receivingoledronic acid and in 4% of the patients on pami-ronate. Histories of underlying dental problemsere significantly more frequent in osteonecrosis

ases. No other concomitant therapies (ie, corticoste-oids or thalidomide) seem to affect the risk.

There are now several other published reports ofell-documented cases of osteonecrosis among BPsers.16-20 Most case series report ONJ among canceratients receiving pamidronate or zoledronic acid,ut reports do exist for ONJ among women treatedor osteoporosis with oral BPs. All the series convergen regard to the following facts:

1) The mean age of patients is close to 60 yearsold or more.

2) Patients diagnosed with metastatic bone dis-ease or hypercalcemia caused by breast can-cer, multiple myeloma, prostate, or lung can-cers and who have received IV BP for severalmonths seem to be the most exposed to risk ofosteonecrosis.

3) ONJ reports do exist among patients whowere receiving BP orally to manage osteopo-rosis.

4) Zoledronic acid seems to be the most toxicagent, followed by pamidronate, and then byalendronate.

5) The disease appears more frequently amongpatients who have received invasive dentaltreatment or among those with active disease(eg, periodontal pockets, untreated caries), al-though spontaneous cases exist.

6) Pain and exposed bone that does not heal arethe most common clinical symptoms.

7) Both jaws can be affected.8) Screening and prevention are needed to iden-

tify early lesions and improve prognosis.9) The disease is difficult to treat with a bone that

seems affected beyond the borders of clinicalnecrosis.

10) Surgical excision, prolonged antibiotic treat-ment, and hyperbaric oxygen treatment seem

to be the most utilized strategies; however,

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more research is needed to determine the besttreatment modality for managing ONJ.

By January 13, 2005, the US Food and Drug Admin-stration had received 654 reports of ONJ in Med-

atch; 49% of the cases were associated witholedronic acid alone, 21% of the cases had receivedamidronate alone, 28% had received both, and an-ther 2% had received IV and an oral BP.21 The USood and Drug Administration Web site containsdded case reports of osteonecrosis in 18 users ofoledronic acid.22 The manufacturer has updated theabels of pamidronate and zoledronic acid to add arecaution of ONJ and warn against invasive dentalrocedures in exposed patients. A “Dear Doctor” let-er was sent to the clinical community in September004 and various activities now exist to inform theealth care community. Articles in popular press andewspapers have also attempted to raise the aware-ess of the public.23

Given their wide, frequent, and chronic use inillions of women nationwide, this link—if it is real—ight have serious public health consequences. Po-

ent IV BPs remain in the ossified tissues for longeriods of time and stopping the drug will not reduce

ts reaction potential as it is active for many years afteriscontinuation. Additionally, the clinical manage-ent of osteonecrosis is complex, often requiring

erial sequestrectomy or radical excision of the man-ible.The aim of our analysis is to alert readers to clini-

ally relevant but preliminary information regardinghe risk of jaw surgery among patients who receivedPs, as compared with patients who did not.

aterials and Methods

We analyzed medical claims data from a largeealth insurance plan providing health coverage topproximately 20 million members from the begin-ing of 2001 through December 2004 across thenited States. The accessible information includesemographics, pharmacy claims for drug dispensings,nd all medical and health facility claims, which pro-ide data on services, procedures, and their accom-anying diagnoses. The limitations of claims-basednalyses are many and preclude any firm conclusions;owever, they also provide the unique benefit ofaving longitudinal health care utilization data from

arge reference populations. The present analysisompared the frequency of outcome (surgical proce-ure to the mandible or the maxilla) between users ofPs and nonusers. The basic null hypothesis was thathe 2 frequencies would not differ significantly andhat both BP users and nonusers would have compa-

able rates of surgery. i

The first step was to identify those who were goodandidates for the analysis. The population we choseo target were individuals with malignancies where IVPs are mostly recommended. The first inclusion cri-erion was ICD9 coding for 1 of the following 4alignancies: cancers of the breast, prostate, lung,

nd multiple myeloma. The master dataset includedll medical claims data from the above-mentionedndividuals.

