Nature and Frequency of Bisphosphonate-Associated Osteonecrosis of the Jaws in Australia

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J Oral Maxillofac Surg65:415-423, 2007

Nature and Frequency ofBisphosphonate-Associated Osteonecrosis

of the Jaws in AustraliaTony Mavrokokki, BDS,* Andrew Cheng, BDS,†

Brien Stein, MBBS, FRACP,‡ and

Alastair Goss, DDSC, FRACDS(OMS), FICD§

Purpose: The purpose of this study is to estimate the frequency and describe the clinical characteristicsof patients diagnosed with bisphosphonate-associated osteonecrosis of the jaws (ONJ) in Australia.

Materials and Methods: Cases of ONJ were identified in 2004 and 2005 primarily by a postal surveyof Australian Oral and Maxillofacial Surgeons (OMS) with additional cases from other dental specialistsand the Commonwealth of Australia Adverse Drug Reaction Committee (ADRAC). The clinical charac-teristics were recorded. The frequency of ONJ cases was estimated from prescription and dentalextraction data. Univariate and bivariate statistics were calculated.

Results: One hundred fifty-eight cases of ONJ were identified. These were primarily in patients withbone malignancy (72%) and the main trigger was dental extraction (73%). The reported number of casesvaried between different Australian States with the highest frequency being reported in the States withthe best integrated health systems. The frequency of ONJ in osteoporotic patients, mainly on weekly oralalendronate was 1 in 2,260 to 8,470 (0.01% to 0.04%) patients. If extractions were carried out, thecalculated frequency was 1 in 296 to 1,130 cases (0.09% to 0.34%). The total dose of oral alendronate atthe onset of ONJ was 9,060 (�7,269) mg. The frequency of ONJ for Paget’s disease cases was 1 in 56 to380 (0.26% to 1.8%). If extractions were carried out, the calculated frequency of ONJ was 1 in 7.4 to 48(2.1% to 13.5%). The frequency of ONJ in bone malignancy cases, treated with mainly intravenouszoledronate or pamidronate was 1 in 87 to 114 (0.88% to 1.15%). If extractions were carried out, thecalculated frequency of ONJ was 1 in 11 to 15 (6.67% to 9.1%) The total dose of pamidronate was 3,285(�2,530) mg and zoledronate 62 (�54.28) mg at the onset of ONJ. The median time to onset of ONJ was12 months for zoledronate, 24 months for pamidronate, and 24 months alendronate.

Conclusions: Before the prescription of bisphosphonates for bone disease the patient should be madedentally fit so that the need for subsequent dental extractions is minimized. Appropriate informedconsent for the risk of ONJ for different bisphosphonates, for osteoporosis, and malignancy both ingeneral and in particular for dental extractions can be provided using this data.© 2007 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 65:415-423, 2007
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isphosphonate-associated osteonecrosis of the jawsONJ) was first reported in the North American liter-ture in 2003.1-4 Since that time multiple case reports

*Staff Dentist, Oral and Maxillofacial Surgery Unit, Adelaide Den-

al Hospital and University of Adelaide, Adelaide, South Australia.

†Registrar, Oral and Maxillofacial Surgery Unit, Royal Adelaide

ospital, Adelaide Dental Hospital and University of Adelaide, Ad-

laide, South Australia.

‡Medical Oncologist, Ashford Cancer Center, Ashford, and Uni-

ersity of Adelaide, Adelaide, South Australia.

§Professor and Director, Oral and Maxillofacial Surgery Unit,

oyal Adelaide Hospital, Adelaide Dental Hospital, Adelaide, and

rofessor of Oral and Maxillofacial Surgery, School of Dentistry,

niversity of Adelaide, Adelaide, South Australia.

415

ave been presented worldwide.5-15 It is evident thatNJ associated with bisphosphonates is uncommon

elative to the wide prescription of these medications

Professor Goss has acted as a consultant to Novartis (Interna-

ional and Australia) and to Merck (International and Australia).

r A. Mavrokokki has acted as a consultant to Novartis (Australia)

nd Dr A. Cheng to Merck (Australia).

