Borromeo et al. BMC Musculoskeletal Disorders 2011, 12:71 Page 2 of 10http://www.biomedcentral.com/1471-2474/12/71highlighted the possible association between bispho- Although ONJ associated with bisphosphonate usesphonate use, especially intravenous (IV) zoledronate or appears to resemble osteoradionecrosis seen followingpamidronate, and jaw osteonecrosis [15-21]. Other stu- jaw radiotherapy, they are now considered different dis-dies have not found any association between bishospho- ease entities . Conventional therapy of this latternate use and ONJ . A study assessing once yearly complication involves local debridement, irrigation andzoledronate for osteoporosis management in 8000 indi- antibiotics . However, this strategy has yieldedviduals reported, following separate case adjudication, a mixed results in bisphosphonate-associated osteonecro-single episode of ONJ in each of the placebo and zole- sis, and may contribute to further tissue breakdown,dronic acid groups . The length of this study was resulting in large fistulas .only three years whereas most ONJ has been reported While jaw osteonecrosis is a devastating end-stage out-in patients taking bisphosphonates for longer periods of come that is currently difficult to manage, various formstime. In a recent survey of over 8000 respondents, ONJ of delayed dental healing may be a less clinically dramatichad a prevalence of 0.10% (95% confidence interval and, therefore, poorly-recognised complications of0.05% to 2.0%) . Previously, similar but less frequent bisphosphonate use. Currently, the likelihood of dentalpresentations with jaw osteonecrosis occurred following complications during bisphosphonate therapy for treat-radiotherapy (Ruggerio et al., 2004) or occupational ment of post-menopausal osteoporosis or other benignexposure to phosphorus . In many of the reports, bone disease is uncertain. It is unclear what factors pre-jaw osteonecrosis occurred in the setting of malignancy, dispose patients to these events [36,37]. Given the largein particular, multiple myeloma [24-26] or breast cancer numbers of patients receiving long-term bisphosphonate[18,19,26]. Recent work has suggested that in myeloma therapy, particularly in benign bone disease, that a highpatients, zoledronate and pamidronate are associated level of professional and public concern has arisen aboutwith a 10% and 3% incidence of jaw osteonecrosis at the issue, and the fact that we are living in an ageing36 months, respectively . In contrast, the prevalence population making the likelihood of levels of osteoporosisof jaw osteonecrosis with bisphosphonate treatment in a increasing, understanding the prevalence and risk oflarge retrospective case series was 2.4% among myeloma bisphosphonates and jaw osteonecrosis is paramount.patients and 1.2% among breast cancer patients . There is some published evidence that chronic low- Hypothesisdose bisphosphonate treatment for osteoporosis or other The hypothesis to be tested is that long-term (morebenign bone disease is associated with jaw osteonecrosis than 1 year’s duration) bisphosphonate use for the treat-[18,27]. However, randomised controlled trials of ment of post-menopausal osteoporosis or other benignbisphosphonates in osteoporosis have not demonstrated bone disease is associated with impaired dental healing.an increased risk of jaw osteonecrosis. The developmentof ONJ has been linked to duration of exposure to Methodsbisphosphonates, and hence a higher cumulative dose, Study designlonger duration of treatment, hence prolonged survival, A case-control study has been chosen to test theas well as potential co-morbidities such as prednisolone hypothesis as the outcome event rate is likely to be veryor thalidomide use . Poor periodontal status low (Figure 1).together with dental interventions, in particular extrac-tions, implants or trauma from dentures for example, Definitionssignificantly increase the risk of developing ONJ in this Delayed dental healingpatient cohort [17,19,20,26,28]. Delayed dental healing (a precursor to osteonecrosis of The exact mechanism by which bisphosphonates may the jaw) is defined as a persistent breach in the oralcontribute to impaired resistance to injury or impaired mucosa and/or exposure of bone in the mandible orhealing of the maxilla or mandible and to osteolytic maxilla that:destruction, remains unclear. However, suppression of • fails to heal within 6 weeks as documented by a den-bone turnover via actions on osteoclasts seems to play a tist despite usual therapy;substantial role [29,30]. Bisphosphonates are not the • occurs either following a dental procedure, foronly medications with this action. Other drugs such as example a tooth extraction or crown insertion, or spon-denosumab (a RANKL antibody which is indicated in taneously, with or without osteonecrosis.cancer patients) and bevacizumab (a human monoclonal Osteonecrosis of the jawantibody to vascular endothelial growth factor) have the • Exposed bone in the maxillofacial area that occurredpotential to alter osteoclast differentiation and function in association with dental surgery or spontaneously withand as such has also been implicated in ONJ [31,32]. no evidence of healing
Borromeo et al. BMC Musculoskeletal Disorders 2011, 12:71 Page 3 of 10http://www.biomedcentral.com/1471-2474/12/71 Outcome CASES CONTROLS (disease = impaired (no disease = normal dental healing) dental healing) Exposure of interest Exposed to oral bisphosphonate ?? ?? therapy not exposed to oral bisphosphonate ?? ?? therapy XX YY Figure 1 Case-controlled study design. • No evidence of healing after 6 weeks of appropriate Dental Specialist Recruitmentevaluation and dental care Specialist dental recruitment will involve contacting • No evidence of the following bone pathology that all registered oral and maxillofacial surgeons andmight explain the findings: metastatic disease in the jaw special needs dentists who were actively practicing dur-or osteoradionecrosis. ing March 2006 through to the end of August 2006. All registered specialists listed in the Yellow PagesSetting and study time frames telephone directory will be cross-matched with thoseThe study will take place in Victoria, the second most currently registered with the Australian Health Prac-populous State in Australia with a population of titioner Regulation Agency. The researchers willapproximately 5 million people. The visit window period also present the study to a Victorian Branch meeting ofstudy period will be March 1st 2006 until August 31st the Australian and New Zealand Association of Oral2006. Participants in the study will have been treated in and Maxillofacial Surgeons. All public hospital dentalspecialist oral and maxillofacial and special needs dentis- specialty clinics in Victoria and associated specialisttry settings during the visit window period. Control sub- dental practitioners will be identified. All registeredjects will have attended local community based referring specialist dental practitioners will be invited to partici-dental practices. A flow diagram of the study protocol is pate in the case-controlled study via introductorydepicted in Figure 2. mail out.