The second step was to apply the temporal se-uence criterion for BP, namely to identify individualsith claims for surgery preceding claims for BP dis-ensing and exclude them. Individuals who had initi-ted BP treatment after having jaw surgery were ex-luded; the exposure should occur before the diseasen our theoretical etiologic model.

BP use was stratified according to mode of admin-stration, and 3 strata were created: 1) “none,” forhose who had no claims for dispensing of any type ofP; 2) “oral,” for those on alendronate or risedronate;nd 3) “IV,” for those on pamidronate and/oroledronic acid. We searched the date of first IV user first pharmacy dispensing of BP and date of sur-ery; we dropped the patients who had surgery be-ore the BP therapy.

Patients who never received any form of BP wereompared to those who were identified by pharmacylaims as taking oral BP (alendronate or ris-dronate) and those who were identified by proce-ure records of “IV” use (pamidronate and/oroledronic acid). Patients with claims for both oralnd IV were analyzed separately but found to haveimilar results with the IV group; because of the highotency and dose of IV BPs as compared with oralrugs and re-confirmed by statistics, they were subse-uently included with the IV group.The outcome we chose to study was surgical

rocedures performed in the mandible or maxillaather than diagnostic codes for osteonecrosis. Sur-ical procedures are recorded validly and accu-ately in medical claims because of administrativetilization review and qualitative review require-ents routinely imposed by health plans. Before

nalyzing the medical claims data we consultedith medical and dental clinicians; both groups

erified our assumptions that the primary CPT pro-edure code used for the surgical treatment ofsteonecrosis is 21025. However, we decided toxtend the search to all CPT codes that identifyajor surgical procedures in both mandible andaxilla, irrespective of implied causation. Thus, the

ollowing CPT codes were also studied: 21015,1026, 21034, 21040, 21045, 21046, and 21047.We calculated descriptive statistics, including me-

ian age and median time to event after first dispens-

ng. We also calculated crude and stratified odds ratios

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nd the corresponding 95% confidence intervals (95%I), by comparing users versus nonusers, which areresented in Table 1.

esults

The study used data from years 2001 to 2004. Med-cal claims from 255,757 cancer patients with breast,ung, or prostate malignancies or multiple myeloma

ere analyzed. We identified 224 cases of jaw sur-ery; of those, 39 cases were found among 26,288 BPsers and 185 cases were found among 229,469 nev-r-users. Intravenous BP users tended to be slightlylder (median age, 64 years) than oral BPs users (me-ian age, 59 years). In both modes of administration,he age difference between cases and controls wasot statistically significant. Median time lapse be-ween first dispensing and day of surgery was 58eeks (409 days) for IV drugs and 44 weeks (308ays) for orally administered drugs. The most preva-

ent CPT procedure code was the code 21025 (52% oflaims), which was always associated with ICD9 diag-ostic codes that were compatible with inflammatoryr necrotic processes (9092, late effect of radiation;3020, 73018, 73028, osteomyelitis; and 5264, inflam-ation of the jaw). Confirming the actual cause that

Table 1. COUNTS AND CRUDE OR (95% CI) FOR JAW SBISPHOSPHONATE ADMINISTRATION AND CANCER IC

Cancer Diagnosis Surgery No BP

ancer (total)‡ Surgery 18No surgery 229,28

reast cancer Surgery 5No surgery 101,25

ung cancer Surgery 5No surgery 42,85

rostate cancer Surgery 6No surgery 86,47

ult. myeloma Surgery 1No surgery 6,13

*J codes specific for zoledronic acid (Zometa; Novartis) and pam†CPT codes specific for alendronate (Fosamax; Merck) and rised‡ICD9 codes specific for breast cancer, lung cancer, prostate ca§P � .05.

avras and Zhu. Is it Osteonecrosis? J Oral Maxillofac Surg 2006

ed to the surgical procedure is beyond the scope of i

his preliminary article. In the near future we plan tobtain institutional review board approval to examinehe actual medical records to validate the claims data.

