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J Oral Maxillofac Surg68:337-343, 2010

The Nature and Frequency ofBisphosphonate-Associated Osteonecrosis

of the Jaws in Dental Implant Patients:A South Australian Case Series

Alastair Goss, DDSc, FRACDS(OMS),*

Mark Bartold, DDSc, FRACDS(Perio),†

Paul Sambrook, MB, BS, FRACDS(OMS),‡ and

Peter Hawker, BDS, MS§

Purpose: To determine the number of bisphosphonate-associated cases of dental implant failure inSouth Australia.

Materials and Methods: All general and specialist dentists who place dental implants in SouthAustralia were contacted and asked to provide information on the total number of implants placed overthe decade to December 2007. Cases of bisphosphonate-associated implant failure were identified.

Results: All 46 practitioners involved in implant placement and the management of bisphosphonate-associated osteonecrosis of the jaws in South Australia were identified. Approximately 28,000 implantshad been placed in 16,000 patients. We identified 7 cases of oral bisphosphonate–associated implantfailure, with 3 cases of failure of osseointegration and 4 cases of successful implants losing integrationafter being placed on oral bisphosphonates. There were 5 women and 2 men, and the mean age was 65.7years (range, 49-75 years). Only 1 was medically compromised, with steroids and diabetes. No cases ofimplant failure in intravenous bisphosphonate cases were identified. On the basis of the assumption that5% of the patients were taking an oral bisphosphonate, 1 in 114 (0.89%) had implant failure.

Conclusion: In patients taking oral bisphosphonates, a failure to integrate or subsequent loss ofintegration may occur when oral bisphosphonates are started after successful implant placement. Therate of failure is low, at less than 1%.© 2010 American Association of Oral and Maxillofacial Surgeons

J Oral Maxillofac Surg 68:337-343, 2010

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here is controversy as to whether it is safe to placemplants in patients taking bisphosphonates for boneiseases. On the one hand, case reports of patientsaking bisphosphonates who either had implants thatailed to integrate or had integrated implants thatubsequently failed have been reported.1-3 Conversely,tudies with moderate numbers of consecutivelylaced implants in patients taking oral bisphospho-ates, albeit for relatively short periods of time, have

*Professor and Director, Oral & Maxillofacial Surgery Unit, The

niversity of Adelaide, Adelaide, Australia.

†Professor and Director, Periodontics Unit and The Colgate Aus-

ralian Clinical Dental Research Centre, The University of Adelaide,

delaide, Australia.

‡Senior Lecturer, Oral & Maxillofacial Surgery Unit, The Univer-

ity of Adelaide, Adelaide, Australia.

§Specialist Prosthodontist, Private Practice, Adelaide, Australia.

Dr Goss has provided advice to Merck (Australia and interna-

ionally), Novartis (Australia and internationally), and Sanofi Aventisd

337

eported that no problems developed.4,5 This issue ofisphosphonate-associated implant failure is clearlyot a simple matter but is a complex inter-relationith the bisphosphonates and their effects on the

aws interacting with implant integration and theaintenance of integration mechanisms.Bisphosphonates have been widely prescribed over

he last decade for a range of bone diseases, mainlyntravenously for bone cancers and orally for osteo-

Australia). He is an expert in a bisphosphonate class-action lawsuit

United States and Australia).

Address correspondence and reprint requests to Dr Goss: Oral

nd Maxillofacial Surgery Unit, Faculty of Health Sciences, The

niversity of Adelaide SA 5005, Australia; e-mail: oral.surgery@

delaide.edu.au

2010 American Association of Oral and Maxillofacial Surgeons

278-2391/10/6802-0017$36.00/0

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338 BISPHOSPHONATE IMPLANT FAILURE

orosis.6 The initial data on their effectiveness andafety were impressive, with studies involving a min-mum of 20 million patient-years not showing anyaw-related problems. However, in 2003 a number ofeports appeared in the United States7-9 and Austra-ia10 of osteonecrosis of the jaws (ONJ) in patients