Borromeo et al. BMC Musculoskeletal Disorders 2011, 12:71 Page 4 of 10http://www.biomedcentral.com/1471-2474/12/71 All OMFS in All SND Specialists in Victoria Victoria Decline Agree to Agree to Decline participation participation participation participation Screening of files meeting age and visit window criteria Identified potential cases to present to CAP no further No not a Yes a potential data case case collection invitation to participate Agree to participate Decline to participate (participating case) (non-participating case) telephone interview and no telephone medical information interview review Match for controls Match for controls from practice where from practice where case was referred case was referred (1:4 case:controls) (1:4 case:controls) Figure 2 Flow diagram of study protocol. Follow up of specialist non-respondents would occur by visit window period will be screened and only those meet-mail at 2-weeks and telephone at 4-weeks. Once specialists ing the age and visit window criteria will be reviewed foragree to participate, then the respective practice will be further potential case information. Once potential casescontacted to determine a suitable time to view patient files are determined then they will be presented to the Caseand identify potential cases. All files within the 6-month Adjudication Panel (CAP) (see further details below).
Borromeo et al. BMC Musculoskeletal Disorders 2011, 12:71 Page 5 of 10http://www.biomedcentral.com/1471-2474/12/71Case Recruitment Once verified as a definite case by the CAP, the indivi-Recruitment of individuals for the study is a two-step dual will be contacted via mail to seek informed writtenprocess, ascertainment of potential cases through dental consent for participation in the study. Non-respondersrecord review then verification by a case adjudication will consist of two main groups; individuals who do notpanel (CAP). The research team would visit each partici- wish to participate and those who cannot be contactedpating practice to identify potential cases from the den- (e.g. changed address or deceased).tal records, which could then in turn be presented tothe case adjudication panel. Each specialist practitioner Recruitment of Control Subjectswould be required to give consent to have patients in Each case will be matched with four controls randomlytheir practice contacted by the research team. selected from those who have undergone dental treat- Participant ascertainment will occur through consecu- ment at the same dental practice from which the casetive screening of oral and maxillofacial and special originated. If access cannot be obtained to recordsneeds dental specialist records in private practices and from the originating dental practice, then a similarpublic hospitals by trained research staff. Once a case type of practice e.g. private practice or hospital - basedhas been confirmed by CAP, each specialist practitioner practice, within a 10 km radius will be approached towould be required to give consent to have patients in provide control subjects. They will be matched for agetheir practice contacted by the research team. (>50 years), gender and visit window period and will To be eligible for participation, the dental record have no known defect in dental wound healing. If con-should indicate that the potential participant is: trols cannot be matched to the 6-month visit window • age ≥ 50 years period then they will be matched to within 12 months • has a dental wound that failed to heal within 6 weeks of the visit window period. Controls will be contacted • had a qualifying visit during the window period. by mail as for cases to obtain informed consent to The exclusion criteria are: study participation. • A history of active malignancy or malignancy withinfive years (excluding basal or squamous cell carcinoma). Data Collection Methods • Previous radiotherapy field that included the jaws. Data collection will involve collecting information per- • Bisphosphonate use for any indication other than taining to demographics, delayed dental healing, bispho-post-menopausal osteoporosis or other benign bone sphonate history and medical history. Data collectiondisease. forms and telephone interviews for controls will be the In order for potential cases to be identified from the same as that used for cases.patient files, the research team reviewing the clinical Part 1: Demographic informationnotes need to be able to identify delayed dental healing. Specialist information, patient details (name, date ofIt is expected that the term “delayed dental healing” as a birth, gender, address and telephone number), name ofpotential descriptor is unlikely to appear in the clinical referring practitioner, referring practitioner contactnotes, as there would be variability in clinical descrip- details, date of presentation of oral problem and referraltions amongst specialists. As such a number of file ter- to specialist date will be collected initially. A list of allminology descriptors will be used to help identify dates within the visit window period together with anpotential cases of DDH and these are outlined within outline of each visit will be recorded. The demographic‘data collection methods’ below. data will be coded for each individual and the code used All records identified as potential cases of delayed in all subsequent data collection in order to de-identifydental healing will