We identified 20 cases among 5,850 users of pam-dronate or zoledronic acid. Our results indicate thatV BPs lead to a significant 4-fold increase in the oddsf having surgery (95% CI, 2.67-6.72). A stratifiednalysis by type of cancer revealed large statisticallyignificant increases in breast and lung cancer and arend of increased risk in prostate and multiple my-loma. Individuals with breast cancer had 6 timesigher risk of receiving jaw surgery as compared withonusers (95% CI, 3,07-11.72), followed by lung can-er patients (odds ratio [OR], 2.7; 95% CI, 1.09-6.80).In regards to oral BP administration, we identified

9 cases among 20,438 individuals exposed to alen-ronate or risedronate, as compared with 185 casesmong the unexposed group, namely those 229,469ancer patients with no claims for (any) BP. Becauseral BPs are indicated for the clinical management ofsteoporosis, individuals with claims for alendronater risedronate were probably treated for osteoporosisefore the occurrence of cancer. The statistical eval-ation showed that orally administered BPs tend to

ncrease the odds ratios by 15%, but this increase isot statistically significant; the confidence intervals

RY CLAIMS, STRATIFIED BY MODE OFGNOSES

Mode of Administration

Intravenous* Oral†

20 195,830 20,419

ORcrude � 4.24§ ORcrude � 1.1595% CI, 2.67-6.72 95% CI, 0.71-1.84

10 132,904 16,266

ORbreast � 5.99§ ORcrude � 1.3995% CI, 3.07-11.72 95% CI, 0.76-2.54

5 41,486 2,509

ORlung � 2.72§ ORcrude � 1.2895% CI, 1.09-6.80 95% CI, 0.47-3.56

1 2753 1,774

ORprost � 1.69 ORcrude � 1.4395% CI, 0.23-12.14 95% CI, 0.35-5.84

7 21,568 503

ORmmyel � 1.61 ORcrude � 1.4395% CI, 0.67-3.87 95% CI, 0.33-6.19

te (Aredia; Novartis).(Actonel; Procter & Gamble and Aventis).

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When we stratified by radiation therapy status (dataot shown), the findings were persistent and mainlyonfined to those who had no claims for radiationreatment. IV users who were radiation-naive exhib-ted a statistically significant 6-fold increase in the riskf having jaw surgery (ORIV � 6.48; 95% CI, 3.8-11.1).similar trend was noted for those on alendronate or

isedronate, but the effect was smaller and not statis-ically significant (OROral � 1.54; 95% CI, 0.9-2.6).

iscussion

Inferences from observational epidemiologic stud-es are subject to 2 factors, confounding (especiallyhe unmeasured confounding) and bias. Inferences aso the clinical role of BPs in ONJs are limited byeveral factors intrinsic to our study. The aim of thetudy was to provide preliminary data regarding therequency of surgical procedures and to evaluate theisk of surgery in the BP strata of cancer patients.

Given the nature of the claims data, we have strat-fied in broad categories of confounders (ie, cancerypes or use of radiation oncology services). Furtheresearch is needed to identify detailed data on thoseonfounders to allow for adequate control. For exam-le, because radiation therapy seems an importantonfounder in this study, a second phase should re-iew the medical records to identify exactly (andontrol for) the radiation therapy protocol that wassed, including date of initiation, dose, field, andrequency. The same applies to concomitant chemo-herapy, especially the use of antiangiogenics. In re-ards to bias, claims data are often vulnerable toisclassification. Misclassification of the outcome

surgery) is one such source of bias. Surgery is wellaptioned in administrative claims because of theigh cost associated with it, and the potential forudit by insurance. It is also possible that some of theancer patients who had initiated BP treatment mightave changed insurance carriers and thus their surgi-al outcome data were not captured in the claims.lthough this is a well-described problem in medicallaims analyses, we also know that the problem is lessignificant among cancer patients. Cancer patientsend to maintain their existing insurance coverage; aew application would carry a risk of higher insur-nce premiums due to pre-existing conditions. Mis-lassification of the exposure (BP use status) is an-ther potential source of bias. Misclassification of thexposure can occur if: 1) BP use is not recorded andhus, those individuals are coded as nonusers, and 2)f nonusers have claims for BP dispensing, and thusre coded as users. Given the high costs associatedith BP therapy along with its repeated and chronicse, we believe that misclassification of the exposure

oes not present a significant problem in this study. p

owever, given the limitations, our results should beegarded as descriptive and hypotheses-generatingnd should be interpreted with caution.