ainly taking intravenous bisphosphonates. The Aus-ralian report, however, concerned patients who hadeen taking oral bisphosphonates for long periods ofime.10 Bisphosphonate-associated ONJ is defined asn area of exposed bone of more than 8 weeks’uration in a patient taking a bisphosphonate forone disease. Exclusions include the presence of ma-

ignancy at the site of the jaw bone exposure andatients who have had radiotherapy to the jaws.isphosphonate-associated ONJ may range from aainless prolonged healing to a seriously painful andebilitating condition that lasts for many years with-ut resolution. Treatment is difficult, and conven-ional surgical treatment for microorganism osteomy-litis of the jaws or osteoradionecrosis of the jaws failsn cases of bisphosphonate-associated ONJ. Indeed,urgical curettage usually makes ONJ worse. Success-ul strategies include cessation of the bisphosphonateith symptomatic treatment with mouth rinses and

ntibiotics as indicated, and this may resolve the con-ition over many months or years.11

Bisphosphonate-associated ONJ has been exten-ively investigated since 2003, with considerablerogress having been made on its nature, frequency,nd management. Although it is still controversial aso precisely how the bisphosphonates work, gener-lly it is accepted that they prevent osteoclast action,ith consequent cessation of osteoblast activity, so

hat the bone turnover is markedly reduced or ceased;here are also reductions in angiogenesis.11-13 In theong bones and spine these actions have the desiredffect of progressively increasing the density of osteo-orotic bone back toward a more normal structure.ith bony malignancy, the bisphosphonates prevent

rogressive bone resorption, thus reducing extensionf the bony metastasis and decreasing pain.Bisphosphonates have similar effects on the jaw

ones, but given that the bone turnover of the alve-lus is up to 10 times greater than that of the longones, there is a more marked reduction in boneurnover.11,13 There are also differences in the naturef jaw osteoclasts as compared with the long bones,nd lastly, the jaw bones are covered by a thin layer ofucoperiosteum from the bacterially infested oral

avity.11,13 When simple oral wounds such as extrac-ions occur, bacteria can freely enter into the socketnd the bone is unable to react, thus triggering ONJ,hich always commences at the alveolus.11,13

In a large Australian study, the frequency of ONJ

ccurring after extractions was estimated at 1 in 296 u

o 1 in 1,130 extractions in patients taking oralisphosphonates.14 The rate of ONJ is much higher inatients receiving intravenous bisphosphonates andas been calculated as occurring in 1 of every 11 to 15xtractions. The original data for this study have sub-equently been externally audited and confirmed.14

imilar results have been subsequently shown inther studies.15,16

Dental implants have revolutionized the manage-ent of tooth loss, and they have been shown to havehigh rate of success when technically correctly

mplanted into the jaws.17,18 Although the successate varies with the position in the jaws and whetherncillary procedures are performed, the success rates generally 95% or better. The successful integrationf an implant to the jaw bones involves 3 phases, therst being osteoconduction, which relies on the recruit-ent and migration of osteogenic cells to the implant

urface. The second healing phase is the formation ofew bone at the junction between the pre-existingone and the implant. These 2 healing phases, osteo-onduction and new bone formation, result in contactsteogenesis against the implant surface. There is ahird healing phase of bone remodeling, which essen-ially involves renewal of the bone and its contact tohe implant surface.19 Given that bisphosphonatesignificantly reduce bone turnover, it is not surprisinghat a patient taking bisphosphonates may have aroblem with integration occurring in the first phaser, if the implants are already successfully integrated,hen there can be a marked delay in bone healing andhus the potential for loss of integration to occur.ccordingly, from this brief review, it is apparent that

or some patients whose alveolus is affected byisphosphonates, implants will either fail to integrater subsequently lose integration.The main difficulty with studies on this issue is