be presented to the CAP for verifica- information as per ethical requirements.tion for inclusion or exclusion. The CAP will include a Part two: Delayed dental healing informationChair who will be an independent specialist endocrinol- Each patient file identified within the visit window per-ogist, 2 other medical practitioners and three dentists iod will be analysed and information relating to the pre-(one Oral Medicine Specialist, one oral and maxillofacial sence of an oral diagnosis (diagnosis, site, precipitant,surgeon and one forensic dentist/bone biologist). treatment, outcome, biopsy report, radiographic investi-A quorum of 4 (2 dental and 2 medical) will be required gation), bisphosphonate history and medical history (co-at each CAP meeting. morbidities and medications) will be recorded. At each CAP meeting all de-identified potential cases The diagnosis will consist of the presence of eitherwill be presented without the panel’s knowledge of oral ulceration (“break in mucosa but no bone visible”)bisphosphonate history and medical status. The records or bone necrosis defined as “bone on view”. A numberpresented will be assessed according to the previously of key words will be used when reviewing patientstated inclusion and exclusion criteria. histories as a number of descriptors can be used to
Borromeo et al. BMC Musculoskeletal Disorders 2011, 12:71 Page 6 of 10http://www.biomedcentral.com/1471-2474/12/71describe delayed dental healing. These will include non- medical history check including bisphosphonate history,healing socket, pus, exudate, swelling, draining sinus, medication profile and smoking history. The telephonedry socket, bone sloughing, sore sockets, OAC, oroantral interview will last approximately 10 minutes. The tele-communication, healing not completed, fistula, OAF, phone questionnaire will be modelled on the Adult Oraloroantral fistula, exposed bone and infection. Health Survey  and include questions relating Information regarding site of the lesion will be further to dental health and general information such as socio-subdivided into single versus multiple sites, quadrant economic status and educational status. A medicationinvolved, palatal, lingual, buccal or labial orientation and check list will also be completed with each case regard-tooth area (one to eight). The main precipitants listed less of the data collected in the original data collectioncan include tooth extraction, implant insertion, removal form in order to cross match bisphosphonate history,of pathological lesion, denture use, spontaneous, no other medical history which could contribute toobvious precipitant or other. In each case the date of impaired wound healing and smoking history.the precipitant will be recorded. If the precipitant is notrecorded in the history this will be marked as such on Ethics Approvalthe data collection form. Human Research and Ethics Committee approvals have Outcome of the delayed dental healing will be been obtained from: Melbourne Health (2005.242) (hos-recorded by including treatment modalities such as anti- pital and private practice cases and controls), Austinbiotics, mouthwashes/irrigation, debridement or other, Heath (H2006/02599; H2010/03794), The Alfred (17/date of the last review together with wound status 09), Barwon Heath (10/99), Dental Health Services Vic-(healed completely, healed partially, no healing or not toria (197), Southern Health (09069A), St Vincent’srecorded) and progress of the wound at the last visit Hospital (009/09) and Western Health (2005.242).(worse, stable, improving or not recorded). Detailsregarding any biopsy or radiographic analysis will also Statistical Analysisrecorded. Demographic and clinical characteristics of cases andPart 3: Medical History controls will be presented to assess whether these vari-Detailed information relating to potential cancer history ables are associated with delayed dental healing.including type, date of diagnosis, remission status, radio- Power and sample sizetherapy to the jaw and chemotherapy will be recorded The sample size estimate is based upon the assumptionas this is a key exclusion criterion. Other co-morbidities that the overall prevalence of bisphosphonate use inwill be recorded including lung disease, heart disease, post-menopausal women is around 10%. Based on Aus-kidney disease, organ transplant, diabetes, rheumatoid tralian Pharmaceutical Benefits Scheme (PBS) and Aus-arthritis or other connective tissue conditions together tralian Bureau of Statistics (ABS) data the upper limitwith smoking, tobacco and alcohol intake as these may estimate is 19% . Assuming that approximately 50%contribute to delayed dental healing. of these patients have used bisphosphonate for at leastPart 4: Medication history one year, then 10% prevalence of long-term use in thisA detailed description of oral glucocorticoids (start/stop population appears to be a reasonable estimate. It isdates, current dose and cumulative dose), hormone hypothesised that the prevalence of bisphosphonate usereplacement therapy and other medications including among those with delayed dental healing may be greaterraloxifene, calcitriol, tibolone, teriparatide and strontium than 10%. A recent case series of patients with frank jawwill be recorded. necrosis found that all were treated with bisphospho- If a bisphosphonate has been prescribed, the type will nates . We infer from this