Address correspondence and reprint requests to Dr Goss: Oral

nd Maxillofacial Surgery Unit, The University of Adelaide, Ad-

laide, Australia, 5005; e-mail: [email protected]

2007 American Association of Oral and Maxillofacial Surgeons

278-2391/07/6503-0008$32.00/0

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416 BISPHOSPHONATE-ASSOCIATED ONJ

or benign and malignant bone disease.7,14 Bisphospho-ates have proved very effective in bone disease man-gement with considerable easing of pain and minimi-ation of complications in the population treated.16-21

owever, when dental treatment is carried out, inarticular on older medically compromised patientseing treated for bone malignancy with potent nitro-en containing bisphosphonates, there is a risk ofsteonecrosis of the jaws. Beyond these broad gener-lizations, however, there are many unknowns.1-15

Bisphosphonates are prescribed widely in differentoses, potencies, and durations for a range of boneiseases including osteoporosis, Paget’s disease, orone malignancy. The registered indications for use inustralia (and many other countries) are metastaticone disease from breast, hormone refractory pros-ate cancer, and multiple myeloma. Extended trialsere conducted before the introduction of bisphos-honates to clinical practice but no cases of ONJ wereetected.17-21

The main reported initiating factor for ONJ is dentalxtraction although periodontal disease and denturerauma have been implicated.2,3,5,7,14,15 Some appar-ntly spontaneous cases have also been reported.2

Dental diseases are ubiquitous and the probabilityf patients having dental trauma and extractions isigh. ONJ presents a new challenge to the dentalrofession as previously bone diseases were periph-ral to the area of interest. There is now a commonisphosphonate-related condition where either the

ack of dental treatment or simple dental treatmentuch as extractions may result in a long-term intrac-able condition for which there is no single immedi-tely effective treatment.7,14,15,22 This has led to theevelopment of preventative proposals to optimizeral health and avoid dental extractions and other jawurgery. These proposals are currently based on ex-ert panel advice and are not evidence-based.23,24

vidence needs to be obtained and some clinical trialsave been started. An important unknown is the fre-uency of ONJ. Generally, when one looks at therequency of the bone conditions and the widespreadse of bisphosphonates, ONJ seems rare. General fre-uency figures of the wide range of 1 in 10,000 forsteoporosis to 1 in 10 for multiple myeloma have beeneported.10,14,24,25 The key issue, however, is the fre-uency related to dental interventions, in particularxtractions and possibly the duration of bisphospho-ate treatment.26,27 This frequency not only has im-ortant clinical implications, it also has importantedico-legal implications in those countries with ad-

anced legal systems.28

Australia has advanced medical, dental, and legalystems. Although the island continent is huge inrea, its population is small at 20.3 million. The bulk
f the population, however, is concentrated in the n
ajor metropolitan capital centers for each State,ith much smaller centers scattered through the rural

reas. The first bisphosphonate-associated ONJ casesere reported in 2003.29 Since that time there haseen a detailed case series on ONJ in South Austra-

ia.7,14 The State of South Australia is unusual in thatlthough it has a vast area (2.3 times the state ofexas), Adelaide is the single major metropolitan cen-

er. Seventy-five percent of the population of Southustralia reside within 15 kilometers of the Adelaideentral Business District. All specialist medical andental services are based in Adelaide with 2 majorroups of hospitals and a single Oral and Maxillofacialurgery service with close links between the publicnd private medical and dental systems. Hence it wastraightforward in early 2004 to communicate warn-ngs about the risk of ONJ to key stakeholders and toocate all cases within the State.14 Good State-basedrospective data collection has been developed forNJ.7,14 This has been broadened to include all ofustralia. Australia has a good national health systemnd the total number of prescriptions for bisphospho-ates is known.30 It also has a well-developed butoluntary adverse drug reporting system8 and a na-ional database on dental health. A national dentalnterview survey showed that in 2002, 62.5% of Aus-ralians received dental treatment and of these 15.4%ad dental extractions.31 These features have beensed in this study.The purpose of this study is to identify as many

ases as possible of bisphosphonate-associated ONJ inustralia. The demographics, drug type, and manage-ent of the cases and in particular the frequency

elated to different types of bisphosphonate, boneisease, and dental extractions are presented.