btaining a large enough prospective sample to de-ermine the rate of failure. Statistically, if an adversevent occurs at a rate of 1 in 100 and one requires atatistical level of significance of P � .05, then a veryubstantial number is required, over 10,000 patients,n each arm of the study to obtain statistical signifi-ance. Studies of this size are not possible in a singleenter. However, in a population sense the low riskill result in a large number of cases because theumber of individuals taking bisphosphonates is high.n Australia approximately 5% of the population isaking bisphosphonates. An alternative strategy torospective studies is to retrospectively review a

arge number of implant cases and determine theumber with bisphosphonate-associated failure. Thisequires the ability to capture all of the patients in-olved in a defined location so that one can reliablyetermine risk. South Australia has a number of

nique features that make such a study possible. Al-

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GOSS ET AL 339

hough the state is large, 2.4 times the size of Texas,he population is small, at 1.6 million persons.20 Sev-nty-five percent of the population resides within 20m of the central business district of the state capitalf Adelaide.20 All major health centers, including allhe dental specialists, are in Adelaide. The dentalrofession is cohesive and has a strong tradition ofontinuing education. The nearest other metropolitanenters of dental specialists are Melbourne, which is05 km to the east, and Perth, which is 2,134 km tohe west. The smaller regional towns either lack spe-ialists or have visiting specialists from the metropol-tan centers.

The aim of this study is to determine the totalumber of implants placed in South Australia and toetermine the number of bisphosphonate-associatedailed implant cases; by this means, the frequency ofhe adverse event can be reliably calculated.

aterials and Methods

A postal questionnaire was sent to the all of the oralnd maxillofacial surgeons, periodontists, prosthodon-ists, and general dental practitioners with large im-lant placement practices in South Australia. Theuestionnaire consisted of a cover letter describinghe nature and purpose of the study and requestednformation on the total number of implants placed,n particular over the last decade or longer if knowny the participants. They were also asked to provideetails on any potential cases of bisphosphonate-asso-iated implant problems. The study was also dis-ussed at local specialist meetings.The questionnaire was followed up by direct per-

onal contact, and the case records of the potentialisphosphonate-associated implant problems were re-iewed. The identified patients were also interviewednd data were obtained from their general dental andedical practitioners as required.The data were recorded on a standalone personal

omputer, and appropriate statistical calculationsade. The study had the ethical approval of our

nstitution.

esults

Forty-six dental practitioners were identified aslacing more than 50 implants per year in Southustralia and/or were likely to see and treat patientsith bisphosphonate-associated ONJ. All fully coop-

rated with the study, and there were no exclusions.ix of the implantologists had been placing implantsor over 2 decades, but most had been active mainlyn the last decade. Records range from standalone full

mplant databases to the patients’ general records. y

he latter cases were cross checked against implanturchases and fee records.The total number of implants placed was approxi-ately 28,000 implants in 16,000 patients. The num-

er of implants was informally confirmed as beingonsistent with industry records from implant suppli-rs to South Australia.Initially, 12 patients were identified as having

isphosphonate-associated problems, but 5 were ex-luded after investigation because either they wereuplicates or they were not taking a bisphosphonate

n the relevant period. Seven cases of bisphospho-ate-associated implant failure were identified; thesere described in Table 1 and Figures 1, 2, and 3. Thereere 5 women and 2 men, and the mean was 65.7

ears (range, 49-75 years). One was immunocompro-ised, with steroids and diabetes, but the others wereealthy with only minor medical comorbidities. Threeere taking bisphosphonates at the time of implantlacement, although this had not been either knownr considered significant by the implantologists. Inhese 3 the implants failed to integrate; it was only athis point that the significance of the bisphosphonateas appreciated by the implantologist in 1 case. In

he other 2, the patients first noted the connection.ne heard a radio interview about bisphosphonate-

ssociated implant problems, and another realized theignificance of her medication when she was discuss-ng her problems with a friend who had a healthackground.Four patients had successfully integrated implants