that the true proportionbe recorded including alendronate, risedronate, tiludro- of women with DDH taking bisphosphonates may benate, pamidronate, zoledronate or etidronate together greater than 30% - 50%. Given the expected low preva-with indication for use (osteoporosis, Paget’s disease, lence of DDH, the study plans to recruit ‘controls’ andglucorticoid-induced osteoporosis, metastatic disease, ‘cases’ in a ratio of 4:1. An observed prevalence ofhypercalcemia). Doses of all bisphosphonates including greater than or equal to 30% bisphosphonate usestart and stop dates and current doses will be recorded amongst women with DDH would correspond to anto allow calculation of cumulative drug doses. odds ratio of around 3.85. Hence, for the purpose ofTelephone interview this study, the minimum detectable difference will corre-A telephone interview will be conducted with all con- spond to an OR greater than or equal to 3.85. Thissenting participants in order to confirm inclusion/exclu- value is based upon a conservative estimate of the effectsion criteria (most of which may already be evident expected, rather than what is considered clinicallyfrom the patient’s dental file) and to determine socio- important. The most relevant measure of clinical impor-economic status, dental health information and a tance will be one derived from a cohort study, that
Borromeo et al. BMC Musculoskeletal Disorders 2011, 12:71 Page 7 of 10http://www.biomedcentral.com/1471-2474/12/71is where the effect of bisphosphonate use can be repre- including bone sequestration, intraoral and extraoral fis-sented in terms of a relative and/or absolute risk of tula formation, secondary paraesthesia and pathologicaldelayed dental healing. Whilst ideal, this would require jaw fractures. The link between this and bisphosphonatea very large sample and long-term follow-up. use is paramount as there are a number of studies A total sample of around 269 subjects (54 cases and reporting the incidence of jaw osteonecrosis (a potential215 controls) will provide 90% power to detect a true sequelae for delayed dental healing) to be as high asOR of at least 3.85, given the expected prevalence of 0.09 - 0.34% in patients receiving oral and 6.7-9.1% in10% bisphosphonate use amongst post-menopausal patients receiving intravenous bisphosphonates followingwomen in the community. dental procedures . Furthermore, whilst the inci- The relationship between bisphosphonate use and dence of ONJ in osteoporosis patients in relation todelayed dental healing will be assessed using a multivari- bisphosphonate use has been reported to occur afterate logistic model incorporating age, duration of expo- prolonged treatment (greater than 3 years), it has beensure, relevant co morbidities, concurrent treatment, and reported following 6-month use . On the otherother potential confounders as covariates. hand, other data suggest an extremely low prevalence/ The prevalence of DDH in the target population will incidence of ONJ in patients treated with bisphospho-be estimated using data collected to determine case nates for osteoporosis and other metabolic bone dis-numbers in both bisphosphonate-treated and non- orders. Although an association between ONJ andbisphosphonate-treated patients. We will also record bisphosphonate use has been suggested by case series,cases of DDH occurring in non-bisphosphonate-treated professional surveys and register data, there is a lack ofpatients with a diagnosis of benign bone disease where controlled, population-based data. A key aim of the pre-bisphosphonates may be indicated (i.e. osteoporosis, sent study is to obtain such controlled data. By record-Paget’s disease of the bone). ing the prevalence of delayed dental healing and ONJ that occur in the absence of bisphosphonate use weOutcome measures hope to be able to estimate the true risk of these disor-Primary outcome measures ders in association with bisphosphonate exposure.The primary outcome will be the incidence of delayed A case-controlled study design has been selected overdental healing that occurs either spontaneously or fol- a prospective cohort study. Whilst both are observa-lowing dental treatment such as extractions, implant tional studies that could further knowledge of delayedplacement, or denture use. dental healing, ONJ and bisphosphonate use, the formerPotential covariates study design has a number of advantages. First, it willPotential covariates include those data collected, which allow us to study an outcome with a potentially lowincrease our knowledge of the potential to develop incidence, less than 1% in patients with osteoporosis orDDH. These include co-morbidities (medication his- Paget’s disease . Second, this approach will minimizetory, smoking history, other medical conditions), oral the problem posed by a long latency between exposurehygiene habits and demographics (socioeconomic to bisphosphonate therapy and the outcome of delayedstatus, nationality). healing and subsequent ONJ, something which cannot Bisphosphonate use is considered an explanatory vari- be accounted for easily in a prospective cohort study,able, which is also our exposure of interest. except by extended follow-up. Third, we will be able to study the effects of other potential risk factors forDiscussion delayed healing such as medical history includingThe present study seeks to determine the level of bisphosphonate usage, smoking