aterials and Methods

A 2-page survey form with a reply-paid envelopeas sent to all of the Australian members of theustralian and New Zealand Association of Oral andaxillofacial Surgeons (ANZAOMS). The cover letter

ndicated the reasons for the survey and gave recipi-nts the options of not participating, simply givinghe number of ONJ cases that they had treated, orroviding details of the cases treated. A working def-

nition of ONJ is an area of exposed bone in theawbones that fails to heal within 6 weeks in patients

ho are on bisphosphonates for bone disease. Thebsence of malignancy at the site of the lesion and thebsence of osteoradionecrosis32 are important exclu-ions. This definition and the nature of ONJ had beeniscussed widely in the oral and maxillofacial surgeonOMS) community before the survey. The diagnosis ofNJ was made by the respondent OMS and there was
o independent adjudication of cases. After 6 weeks a

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MAVROKOKKI ET AL 417

eminder was sent out to non-respondents and subse-uently an individual phone follow-up was carriedut.From responses to the survey it was apparent that

here were some other cases that had been managedy other dental specialists and these clinicians wereontacted directly for information. The Common-ealth of Australia Adverse Drug Reaction Advisoryommittee (ADRAC) was contacted and they pro-ided details of cases voluntarily reported to them byrescribers.These data elements were recorded on a non-net-orked personal computer. Comparisons of age, gen-er, drug, and disease were made to exclude doubleounting. The data were checked to confirm that theases recorded were consistent with the diagnosis ofNJ.

ESTIMATION OF ONJ FREQUENCY

The total number of prescriptions for all bisphos-honates in Australia was obtained from Medicareustralia of the Commonwealth of Australia.30 Theumber of patients receiving the drug was calculatedy dividing the number of prescriptions for osteopo-osis and Paget’s disease by 9 as the compliance of theonthly oral prescription is estimated at 75% (M.ttia, Merck Sharp Dohme–Australia, personal com-unication, March 2006). The total number of pa-

ients receiving bisphosphonates for malignancy wasore difficult to calculate as part receive it via Medi-

are-funded prescriptions30 and some from State gov-rnment-funded oncology sources. These data werebtained from a combination of Federal and Stateovernment pharmacy sources (C. Doecke, Royal

Table 1. FREQUENCY CALCULATIONS

enominator – No. of patientsPrescription data30

State prescription data for oncology patients (33%)Reduction for compliance and mortality, 75% benign

and 50% malignantumerator – No. of ONJ casesMinimum

● Survey data � ADRAC dataMaximum

● South Australian data extrapolation7,14

requencyONJ overallDisease state

xtraction dataTrigger 73%9.6% Patients having extractions31

requency ONJ by extractionsOverallDisease state

pavrokokki et al. Bisphosphonate-Associated ONJ. J Oral Maxil-

ofac Surg 2007.

delaide Hospital Pharmacy, personal communica-ion, July 2006).30 Malignancy patients on averageeceived 6 doses per year, this relating to compli-nce and morbidity. The frequency of ONJ per pre-criptions and per person was calculated both overallnd then further subdivided as to type of bone diseasend type of bisphosphonate prescribed. The percent-ge of Australians receiving dental treatment in aiven year and the percentage requiring dental extrac-ions was obtained from the Dental Research Unit ofhe Australian Institute of Health of the Common-ealth Government of Australia. This was used toetermine the number of patients in Australia requir-

ng extractions.31 The frequency of ONJ related toental extractions was then calculated. The informa-ion used to determine the frequency of ONJ is sum-arized in Table 1. To account for the attrition ofatients treated for malignancy where the total num-er of prescriptions is likely to underestimate theumber of people exposed, data from 1 community-ased center were gathered to see if current practiceirrors the data found in clinical trials.33,34