laced before they were diagnosed as having osteo-orosis. They were medically prescribed an oralisphosphonate, and some of their implants subse-uently lost integration and failed. In the case of the

mmunocompromised patient, who was a medicalractitioner, he self-diagnosed the cause of the prob-

em. The failure occurred within 12 weeks of whenhe patient began taking the bisphosphonate, whenhe implant fell out. However, he had had minorroblems with the implant before the commence-ent of the bisphosphonate. The others were slow,rogressive failures, and it took some time for the trueature of the problem to be determined. None of theedical practitioners who prescribed the bisphos-honates were aware that the patients had implantsr that there potentially may have been a problem.hen the implant showed problems, 6 of the patients

nderwent attempts by the implantologist to salvagehe implant by surgery and antibiotics. Two had ag-ressive bone grafting procedures. All of the attemptst salvage failed and indeed hastened the loss of themplants.

Three patients had been taking alendronate forver 3 years, with a mean of 5.2 years (range, 3-10

ears), and one who was immunocompromised had

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340 BISPHOSPHONATE IMPLANT FAILURE

een taking alendronate for only 12 weeks. Twoad been taking risedronate for 5 years each. One hadeen taking risedronate for 10 weeks but previouslyad been taking alendronate for approximately 5ears, with a gap to when the risedronate was started.o patients were receiving intravenous bisphospho-ates.The calculated rate of implant failure in the whole

roup is 1 in 2,286 patients (0.04%). On the basis ofhe assumption that 5% of the population was takingisphosphonates, the calculated rate of implant fail-

IGURE 1. Computed tomography scan in case 1. A hydroxyap-tite-coated implant was placed in the left maxillary first molar siteith sinus lift and autogenous bone. It failed to integrate at theuccal site with oroantral communication. It was integrated on thealatal side. Two attempts at surgical salvage made the situationorse.

oss et al. Bisphosphonate Implant Failure. J Oral Maxillofacurg 2010.

IGURE 2. Computed tomography scan in case 3. A titaniummplant was placed in the left mandibular first incisor site. It failedo integrate and was painful. One attempt at surgery made theituation worse. The implant was removed with light fingerressure.

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re for patients taking oral bisphosphonates is 1 in14 (0.89%). This is higher than the rate for dentalxtractions.14

iscussion

The study shows that there is a risk of failure ofmplants related to oral bisphosphonates. This mayccur either when there is a failure to integrate when

mplants are placed in patients taking oral bisphos-honates or when there are existing integrated im-lants and the patient subsequently prescribed beginsaking oral bisphosphonate for osteoporosis. The risks relatively low, less than 1%, but is devastating to theatient. The study also helps explain the dichotomyetween the few reported cases of bisphosphonate-ssociated implant failure and prospective studies thatave not shown evidence of problems.4,5 This high-

ights the difficulty of developing a study of sufficientower when the frequency of the problem develop-

ng is low. However, there are large numbers of pa-ients in our aging population having both osteopo-osis and implant placement for tooth loss. Implant

IGURE 3. A, Computed to-ography scan in case 4, withreviously integrated implant in

he left mandibular second pre-olar site. It was removed with

ight pressure. Imaging showedhe implant defect and surround-ng ONJ. B, Previously inte-rated implant in the left man-ibular second molar site, whichas removed with light pres-

ure. Imaging showed the im-lant defect and surroundingNJ, which was continuousith the left mandibular sec-nd premolar site. C, Extent ofNJ in left mandible. D, Im-lant in the left mandibular firstremolar site. It was mobile butttached. The dense surround-

ng bone should be noted. Themplant unloaded, with border-ine integration.

oss et al. Bisphosphonate Im-lant Failure. J Oral Maxillofacurg 2010.