history, dental hygiene,delayed dental healing that occurs either spontaneously dental trauma including tooth extractions and implantor after dental procedures such as tooth extraction and placement, and denture usage on the outcome of inter-how this relates to bisphosphonate usage. Delayed den- est, namely delayed dental healing. It is understood thattal healing may be an earlier or less advanced lesion a prospective cohort study would provide the most reli-compared to ONJ but with a similar pathogenesis. By able assessment of the incidence of delayed healing,observing delayed dental healing as well as ONJ we may ONJ and bisphosphonates but to date such studies havetherefore more broadly describe bisphosphonate asso- not been conclusive .ciated dental disorders and increase our power to find One of the major limitations of this case-controlledan association between bisphosphonate use and asso- study design is that it is reliant on information as it isciated dental disorders. It is imperative to obtain a bet- recorded in the medical or dental history that may beter understanding of this condition and its potential incomplete and is subject to clinician bias andlinks to bisphosphonate use as it is often refractory to researcher interpretation. This is compounded by thetreatment and can lead to significant morbidity fact that in 2006 there was considerable controversy
Borromeo et al. BMC Musculoskeletal Disorders 2011, 12:71 Page 8 of 10http://www.biomedcentral.com/1471-2474/12/71regarding the role played by bisphosphonates in ONJ healing from complications such as a dry socket.and the definition of the condition. Furthermore, Furthermore, in 2008, a report from the task force ofresources required to access and collect data from thou- the American Society for Bone and Mineral Researchsands of medical and dental histories could result in a proposed that a “suspected” case of ONJ would beprolonged study period. defined as “an area of exposed bone in the maxillofacial The present study also relies on recruitment of specia- region that had been identified by a health care providerlists to allow access to patient records followed by and have been present for less that 8 weeks” which wasrecruitment of cases and controls. All oral and maxillo- supported by others [42,44]. By this time, soft tissue clo-facial specialists and special needs dentists in the state sure and exposed bone would no longer be present.of Victoria will be invited to participate in the study but ONJ would then be the definitive diagnosis if greaterit will be difficult to control for ascertainment bias. Are than 8 weeks had lapsed for healing to occur [42,45,46].practitioners who see delayed dental healing and ONJ The current definition for bisphosphonate associatedmore willing to allow review of their patient records? ONJ includes the following features:Are those who have a greater interest in the role played 1. Current or previous treatment with a bisphosphonateby bisphosphonates more likely to want to become 2. Exposed bone in the maxillofacial region that per-involved? It is difficult to control for this even with the sisted for greater than 8 weeks anduse of random sampling because practitioners’ consent 3. No history of radiation therapy to the jaws .is required to allow file review. To some degree the An attempt also has been made to define clinicalsame can also be said for patients with delayed dental stages of ONJ [45,48] (AAOMS, 2007). Stage 1 involvedhealing. The patient information and consent brochure the presence of exposed or necrotic bone that is asymp-stipulates that this is an important study to further our tomatic with no evidence of infection. Stage 2 related tounderstanding of the link between delayed dental heal- the presence of exposed necrotic bone and infection,ing and bisphosphonate use. Whether an individual who erythema and the presence or absence of a purulent dis-has taken a bisphosphonate may be more or less likely charge. Finally stage 3, the most severe form of ONJ,to participate is difficult to determine. Another potential contained all the characteristics of stage 2 but in addi-limitation of the study is recollection bias given that tion, the presence of features such as a pathologicalsome data will be collected via participant telephone fracture, draining sinus or communication either intrainterview. Furthermore, control subjects reading the oral or extraoral and osteolysis. Since then, Stage 0 haspatient information and consent brochure may feel that been included to encompass patients with signs of ONJthe study does not really benefit them and hence may but no exposed bone .be less likely to respond. The same can also be said for Potential covariates to be collected in this study are inthe general dental practitioners via whom the control line with those suggested as risk factors for ONJ andsubjects will be identified. If they have little experience include dental factors such as tooth extraction, implantwith patients taking bisphosphonates or delayed dental placement and denture use, treatment factors such ashealing, then they may have little motivation to allow a use of glucocortocoids and smoking status [26,29,49].third party to access their patient records. A critical component to the success or failure of any A key feature of the present study relates to the defi- case-controlled study is recruitment of participants. Thenition of