The South Australian subset,7,14 which was pro-pectively collected through a single center, showedhigher frequency than elsewhere in Australia and

he South Australian findings were extrapolated to theustralian population.

esults

One hundred thirteen questionnaires were mailedo all of the clinically active members of ANZAOMS,ith 94 (83%) responding. One hundred and three

ases of ONJ were identified with completed ques-ionnaires being provided for 78 cases. Many ques-ionnaires were incomplete. Hence the variable numbers reported in the tables. The survey was com-leted in September 2005. Only a few cases wereeported to occur before September 2003, hence thetudy period was 2 years. A further 6 cases weredentified as under the care of other dental specialists

ith 4 cases having detailed records. It was found that2 cases had identical age, gender, bone disease, andrug prescription profiles when the dental clinicianata were compared with the ADRAC data. Theseere considered duplicates and only counted once.fter duplicate exclusion ADRAC had reports of 49ases, with age, gender, drug, and bone disease beingdentified for 32. A total of 158 cases, with details on14, forms the basis of this study.The demographics of the ONJ cases are presented

n Table 2. This shows that predominantly patientsith ONJ were older, with malignant bone disease

nd on potent nitrogen-containing bisphosphonates.he presentation and treatment outcomes of ONJ are
resented in Table 3. Most cases were ongoing at the

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ime of completion of the survey. Six cases (7%) diedf their malignancy during the survey period.Chi-square tests were carried out between paired

ariables from Tables 2 and 3 and most were nottatistically significant. There was a weak correlationetween alendronate and mild/moderate ONJ as com-ared with pamidronate and zoledronate and severeNJ (P � .06).The relationship of ONJ cases to the different

isphosphonates and different bone diseases is pre-ented in Table 4. The average dose and range ofisphosphonate to the time of onset of ONJ is pre-ented in Table 5. The time of onset of ONJ is plottedn Figure 1. The duration of administration to onsetime was plotted against the cumulative frequency inach treatment group. This shows that there is aignificant delay in onset for the majority of casesmedian onset at 12 months with zoledronate, 24onths with pamidronate, and 24 months with alen-

ronate). Furthermore there is a significantly shorterime to onset with zoledronate (P � .0015 by log-rankesting of survival curves). The response and fre-uency by different Australian States is presented inigure 2.The total number of prescriptions for bisphospho-

ates in the year July 2003 to June 2004 was 2.34illion, of these 2.26 million (96.6%) were for osteo-orosis, 27,900 (1.2%) for Paget’s disease and 51,5002.2%) were for bone malignancy.30 In July 2004 toune 2005, there were 2.83 million prescriptions and

Table 2. DEMOGRAPHICS OF ONJ

N (%)

ge and gender (n � 114)Age (average, 66.8; range, 39-99 yr)Gender

Female 63 (55)Male 51 (45)

one disease (n � 114)Osteoporosis 26 (23)Paget’s disease 6 (5)Bone metastasis 51 (45)Multiple myeloma 31 (27)

isphosphonate (n � 114)Zoledronate* 43 (38)Alendronate 30 (26)Pamidronate* 20 (18)Pamidronate*/zoledronate* 13 (11)Risedronate 2 (2)Clodronate 2 (2)Alendronate/risedronate 2 (2)Pamidronate*/alendronate 1 (1)Zoledronate*/ibandronate 1 (1)

*Intravenous agents.

avrokokki et al. Bisphosphonate-Associated ONJ. J Oral Maxil-ofac Surg 2007.

iven the ongoing nature of bisphosphonate medica-Ml

ions this represents 2.34 million repeat prescriptionsnd 0.49 million prescriptions for new patients. Overhe 2-year period the total prescriptions for non-re-eat patients was 2.83 million, with 2.74 million forsteoporosis, 27,300 for Paget’s disease, and 61,500or bone malignancy.30

Patients prescribed oral bisphosphonates for osteo-orosis and Paget’s disease do not always completehe course with the compliance rate being estimatedt 75%. Hence the number of patients on oral bisphos-honates for osteoporosis is estimated at 304,900 andaget’s disease at 3,030.Patients with bone malignancy usually have the

rug administered intravenously but a drop-out rateelates to morbidity and mortality. The total numberf patients with bone malignancy from the Federalnd State sources was 12,970.30