The biology of this elusive disease remains un-nown. Dispensing of BPs in patients with a highrobability of metastatic disease to the mandible cre-tes a question about the underlying presence ofome form of malignant process. Similarly, it is wellocumented that both chemotherapy and radiother-py are risk factors for osteonecrosis. The exposure tooxic chemotherapeutic agents and the exposure tocattered radiation to the head and neck increases thehance of bone necrosis even without the presencef BPs.One of the hypothesized reasons for bone necrosis,

specially in the mandible, is compromised bloodow and lack of oxygenation. As BPs seem to haventiangiogenic properties, there might be a synergis-ic effect to further affect a vascular endothelium thats already compromised by chemotherapy. In a seriesf in vitro and in vivo experiments, Fournier et al24

howed that BPs inhibit endothelial cell function.fter treating endothelial cells with several types ofPs, the authors noted reduced proliferation, in-reased apoptosis, and decreased capillary-like tubeormation in vitro. Then, they replicated the findingsn vivo by using a rat angiogenesis model and foundhat zoledronic acid induced a 50% reduction of re-ascularization. Although this strong antiangiogenicroperty is of value to oncologists, especially in theanagement of solid tumors of the lung and prostate,ore studies are needed to evaluate blood vessel

mmunostaining on the mandible.A different pathway to decreased ischemia would

e through the induction of osteopetrosis, a conditionharacterized by dense, poorly formed and brittleone. Whyte et al25 report a pediatric case of osteo-etrosis in a 12-year-old child on prolonged pami-ronate therapy. The patient, who had received aotal of 2,800 mg of pamidronate over a 2.75-yeareriod, developed club-like metaphyses because ofefective osteoclast action. Instead of dissolving, therimary spongiosa had become encased in trabecularone. His serum acid phosphatase was significantlylevated along with his creatine kinase BB-CK. Afterxtensive genetic screening and in the absence of anyongenital disease, the authors concluded that thisas an acquired osteopetrosis.The traditional concept of ischemia as a key etiol-

gy in osteonecrosis is challenged by the observationhat, in contrast to osteoradionecrosis which uni-ormly affects the lower jaw, BP-associated osteone-rosis is not limited to the mandible. It affects theaxilla in as many as 40% of the reported cases.ellstein and Marek17 propose an alternative etiologic

athway to explain their histopathologic finding of

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ntact vascular channels. According to these authors,t is the affected osteoblast/osteoclast axis that resultsn compromised bone with diminished adaptability.uch poorly formed bone is vulnerable to internalmmune insults or to external bacterial insults preva-ent in the oral cavity.

Because of the rarity of the condition, most of theublished literature consists of anecdotal reports orell-characterized case series. The published case se-

ies presented very valuable information on the clin-cal problem and the historical use of BPs amongatients with ONJ. The vast majority of investigatorsocument cases of osteonecrosis that occur almostniformly among BP users. They also note that the

ncrease in ONJ coincides with the advent ofoledronic acid administration. Some of the inherentimitations of the case series are that the informations always retrospective and they lack appropriate con-rols for comparisons. In the majority of the reportedases, osteonecrosis is diagnosed at a late stage, afterymptoms have already occurred and necrosis hasrogressed considerably. More studies are needed toocument some of the early signs of disease or earlyadiographic findings to observe the degree of ossifi-ation or the potential presence of osteopetrotic find-ngs. Currently, it is difficult to evaluate the biologicarameters of this condition in great detail.Temporal sequence, having the exposure occur-

ing before the disease, is a required criterion tostablish causation. In our study, we evaluated onlyndividuals who had received BPs before receivingurgery of the mandible or the maxilla.