DDH and ONJ. In 2005 the definition of osteo- study was designed as a two-step recruitment processnecrosis of the jaw was unclear and constantly changing requiring not only patient participation but also clinicianin the literature and as such it was difficult to adhere to participation otherwise access to patient data and poten-a single definition. The main disparity at the time was tial cases would have not been possible without employ-related to the length of time a wound took to heal ing more complex recruitment protocols. It is alsobefore it fell into the category of osteonecrosis of the imperative we seek the assistance of specialist practi-jaw. Initial healing, that is re-epithelialisation, of dental tioners in order to gain permission to screen consecutivewounds such as those from dental extractions usually patient records during the defined study time period intakes between 1 and 2 weeks . Once the clot forms, order to avoid selection bias associated with specialistfibrin and connective tissue begins to develop before the recall of individual patient cases. Hence there are twowound (in this case a dental socket) is closed over by potential problems with recruitment. The first lies withepithelium. It then takes some weeks for the underlying recruiting specialists. A number of key features have beensocket to fill with bone and healing to be complete. identified to be essential to increase response rates in Hence up to 6 weeks for healing of a dental wound postal questionnaires . A number of these featureswould be reasonable taking into account potential are also pertinent in the following study. Firstly, Edwardseffects of delayed healing from medical co-morbidities et al., (2002) suggested that contacting participants beforesuch as steroid use or development and subsequent sending out questionnaires would be important. In the
Borromeo et al. BMC Musculoskeletal Disorders 2011, 12:71 Page 9 of 10http://www.biomedcentral.com/1471-2474/12/71current study, the researchers presented the study outline and Academic Associate Professor. CB is a consultant Physician, Rheumatologist and Health Services Researcher and JDW is anand requirements of participants (clinician and patient) Endocrinologist and Professor of Medicine with major interest in bone andto oral and maxillofacial surgeons at a continuing profes- mineral disorders. WT and EF are research assistants.sional development meeting. It is considered crucial to Competing intereststhe study to recruit a high proportion of oral and maxil- The authors declare that they have no competing interests.lofacial surgeons as these are recognized as the groupmost likely to treat patients delayed dental healing follow- Received: 13 March 2011 Accepted: 10 April 2011 Published: 10 April 2011ing dental procedures. During this presentation thepotential benefits of determining incidence of delayed Referencesdental healing with reference to bisphosphonate usage 1. Lindsay R: Modeling the benefits of pamidronate in children withwere discussed, which was considered to be of great osteogenesis imperfecta. J Clin Invest 2002, 110(9):1239-1241. 2. Hillner BE, Ingle JN, Berenson JR, Janjan NA, Albain KS, Lipton A, Yee G,interest to practicing specialists. This has also been deter- Biermann JS, Chlebowski RT, Pfister DG: American Society of Clinicalmined as a potential method to increase response rate to Oncology guideline on the role of bisphosphonates in breast cancer.postal surveys . American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol 2000, 18(6):1378-1391. Other key factors employed to increase clinician 3. Durie BG: Use of bisphosphonates in multiple myeloma: IMWG responserecruitment included using personalized introductory to Mayo Clinic consensus statement. Mayo Clin Proc 2007, 82(4):516-517,letters, short questionnaires, follow-up letters to non- author reply 517-518. 4. Berenson JR: Zoledronic acid in cancer patients with bonerespondents and telephone follow-up. These are recog- metastases: results of Phase I and II trials. Semin Oncol 2001, 28(2nized strategies to increase recruitment . Similar Suppl 6):25-34.measures were also employed when recruiting potential 5. Delmas PD, Munoz F, Black DM, Cosman F, Boonen S, Watts NB, Kendler D, Eriksen EF, Mesenbrink PG, Eastell R: Effects of yearly zoledronic acid 5 mgcases and controls. on bone turnover markers and relation of PINP with fracture reduction in postmenopausal women with osteoporosis. J Bone Miner Res 2009,Conclusions 24(9):1544-1551.The study uses a case-controlled design to assess the 6. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, et al: Once-yearly zoledronic acid forhypothesis that long-term (more than 1 year’s duration) treatment of postmenopausal osteoporosis. N Engl J Med 2007,bisphosphonate use for the treatment of postmenopausal 356(18):1809-1822.osteoporosis or other benign bone disease is associated 7. Reid DM, Devogelaer JP, Saag K, Roux C, Lau CS, Reginster JY, Papanastasiou P, Ferreira A, Hartl F, Fashola T, et al: Zoledronic acid andwith impaired dental healing and subsequent develop- risedronate in the prevention and treatment of glucocorticoid-inducedment of ONJ. All Victorian Oral and Maxillofacial Sur- osteoporosis (HORIZON): a multicentre, double-blind, double-dummy,geons and Special Needs Dentists, by far the largest randomised controlled trial. Lancet 2009, 373(9671):1253-1263. 