oss and ONJ are devastating to the individual. t

There was full cooperation from all implantologistsn South Australia with the study to capture the re-uired data. The numbers were independently crosshecked by contact with the involved practitioners,nd the numbers of implants placed were informallyonfirmed as being consistent with industry sales. Anyatient with a bisphosphonate-associated implantroblem was identified and the details authenticatedy discussion with the patient and his or her variousedical and dental practitioners.As a group, the patients were all orally conscious,

ne was a medical practitioner, one was the sister ofdentist, and all had had successful occupations. Allad invested considerable time and finance in theireneral oral and implant state of health. All wereggrieved with the implant failure and in particularere concerned that neither the dental nor medicalractitioner had warned them that potentially thereas a problem.The main weakness of the study is that the number

f patients who had implants and were takingisphosphonates was not precisely known; thus theustralian community figure of 5% was used.14 Given

hat the target population for implant placement is

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lder, wealthy, and more oral and general health con-cious, the figure of 5% is probably an underestima-ion because the key group taking oral bisphospho-ate is also older and health conscious. Currently, inur practices, the percentage of patients takingisphosphonates presenting for possible implantreatment is higher than 5%. On informed-consentiscussions with the patient, the percentage de-reases for those who actually proceed to havingmplant placement. Strategies, besides consideringhe oral bisphosphonate as an absolute contraindica-ion, include having the patient re-evaluated medi-ally as to the need for the bisphosphonate treatmentr whether he or she can be managed alternatively.21

he serum beta cross laps test measures bone turn-ver and is a predictor of the risk of decreased boneurnover and ONJ.22 It is independent of the otherisk factors, such as age, medical compromise, anduration of bisphosphonate dosage. If the patientontinues to take a bisphosphonate, then the dosageould be adjusted so that the bone turnover is keptround 200 pg/mL and both the patient’s osteoporo-is is being controlled and osseointegration is noteing interfered with. This, however, has not beenhown in a prospective clinical trial. In this study 2atients had serum beta cross laps testing at the timef implant failure (patients 3 and 4). Both had valuesf less than 100 pg/mL, which indicates little or noone turnover.The main problematic group is patients who have

uccessfully integrated implants but in whom osteo-orosis then develops, who have not consulted withheir implantologists, and are prescribed oral bisphos-honates by their medical practitioner. If the medicalractitioners remember to enquire as to whether theatient is dentally healthy, then reasonably the pa-ients could respond in the affirmative. Given that theain difficulty is making medical practitioners even

onsider the patient’s oral health, it is currently prob-bly unrealistic to make them ask about the presencer absence of dental implants.23

The conclusion of this study is that there is a smallisk of additional implant failure for patients takingisphosphonates, over and above the other factors

nvolved in dental implant failure. The treating im-lantologist should give the patient complete infor-ation on the risks before implant placement. This

tudy provides guidance on the magnitude of the risk.hen implants either fail to integrate or lose their

ntegration, the medical history of the patient needso be taken again and in particular the history ofisphosphonate use checked. This should be doneefore attempts at salvage, because conventional sal-age techniques are likely to fail in patients takingisphosphonates. Consideration should be given to

hanging the management of the patient’s osteoporo-

is. If, with appropriate medical advice, it is possibleo cease the bisphosphonate and change the strategy,hen future implants are not contraindicated. Once aisphosphonate has been eliminated from the systemo an appropriate clinical level and bone turnover haseturned to a reasonably normal rate, then it is possi-le to consider placing further implants. This strategyas followed for 2 patients (patients 1 and 7) in this

tudy.Overall, given the low rate of failure of less than 1%

nd given that the general failure rate for implants isn the order of 5%, osteoporosis being treated withral bisphosphonates is a relative rather than absoluteontraindication to implant placement.

cknowledgments

The authors acknowledge the statistical advice of Dr Tobyughes, Statistician, The University of Adelaide, and the partialnancial support of the Australia & New Zealand Association ofral and Maxillofacial Surgeons Research and Education Fund.

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