Dose-response is often considered one of the essen-ial criteria in evaluating causation. In our study, webserved high increases in the risk of having surgerymong IV BPs and lower increases in the risk for oralPs. Intravenous BPs are more potent than the oral,nd their effects last longer. Although we did noterform a formal test for dose-response, the large

ncrease in risk associated with IV BPs is consistentith a dose-response phenomenon. However, more

tudies are needed to calculate a standardized totalifetime dose of BPs.

Given the results of our study and the observationsf others that ONJ occurs more frequently in BP-xposed individuals, is it possible that a correlationxists, as opposed to causation? In an interestingxperiment, Astrand and Aspenberg6 showed that anncreased dose of alendronate prevents resorption ofecrotic bone in rats and gives time for new bone

ngrowth. If this is indeed true in humans, one mightypothesize that BPs just delay the appearance oflinical symptoms in individuals with osteonecrosisecause of a delay in structural failure of the bone. Inur study, we documented that the probability of

aving surgery (and perhaps structural failure) was

ncreased in those receiving BPs, especially IV. If BPsave no association with bone death, the only plausi-le explanation of such observed association mighte differential prescription of BPs in those at high riskor osteonecrosis, a condition that is often called “biasy indication.” Evaluating the risk/benefit of suchypothesized effect is complex. Prolonging the timeo experience symptoms seems beneficial only tohose individuals who will not survive the time re-uired for structural failure to manifest; although clin-

cal trials have shown high mortality rates, survivalime is difficult to predict on an individual basis (thusegating the above clinical strategy).Irrespective of causation, one needs to know the

ncidence of jaw osteonecrosis in cancer patients be-ause diagnosed ONJ directly affects survival and theatients’ quality of life. Currently, it seems that osteo-ecrosis remains undiagnosed to a large extent. Thisnding is probably true for our study, which reflectsoutine clinical practice. We found 1 affected individ-al for every 292.5 IV users (20 out of 5,850), or.34%. In other surveys, incidence ranged from 2% to0%.15 A longitudinal follow-up study is needed toapture the exposed and unexposed person timeith accuracy, along with early disease. Pharmacoge-etic evaluations should be nested within the pro-pective studies, and patients should be asked torovide DNA to evaluate biomarkers of genetic sus-eptibility. In the meantime, all patients who haveeceived IV BPs should be screened for radiographicigns of ONJ as soon as possible and at least biannuallyhereafter.

This is a preliminary report of an increased risk ofaw surgery in patients receiving IV or oral BPs. Aumber of confounders may explain this association,

ncluding radiation oncology (eg, type, dose) and con-omitant chemotherapy. Both have previously beeninked to an increased risk of bone necrosis. Moretudies are needed to characterize the group thatevelops osteonecrosis along with the risk factors andhe biologic pathways that lead to osseous necrosis.

cknowledgments

The authors did not receive pharmaceutical industry funding forhis project. Preparation of the manuscript was partially supportedy the National Institute of Dental and Craniofacial Researchhrough a Career Transition Award to Dr Zavras and by Ingenixhrough its contribution of the medical claims data. The authorshank Dr Alexander Walker and Dr John Seeger of i3 Epidemiologyor their valuable review and comments.

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ZAVRAS AND ZHU 923

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5. Brixen K: Bisphosphonates as a potential treatment for osteo-genesis imperfecta. Proceedings of the OIFE meeting, Septem-ber 25-26, 1998. Vingsted, Denmark. Available at: www.brandx.net/markgash/bispho.html. Accessed February 24,2006

6. Astrand J, Aspenberg P: Systemic alendronate prevents resorp-tion of necrotic bone revascularization. A bone chamber studyin rats. BMC Musculoskelet Disord 3:19, 2002

7. Gralow J: Evolving role of bisphosphonates in women under-going treatment for localized and advanced breast cancer. ClinBreast Cancer 5:S54, 2005 (suppl 2)

8. Bone HG, Hosking D, Devogelaer JP, et al: Alendronate PhaseIII Osteoporosis Treatment Study Group. Ten years’ experi-ence with alendronate for osteoporosis in postmenopausalwomen. N Engl J Med 350:1189, 2004

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