8. Sambrook P, Cooper C: Osteoporosis. Lancet 2006, 367(9527):2010-2018.groups managing these patients, will be invited to parti- 9. Wells GA, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, Coyle D,cipate making this the largest such study in Australia. Tugwell P: Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 2008, , 1: CD001155.Acknowledgements 10. Cranney A, Waldegger L, Zytaruk N, Shea B, Weaver B, Papaioannou A,This study is funded by the National Health and Medical Research Council Robinson V, Wells G, Tugwell P, Adachi JD, et al: Risedronate for the(Project number 454683) and part-funded by a grant-in-aid from Novartis prevention and treatment of postmenopausal osteoporosis. CochranePharmaceuticals. Database Syst Rev 2003, , 4: CD004523.None of the funders have any role other than to provide funding. The 11. Wells G, Cranney A, Peterson J, Boucher M, Shea B, Robinson V, Coyle D,authors would like to acknowledge Dr Peter Wong for initial involvement in Tugwell P: Risedronate for the primary and secondary prevention ofprotocol design and assistance in securing funding. The authors would also osteoporotic fractures in postmenopausal women. Cochrane Databaselike to acknowledge Ms Lisa Crighton for initial involvement in the project Syst Rev 2008, , 1: CD004523.and assistance in recruiting oral and maxillofacial surgeons. 12. Schweitzer DH, Oostendorp-van de Ruit M, Van der Pluijm G, Lowik CW, Papapoulos SE: Interleukin-6 and the acute phase response duringAuthor details treatment of patients with Paget’s disease with the nitrogen-containing1 Melbourne Dental School, The University of Melbourne, 720 Swanston bisphosphonate dimethylaminohydroxypropylidene bisphosphonate.Street Victoria, 3010, Australia. 2University of Melbourne, Department of J Bone Miner Res 1995, 10(6):956-962.Medicine, and Bone and Mineral Service Royal Melbourne Hospital, Parkville, 13. Chapurlat RD, Delmas PD: Drug insight: Bisphosphonates for3050, Australia. 3Clinical Epidemiology and Health Service Evaluation Unit, postmenopausal osteoporosis. Nat Clin Pract Endocrinol Metab 2006,Royal Melbourne Hospital, Parkville, 3050, Australia. 2(4):211-219, quiz following 238. 14. Pazianas M, Cooper C, Ebetino FH, Russell RG: Long-term treatment withAuthors’ contributions bisphosphonates and their safety in postmenopausal osteoporosis. TherGLB conceived the project and has been involved in co-ordination of the Clin Risk Manag 6:325-343.project. GLB, CB, JC, MM and JDW assisted with protocol design and 15. Cetiner S, Sucak GT, Kahraman SA, Aki SZ, Kocakahyaoglu B, Gultekin SE,obtaining funding. GLB, WT, EF and MM are involved in data collection. GLB, Cetiner M, Haznedar R: Osteonecrosis of the jaw in patients with multipleCB and JDW wrote the manuscript. All authors provided feedback on drafts myeloma treated with zoledronic acid. J Bone Miner Metab 2009,of this paper and read and approved the final draft before submission. 27(4):435-443. 16. Fehm T, Beck V, Banys M, Lipp HP, Hairass M, Reinert S, Solomayer EF,Authors’ information Wallwiener D, Krimmel M: Bisphosphonate-induced osteonecrosis of theGLB is a Special Needs Dentist, senior lecturer and researcher, JC is a Bone jaw (ONJ): Incidence and risk factors in patients with breast cancer andBiologist and Forensic Dentist and MM is an Oral Medicine Clinical Specialist gynecological malignancies. Gynecol Oncol 2009, 112(3):605-609.
Borromeo et al. BMC Musculoskeletal Disorders 2011, 12:71 Page 10 of 10http://www.biomedcentral.com/1471-2474/12/7117. Carter G, Goss AN, Doecke C: Bisphosphonates and avascular necrosis of 38. Slade GSA, Roberts-Thompson K: Australia’s dental generations: the the jaw: a possible association. Med J Aust 2005, 182(8):413-415. National Surveyof Adult oral 2004-6. Canberra: Australian Institute of Health18. Purcell PM, Boyd IW: Bisphosphonates and osteonecrosis of the jaw. Med and Welfare (Dental Statistics and Research Series No 34) 2007. J Aust 2005, 182(8):417-418. 39. Statistics ABo: National Health Survey: Summary of results, Australia.19. Bagan JV, Murillo J, Jimenez Y, Poveda R, Milian MA, Sanchis JM, Silvestre FJ, 2004. Scully C: Avascular jaw osteonecrosis in association with cancer 40. Mavrokokki T, Cheng A, Stein B, Goss A: Nature and frequency of chemotherapy: series of 10 cases. J Oral Pathol Med 2005, 34(2):120-123. bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral20. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced Maxillofac Surg 2007, 65(3):415-423. avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 41. Takagi Y, Sumi Y, Harada A: Osteonecrosis associated with short-term oral 2003, 61(9):1115-1117. administration of bisphosphonate. J Prosthet Dent 2009, 101(5):289-292.21. Aragon-Ching JB, Ning YM, Chen CC, Latham L, Guadagnini JP, Gulley JL, 42. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Arlen PM, Wright JJ, Parnes H, Figg WD, et al: Higher incidence of Gagel RF, Gilsanz V, Guise T, Koka S, et al: Bisphosphonate-associated Osteonecrosis of the Jaw (ONJ) in patients with metastatic castration osteonecrosis of the jaw: report of a task force of the American Society resistant prostate cancer treated with anti-angiogenic agents. Cancer for Bone and Mineral Research. J Bone Miner Res 2007, 22(10):1479-1491. Invest 2009, 27(2):221-226. 