The total number of patients identified with ONJas 158, with osteoporosis 36, Paget’s disease 8, andone malignancy at 114. This gives an overall fre-uency of 1 in 2,030, with 1 in 8,470 for osteoporosis,in 380 for Paget’s disease, and 1 in 114 for bonealignancy cases.In Australia, 62.5% of the population received den-

al care in 2002 and 15.4% had 1 or more teeth

Table 3. CLINICAL CHARACTERISTICS ANDTREATMENT OUTCOMES OF ONJ

N (%)

one Involved (n � 89)Mandible only 57 (64)Maxilla only 24 (27)Maxilla and mandible 8 (9)

rigger for ONJ (n � 112)Extraction 82 (73)Denture 6 (5)Spontaneous 23 (21)Mandible fracture 1 (1)

everity (n � 75)Mild* 22 (29)Moderate† 9 (12)Severe‡ 44 (59)

reatment (n � 82)Nonsurgical 22 (27)Curretage only 32 (39)Major surgical 28 (34)utcome (n � 83)Resolved 19 (23)Ongoing 58 (70)Death from malignancy 6 (7)

*Exposed bone and low grade pain only.†Exposed bone, severe pain and intermittent soft tissue infec-

ion.‡Extensive sequestration, severe continuous pain � pathologic

racture, orocutaneous fistula, severe neck infection, and weightoss.


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xtracted. This indicates that 9.6% of the populationave an extraction in any given year. Of the totalatients on bisphosphonates 30,800 would have hadn extraction. Most of these 29,270 have osteoporo-is, 290 Paget’s disease, and 1,245 with bone malig-ancy.The overall frequency of extraction-related ONJ is 1

n 270, for osteoporosis 1 in 1,130, for Paget’s diseasein 48, and 1 in 15 for bone malignancy.These frequency figures are summarized in Table 6.

hey represent the minimum risk of ONJ for patientsn bisphosphonates overall, for specific bone condi-ions and for the ONJ risk of patients on bisphospho-ates needing dental extractions.The South Australian experience was different as

his was a prospective capture of all of the knownases14 in the State. Of 25 cases, 10 were in osteopo-otics, 4 in Paget’s disease, and 11 with bone malig-ancy. The population of South Australia is 1.5 millioniving a population frequency of 1 in 60,000 people.f this experience is projected to the total Australianopulation of 20.3 million people then one wouldxpect 338 cases of ONJ with 135 in osteoporotics,4 Paget’s, and 149 with bone malignancy. When this

s compared with the patients on bisphosphonateshen the overall frequency is 1 in 930, with 1 in 2,260or osteoporotics, 1 in 56 Paget’s, and 1 in 87 for bone

Table 4. ONJ CASES STRATIFIED BY BISPHOSPHONATE

Drug Osteoporosis Paget’s

lendronate 22 3oledronate* – –amidronate* – 2amidronate*/zoledronate* – –isedronate 2 –lodronate – –lendronate/risedronate 2 –lendronate/pamidronate* – 1oledronate*/ibandronate – –

*Intravenous agents.

avrokokki et al. Bisphosphonate-Associated ONJ. J Oral Maxillo

Table 5. AVERAGE DOSE OF BISPHOSPHONATE TOTHE ONSET OF ONJ*

Drug No.Average Dose (mg) and

Range (mg)

oledronate 26 62 (4-240)lendronate 19 9,060 (900-26,100)amidronate 14 3,285 (630-8,640)

*Most common single drug regimens (�3 cases of ONJ and notossible to calculate the dosage for combinations).

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alignancy. Dental extractions as a trigger for 73%,ould result in 247 cases overall, 99 osteoporotics, 39aget’s, and 109 bone malignancy cases being relatedo extractions.

The overall maximum frequency of extraction-re-ated ONJ is 1 in 125, with 1 in 296 for osteoporosis,

in 7.4 for Paget’s, and 1 in 11 for bone malignancy.hese figures are summarized in Table 6.

iscussion

This study shows that bisphosphonate-associatedNJ is a recent and severe condition in Australia.iven the increasing frequency of osteoporosis as theopulation of Australia progressively ages then these of oral bisphosphonates is likely to increase. Sim-

larly the bisphosphonates have been shown to be anffective drug in the management of bone malig-ancy. ONJ is an ongoing and probably increasing

IGURE 1. Cumulative frequency of osteonecrosis in 59 patients inhom duration of therapy was known, grouped by therapy.

BONE DISEASE (N � 114)

onetastasis

MultipleMyeloma

TotalBenign

TotalMalignant Total

5 – 25 5 3027 16 – 43 43

9 9 2 18 208 5 – 13 13– – 2 – 21 1 – 2 2– – 2 – 2– – 1 – 11 – – 1 1

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hallenge that needs to be understood and strategieseveloped to prevent its occurrence.The patients identified in Australia were similar to

hose described previously in South Australia7,14 andhe United States.1-6,15 Patients were mainly olderith an average of 67 years and predominately withalignant bone disease (72%), the mandible wasore involved (64%) and the maxilla (27%), or in both

aws (9%). The most common trigger for bisphospho-ate-associated ONJ was dental extractions (73%).he Australian series had a lower incidence fromeriodontal disease, trauma to tori, or implant-relatedases than the American series.5,15,22,24 Most Austra-ian cases were severe (59%) and most were ongoing70%). There was an equal spread of nonsurgical27%), curettage (39%), and major surgical treatment34%). This probably reflected uncertainty as to theppropriate method of treatment, and with the ex-eption of the South Australian series, most oral andaxillofacial surgeons had experience of only a few

ases, ranging from 0 to 8.In South Australia, arrangements were put in place

arly so that all 25 cases reported in that State wereeen at the single Oral and Maxillofacial Surgery Unit

FIGURE 2. Responses by Australian State (n � 109).


Table 6. MINIMUM AND MAXIMUM FREQUENCY OF OEXTRACTION IS CARRIED OUT

Frequency of ONJ Per Patient Overall %

n bisphosphonatesMin 1/2,030 0.05Max 1/950 0.10n bisphosphonates having extractionsMin 1/270 0.37Max 1/125 0.80

avrokokki et al. Bisphosphonate-Associated ONJ. J Oral Maxillofac Su

t the major teaching hospital. Beside the bone ma-ignancy-associated cases of ONJ, the South Australianroup also reported 10 of 25 (40%) osteoporotic casesn weekly oral bisphosphonates, mainly alendronate,

n this study. The explanation of this is that the Oralnd Maxillofacial Surgery Unit in South Australia alsoonducts a large extraction clinic for public patients,hese are predominantly older, more medically com-romised patients and have more extractions as com-ared with the private sector. Early in 2004 a directiveas sent out to all the government-funded communityental clinics in South Australia that patients onisphosphonates requiring extractions should be re-erred to the specialist OMS unit. Hence a large groupf osteoporotic patients on bisphosphonates requir-

ng extractions were seen and postextraction healingvaluated carefully. It was found that osteoporoticatients on oral bisphosphonates usually have a lessevere form of ONJ that is likely to eventually resolvever a year. This is particularly so if the bisphospho-ates are withdrawn.7,14

It is noted that the distribution of South Australianases is different to the United States studies. Thearticular circumstances of health delivery allow foromplete capture of all cases from minor to major,hich is more difficult in larger and more compli-

ated populations and health centers. Although casesere not independently adjudicated, all were seen by

everal experienced clinicians.A detailed understanding of the frequency of the

omplication of ONJ is important so that medicalractitioners who prescribe bisphosphonates for os-eoporosis and bone malignancy can give their pa-ients appropriate advice and choice before com-encing bisphosphonate treatment. An important

spect is the patient’s oral health before commence-ent of bisphosphonates. Dentists need to under-

tand the issues to prepare patients before the com-encement of bisphosphonate therapy. In particular,atients who are already on bisphosphonates whoequire dental extractions need to be provided in-ormed consent about the risk of ONJ. Establishedases of ONJ require specialist management.

ERALL FOR DIFFERENT BONE CONDITIONS AND IF

eoporosis % Paget’s % Malignancy %

/8,470 0.01 1/380 0.26 1/114 0.88/2,260 0.04 1/56 1.8 1/87 1.15

/1,130 0.09 1/48 2.1 1/15 6.67/296 0.34 1/7.4 13.5 1/11 9.1

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To calculate the frequency of ONJ in the Australianopulation involves a combination of a number ofnown facts and assumptions (Table 1). The firstssumption is that when ONJ occurs, general medicalnd dental practitioners would refer the patient to anral and maxillofacial surgeon. Although this practice

s not universal this is the usual referral pattern. Theumber and contact address of oral and maxillofacialurgeons in Australia who are members of ANZAOMS,s known as this organization represents over 90% ofll registered OMS specialists in Australia. The retro-pective postal questionnaire was sent to all activeNZAOMS members in Australia. There was a variableesponse with the largest number of ONJ cases iden-ified in South Australia and Victoria and the lowestrom New South Wales. A similar pattern has beenoted in previous surveys unrelated to ONJ.35 Theesponse to the questionnaire showed varying de-rees of detail as is usual for retrospective clinicaluestionnaires. This was calculated by using the ac-ual response rate for each question, hence the vari-ble n numbers presented in the tables.

It was also indicated by some respondents that theynew that a few other specialists had patients withNJ and these were contacted and included. ADRAC

eceives voluntary reports from medical, dental, andharmaceutical sources, also has an Australian data-ase on this adverse reaction. Their data were ac-essed but was limited to age, gender, drug, andondition treated, without greater detail. When theuestionnaire and ADRAC data were compared, 22ases were removed as duplicates. By these means anstimate of the number of cases of ONJ in Australiaas determined.The total number of prescriptions for bisphospho-

ates per year is available from the Federal govern-ent agency responsible for prescriptions in Austra-

ia,30 with additional data from State and Federalources for bone malignancy cases (C. Doecke, per-onal communication). This is divided into the differ-nt types of bisphosphonates and also whether theyere prescribed for osteoporosis, Paget’s disease orone malignancy.The number of patients for whom the bisphospho-

ates are prescribed is not readily available but wasalculated with an adjustment for compliance, and inhe case of malignancy, for patient attrition fromeath or disease progression. By this means, the num-er of cases per prescription and per patient wasalculated. The estimated number of 304,900 (2004o 2005) and 251,000 (2003 to 2004) patients onisphosphonates for osteoporosis is consistent withhe most recent pharmaceutical company estimate of75,000 patients on alendronate (M. Attia, personal
omminication). 1
The number of malignancy cases for 2004 to 2005as 12,97030 that correlates with the pharmaceutical

ompany estimate (V. Ferrari, Novartis–Australia, per-onal communication, May 2006).

Shortly after the finalization of the survey the au-hors published a review for Australian general dentalractitioners14 and since that time more cases in gen-ral dental practice have been brought to the authors’ttention. ADRAC has had a further 69 cases, in addi-ion to the 49 reported in this study, in the periodeptember 2005 to May 2006. Of 118 cases, 64 (54%)elated to zoledronic acid. After a recent nationaledia report, health professionals and patients with

urther cases have contacted the corresponding au-hor.36

Although the frequency of ONJ per patient withone disease is important because the condition isriggered primarily by dental extraction and dentalisease, the frequency of ONJ to extraction is the keyariable. Australia has good data on dental disease andts management.31 The frequency of extractions doesot vary greatly over the adult age range. If onessumes that patients with bone disease have similarral health to the overall population then the assump-ion that in any one year 9.6% of patients will have aental extraction is a reasonable estimate.31 Thisould be particularly so for osteoporotic and Paget’sisease patients. Patients with malignancy are less

ikely to seek elective dental care in the active phasef their disease. Once they are in remission and feeletter then they may seek dental care, this may be aactor in the later presentation of ONJ.

The key question confronting a dentist about toxtract a tooth for a patient on bisphosphonates is,hat is the risk of ONJ? The overall frequency of ONJ

fter extraction is at minimum the risk determinedrom the survey and more likely maximum from thextrapolation to Australia of the South Australian data.Health professionals have an obligation under the

tate and Federal law to provide patients with in-ormed consent about their treatment.37,38 The con-ition of bisphosphonate-associated ONJ was notnown before 2003. Since then there has been littlenformation about the true frequency of ONJ andence the risk, particularly relating to extractions. Toate it has been difficult for health professionals torovide evidence-based information. This could beonsidered somewhat surprising in bone malignancyhere our frequency is about 1% and others reportigher.26 With an event frequency like this, one needsbout 3 times the number of patients to have the 95%onfidence limits exclude zero, thus 50 to 100 pa-ients in a trial arm should be sufficient. The trials ineoplastic diseases seemed to have sufficient powers typical numbers enrolled in treatment arms were
80 to 220.26,27,33,34 The time-dependent risk that this

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tudy and the study by Bamias et al26 find, requires uso consider the number of patients treated at length.his is considerably smaller, and in 2 large trials theatients completing 2 years of therapy varied from 3615% of the entry cohort)33 to 65 (�30%).34 Thelinical trials thus had a substantial chance of missinguch a side effect via chance, not to consider theossibility of missing the diagnosis in a group withhort survival and potentially many distracting symp-oms from their malignancies.

This study indicates that the overall risk for patientsn bisphosphonates (mainly oral alendronate) for os-eoporosis is low (Table 6). The patient generallyeeds to have been on the regular weekly oral doseor several years before ONJ occurs. The patienteeds to be warned and advised to be dentally fit. Ifhey need extractions or develop ONJ it is appropri-te for their physician to review their current osteo-orotic status. Consideration should be given to theithdrawal of the bisphosphonates, calcium and vita-in D continued, and if appropriate an alternative

gent may be required.Patients on bisphosphonates, usually intravenous

oledronate or pamidronate for bone malignancy,ave a higher risk of ONJ (Table 6). If extractionsere carried out, then the calculated frequency ofNJ ranges from 6.67% to 9.1%. These high risks muste balanced against the significant benefits of bisphos-honates for bone malignancy. It confirms that pa-ients being prescribed bisphosphonates for bone ma-ignancy should be made dentally fit to minimize theubsequent chance of extractions.

Two further considerations are raised by Table 4nd by Bamias et al.26 First, do bisphosphonates varyn their propensity to cause ONJ? Both suggest zole-ronate may carry a higher risk of ONJ. In the absencef a large prolonged comparative study this is unlikelyo be shown absolutely, but further data may supporthis theory. Second, duration of treatment may be anmportant predictor. There is likely to be some con-ounding in this inasmuch as patients will vary whenhey seek dental treatment in relation to onset ofisphosphonate treatment. With the majority of casesith alendronate or pamidronate occurring over 2

ears after starting treatment, however, this seemsnlikely.There is a need for further research on all aspects of

he bisphosphonates, their effect on the jaws andxtraction healing, the variation between the agents,nd the relationship between duration of therapy andisk. This retrospective postal survey with multiplessumptions and without independent assessment ofases, shows the need for prospective clinical trials.n the meantime however, if the patient is dentally fit
efore commencement of bisphosphonate therapy
nd oral health maintained without extractions, thenhe risk of ONJ should be reduced markedly.39

cknowledgments

The authors thank members of ANZAOMS for their assistance inesponding to the questionnaire and to ADRAC for the data theyenerously shared. The statistical advice of Dr D. Brennan androfessor A.J. Spencer, The University of Adelaide, is acknowl-dged. The constructive criticism and assistance of multiple boneetabolic, oncology, pharmaceutical, and dental colleagues, bothithin Australia and globally, are acknowledged.

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Documents

Nature and Frequency of Bisphosphonate-Associated Osteonecrosis of the Jaws in Australia