43. Vinckier F, Vermylen J: Wound healing following dental extractions in22. Lo JC, O’Ryan FS, Gordon NP, Yang J, Hui RL, Martin D, Hutchinson M, rabbits: effects of tranexamic acid, warfarin anti-coagulation, and socket Lathon PV, Sanchez G, Silver P, et al: Prevalence of osteonecrosis of the packing. J Dent Res 1984, 63(5):646-649. jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 44. Bagan J, Blade J, Cozar JM, Constela M, Garcia Sanz R, Gomez Veiga F, 68(2):243-253. Lahuerta JJ, Lluch A, Massuti B, Morote J, et al: Recommendations for the23. Hellstein JW, Marek CL: Bisphosphonate osteochemonecrosis (bis-phossy prevention, diagnosis, and treatment of osteonecrosis of the jaw (ONJ) jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 2005, in cancer patients treated with bisphosphonates. Med Oral Patol Oral Cir 63(5):682-689. Bucal 2007, 12(4):E336-340.24. Wang EP, Kaban LB, Strewler GJ, Raje N, Troulis MJ: Incidence of 45. American Association of Oral and Maxillofacial Surgeons position paper osteonecrosis of the jaw in patients with multiple myeloma and breast on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac or prostate cancer on intravenous bisphosphonate therapy. J Oral Surg 2007, 65(3):369-376. Maxillofac Surg 2007, 65(7):1328-1331. 46. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B:25. Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw and American Association of Oral and Maxillofacial Surgeons position paper bisphosphonates. N Engl J Med 2005, 353(1):99-102, discussion 199-102. on bisphosphonate-related osteonecrosis of the jaws–2009 update.26. Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, J Oral Maxillofac Surg 2009, 67(5 Suppl):2-12. Sayegh G, Guarneri V, Desrouleaux K, et al: Frequency and risk factors 47. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B: associated with osteonecrosis of the jaw in cancer patients treated with American Association of Oral and Maxillofacial Surgeons position paper intravenous bisphosphonates. J Bone Miner Res 2008, 23(6):826-836. on bisphosphonate-related osteonecrosis of the jaw - 2009 update. Aust27. Migliorati CA: Bisphosphonate-associated oral osteonecrosis. Oral Surg Endod J 2009, 35(3):119-130. Oral Med Oral Pathol Oral Radiol Endod 2005, 99(2):135. 48. Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related osteonecrosis28. Wilkinson GS, Kuo YF, Freeman JL, Goodwin JS: Intravenous of the jaw: background and guidelines for diagnosis, staging and bisphosphonate therapy and inflammatory conditions or surgery of the management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006, jaw: a population-based analysis. J Natl Cancer Inst 2007, 102(4):433-441. 99(13):1016-1024. 49. Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME:29. Ruggiero S, Gralow J, Marx RE, Hoff AO, Schubert MM, Huryn JM, Toth B, Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum Damato K, Valero V: Practical guidelines for the prevention, diagnosis, 2002, 32(2):94-124. and treatment of osteonecrosis of the jaw in patients with cancer. 50. Edwards P, Roberts I, Clarke M, DiGuiseppi C, Pratap S, Wentz R, Kwan I: J Oncol Pract 2006, 2(1):7-14. Increasing response rates to postal questionnaires: systematic review.30. Fleisch H: Bisphosphonates in osteoporosis. Eur Spine J 2003, 12(Suppl 2): Bmj 2002, 324(7347):1183. S142-146.31. Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G, Huryn JM: Osteonecrosis Pre-publication history of the jaw related to bevacizumab. J Clin Oncol 2008, 26(24):4037-4038. The pre-publication history for this paper can be accessed here:32. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, http://www.biomedcentral.com/1471-2474/12/71/prepub Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, et al: Denosumab compared with zoledronic acid for the treatment of bone metastases in doi:10.1186/1471-2474-12-71 patients with advanced breast cancer: a randomized, double-blind Cite this article as: Borromeo et al.: Is bisphosphonate therapy for study. J Clin Oncol 28(35):5132-5139. benign bone disease associated with impaired dental healing? A case-33. Hansen T, Kirkpatrick CJ, Walter C, Kunkel M: Increased numbers of controlled study. BMC Musculoskeletal Disorders 2011 12:71. osteoclasts expressing cysteine proteinase cathepsin K in patients with infected osteoradionecrosis and bisphosphonate-associated osteonecrosis–a paradoxical observation? Virchows Arch 2006, 449(4):448-454.34. Greenberg MS: Intravenous bisphosphonates and osteonecrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004, 98(3):259-260.35. Ruggiero SL, Mehrotra B: Bisphosphonate-related osteonecrosis of the Submit your next manuscript to BioMed Central jaw: diagnosis, prevention, and management. Annu Rev Med 2009, and take full advantage of: 60:85-96.36. Grbic JT, Black DM, Lyles KW, Reid DM, Orwoll E, McClung M, Bucci- • Convenient online submission Rechtweg C, Su G: The incidence of osteonecrosis of the jaw in patients receiving 5 milligrams of zoledronic acid: data from the health • Thorough peer review outcomes and reduced incidence with zoledronic acid once yearly • No space constraints or color ﬁgure charges clinical trials program. J Am Dent Assoc 141(11):1365-1370.37. Jung TI, Hoffmann F, Glaeske G, Felsenberg D: Disease-specific risk for an • Immediate publication on acceptance osteonecrosis of the jaw under bisphosphonate therapy. J Cancer Res • Inclusion in PubMed, CAS, Scopus and Google Scholar Clin Oncol 136(3):363-370. • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit