Bisphosphonate related osteonecrosis of the jaw: A minipig large animal model

Bisphosphonate related osteonecrosis of the jaw: A minipig large animal model
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  This article appeared in a journal published by Elsevier. The attachedcopy is furnished to the author for internal non-commercial researchand education use, including for instruction at the authors institutionand sharing with colleagues.Other uses, including reproduction and distribution, or selling orlicensing copies, or posting to personal, institutional or third partywebsites are prohibited.In most cases authors are permitted to post their version of thearticle (e.g. in Word or Tex form) to their personal website orinstitutional repository. Authors requiring further informationregarding Elsevier’s archiving and manuscript policies areencouraged to visit:  Author's personal copy Short Communication Bisphosphonate related osteonecrosis of the jaw – Manifestationin a microvascular iliac bone flap Christoph Pautke a, ⇑ ,e , Sven Otto a,e , Simone Reu b , Andreas Kolk c , Michael Ehrenfeld a ,Stephen Stürzenbaum d , Klaus-Dietrich Wolff  c a Department of Oral and Maxillofacial Surgery, University of Munich, Lindwurmstr. 2a, D-80337 Munich, Germany b Department of Pathology, University of Munich, Thalkirchner Str. 36, D-80337 Munich, Germany c Department of Oral and Maxillofacial Surgery, Technische Universität München, Ismaningerstr. 22, D-81675 Munich, Germany d Pharmaceutical Science Division, King’s College London, 150 Stamford Street, London SE1 9NH, UK  a r t i c l e i n f o  Article history: Received 14 January 2011Received in revised form 12 March 2011Accepted 15 March 2011Available online 7 April 2011 Keywords: OsteonecrosisNecrosisBisphosphonateBRONJBP-ONJONJBONJBone graftMandibula reconstructionOsseous microvascular reconstruction s u m m a r y Bisphosphonate related osteonecrosis of the jaw (BRONJ) is a side effect that may emerge due to a long-term bisphosphonate therapy. Although the timely diagnosis and initiation of treatment are associatedwithgoodoutcomeresults,extendedcasesrequirewholepartsofthejawtoberesected.Apossibletreat-ment option is the bony reconstruction of the jawusing microvascular bone flaps. Wereport, for the firsttime, the development of a bisphosphonate related osteonecrosis in a microvascular iliac bone graft, areconstructionthatwasperformedfollowingapartialmandibulectomyduetoBRONJstageIII.Theobser-vation of BRONJ manifestation in an osseous microvascular transplant is a novel finding that sheds newlight on current pathogenesis theories that surround this entity. Furthermore, it is hypothesized thatBRONJ is able to progress to adjacent bone. In addition, bone reconstruction in patients suffering fromBRONJ may be seen more critically.   2011 Elsevier Ltd. All rights reserved. Introduction The bisphosphonate related osteonecrosis of the jaw (BRONJ),an entity that was first described in 2003, 1–3 is most frequentlydiagnosed in patients receiving nitrogen-containing bisphospho-nate(BP)infusionsduetometastaticbonedisease. 4 Theprevalencehas been reported to approach 18%. 5,6 BRONJ is broadly defined bythe presence of a positive BP drug history, exposed bone for a per-iodthatexceeds8weeksandtheabsenceofpreviousirradiationtotheheadandneckregionAAOMFS. 7,8 Recently,amoredetailedcat-egorizationintofourstages(0–III) has beensuggested. 9 InstageIII,exposed and necrotic bone is accompanied by pain, infection, andoneormorefurthercomplicationsincludingnecroticbonethatex-tends beyond the region of alveolar bone (i.e. inferior border andramus of the mandible), pathologic fractures or extraoral fistula.Surgical approaches have shownto result in superior treatmentoutcomes compared to conservative therapy regimens with suc-cess rates of 80–90% 10–14 and 10–62%, 15–19 respectively. However,no standardized therapy has been defined for advanced cases,whichtypicallyrequireapartialmandibulectomy. 20 Takingthepa-tients’ general health and the life expectancy into considerationthe treatment options range from a resection without reconstruc-tion, 10 thestabilizationofthejawwithosteosynthesisplates 10,21,22 to the bony jaw reconstruction using avascular 22 or microvascularbone flaps. 23–26 The finding that BRONJ can develop in an iliac crest flap, as pre-sented in this study, puts a different complexion on current theo-ries and accentuates the notion that the local tissue pH value dueto infection may constitute a significant factor that drives thepathomechanism of BRONJ. 27,28 Report of a case A 76-year-old white male was diagnosed in January 2005 withprostate adenocarcinoma (Gleason score 3+4=7) with bone 1368-8375/$ - see front matter   2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.oraloncology.2011.03.022 ⇑ Corresponding author. Tel.: +49 (0) 89 5160 2919, fax: +49 (0) 32121 007467. E-mail address: (C. Pautke). e Shared first authorship. Oral Oncology 47 (2011) 425–429 Contents lists available at ScienceDirect Oral Oncology journal homepage:  Author's personal copy metastasis.Neoadjuvanttherapy(February2005)withLH–RHana-loguesandbisphosphonate(Zometa4mg/month)was followedbya transurethral prostate resection (May 2005). Hormone and bis-phosphonate therapy was continued after the operation. The pa-tient’s general medical history included peripheral artery disease(bilateral stentingof the iliacarteries in December 2007), coronaryartery disease (coronary artery bypass surgery 22years ago), caro-tid artery stenosis, arterial hypertension, hypercholesterolemia,and heavy smoking (over 40 pack-years).InDecember2007,thefirstandsecondrightmolarsintheman-dible were extracted. In January 2008, the patient was admitted tothe Department of Oral and Maxillofacial Surgery, Technical Uni-versity of Munich, with a mandibular abscess and exposed boneintherightlowerjaw. Theabscess wasincised, teeth44and45re-moved and necrotic bone resected under local anesthesia. In Julyand December 2008 fluorescence guided bone resection was per-formed under general anesthesia. 29 The supportive bisphospho-nate therapy was continued until the relapse of the BRONJ in therightmandiblewasdiagnosedinAugust2008andthenterminatedby the treating urologist (thus equating to a total Zometa adminis-tration of 40months). Due to the extent of the necrosis wounddehiscenceandexposedboneintherightlowerjaw,apartialman-dibulectomy and immediate bony reconstruction using a micro-vascular iliac crest flap was performed in May 2009. Shortly afterthe bone transplantation, the patient presented an intra-extraoralfistulaintheright mandiblesotheosteosynthesismaterial wasre-movedinSeptember2009andthefistulawasexcised.Nonethelessthe fistula reoccurred (Fig. 1) and the patient suffered from puru-lent exudation, swelling and pain, thus calling for another opera-tion (March 2010). Intraoperatively, the iliac bone transplant wasvital (Fig. 2a) but no signs of bone remodeling were found at themargins of the transplant. Fibrous healing took place resulting inpseudarthrosis. In addition, areas with signs of osteonecrosis inthe vital bone transplant were apparent, fromwhichbiopsieswereharvested(Fig. 2b). Themandiblewasstabilizedusingalargeoste- Figure 1  Displayingthepatients’preoperativestatuswith(a)extraoraland(b)intraoralfistulaewithpurulentexudationintherightmandible.Intheorthopantomograph(c)only fewsigns of bony osteointegration of the iliac crest transplant can be found 8months after microvascular bone transfer. Note that signs of osteonecrosis in particular inthe distal and crestal transplant margins are visible with less trabecular bone and small sequestrae. Figure 2  Displays the intraoperative situation (a) before and (b) after removal of the osteonecrosis, removal of the pseudarthrosis and stabilisation of the mandibleusing an osteosynthesis plate. Note, that in (a) no osteointegration but apseudarthrotic healing of the iliac bone flap took place (arrows) and that the boneappears altered in the lateral aspect (asterisk). (b) shows the site of bone biopsy(black arrows). (c) the lingual bone healing after removal of the pseudarthrosis(white arrows) as well as the bleeding fromthe transplant are clear signs of vitalityof the bone transplant.426  C. Pautke et al./Oral Oncology 47 (2011) 425–429  Author's personal copy osynthesis plate (Fig. 2c). The histopathology revealed the typicalsigns of a bisphosphonate related osteonecrosis in the biopsies ta-ken from the bone transplant including bone necrosis, bacterialcolonisation by actinomyces species, and hypervascular tissue sur-rounding the bone necrosis (Fig. 3). Six weeks post-operation, thepatientwasfreeofsymptomsandnosignsofintra-orextraoralfis-tula were present (Fig. 4). In the further course of the disease, thepatientdevelopedaBRONJstageIwithbonesequestersintherightupper jaw as well as in the ascending ramus of the right mandiblewhich have been treated surgically. The vitality of the iliac bonetransplant was checked by fluorescence control during sequester-otomyoftheascendingramus.Thepatientisfineandfreeofsymp-toms or exposed bone. Discussion The pathogenesis of bisphosphonate related osteonecrosis of the jaw (BRONJ) has only partially been deciphered and differenttheories have emerged. 30 The most popular one stipulates thatBRONJ manifestation is limited to the jawbone because its boneturnover is higher than in other bones. 31,32 Thus, it is argued thatthe suppression of bone turnover by bisphosphonates (BPs) mightinduce an over-suppression in areas of increased activity, which inturn results in osteonecrosis of the jaw. 33,34 Other theories assumethat the inhibition of angiogenesis, the soft tissue toxicity, specificinfections or a modulated immune response play key roles in thepathogenesis of BRONJ, but concrete evidences is still sparse. 30,35 Although the manifestation of a BRONJ in a microvascular boneflaphas,untilnow,neverbeenreported,itshouldbenotedthatthepresentation of a single case cannot be deemed to be sufficientevidence to categorically prove or indeed disprove existing BRONJpathogenesis theories. However, the fact that a BRONJ was Figure 3  Histology of a bisphosphonate related osteonecrosis in an iliac bonetransplant (hematoxylin-eosin staining, 200-fold magnification) with the typicalhallmarks as (a) necrotic bone with no osteocytes (black arrows) and bacterialcolonization with actinomyces like growth (white arrows). (b) the necrotic bone issurrounded by hypervascular tissue (black asterisks) and new trabecular boneformation (white asterisks). Figure 4  Shows the patient 8weeks after the operation. The patient is free of symptoms and no signs for (a) extraoral or (b) intraoral fistula were present. (c) 9months aftersurgery clear signs of osseointegration on the anterior and posterior margin of the bone graft are visible in the orthopantomograph indicating that the vascular supply of thebone graft is sufficient. C. Pautke et al./Oral Oncology 47 (2011) 425–429  427  Author's personal copy observedto developinaniliaccrest flapchallengesthe notionthatthe jawbone is the exclusive BRONJ target, either by nature or dueto its increased bone turn-over. Further support is offered by theobservations that BPs neither overly accumulate in the jawbones, 36 nor suppress the turn-over of the jawbone more com-pared to other sites as shown in scintigraphy investigations. 18 If,as shown here, BRONJ can be present in a bone transplant, thenthe jawbone  per se  cannot be of etiological importance but ratherthe localizationof the bone inor adjacent to the oral cavity. At thisstageitisnotpossibletodeducewithcertaintywhethertheBRONJin the bone iliac graft represents a  de novo  manifestation or a con-tinuation srcinating from the stump of the mandible in the senseof a progressive infection. The latter is feasible, if not likely, be-cause the BRONJ was located at the distal margin of the transplantadjacent to the ascending ramus of the mandible, where a bonesequester was removed in the further course of the disease. Thisnotion is in agreement with recent reports stating that infectionsas well as an acid local pH value are, at large, responsible for theBRONJ development. 27,28 Indeed, if infection and a subsequent tis-sue acidification play key roles in the BRONJ manifestation, it isconceivablethatthesemechanismsarealsocrucialfortheprogres-sion of the disease. The fact that BRONJ almost exclusively affectsthe jawbone can be explained by two facts, namely that no otherbone is as frequently subjected to infections as the jawbone (92%of the seniors suffer from moderate to severe inflammatory peri-odontal disease 37 ) and that infections cause local tissue acidosis.Indeed, BPs are known to be released and from bone and 38,39 acti-vated 39,40 in acidic milieus, thus, recurrent or chronic infectionscan lead to locally increased BP concentrations. 41,42 Once a criticallevel is reached, the above mentioned cellular pathomechanismsmay be triggered and initiate BRONJ. 28 Althoughthehistologicaldifferentiationbetweenasimpleoste-omyelitis and a BRONJ can be challenging, the present case dis-played all clinical and histological hallmarks typical of BRONJ.The reconstruction of the mandible is a challenging endeavorthat typically involves autogenous osseous bone grafts and oftendental rehabilitation by dental implants in order to increase of the quality of life. 43,44 In patients suffering from BRONJ additionalfactors have to be considered. Firstly, the life expectancy is limitedin particular when patients receive BPs due to bone metastasis of advanced cancer. 18 Secondly, the wound healing and especiallythe bone remodeling are altered. 34,45 Therefore, the osseointegra-tion of autogenous bone grafts may be delayed or impaired asshown in the present case. Thirdly, bone grafts themselves areloaded with bisphosphonates, which covalently bind to any bonein the body with half-life of approximately 10years and more. 39 It is possible that pathomechanisms analogous to BRONJ in jaw-bone may emerge in the bone transplant in cases where specificprerequisites are realized, namely the release of bone bound bis-phosphonates in infectious (acid) milieus and the accumulationabove local toxic levels. Alternatively, prolonged exposure to bis-phosphonates may alter the quality of bone transplants, as ob-served in patients that receive long-term bisphosphonatesadministration following atypical femur fractures. 46 Conclusion A bisphosphonate related osteonecrosis can also develop inother bones than the jawbones when transplanted to the oral re-gion. We call for existing theories to reflect upon this observationandproposethatfrequent,chronicandrecurrentinfectionsleadingto local tissue acidosis may act as a defining trigger of BRONJ. Inaddition, bone reconstruction in patients suffering from BRONJmay be seen more critically. Conflict of interest statement None declared. References 1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascularnecrosis of the jaws: a growing epidemic.  J Oral Maxillofac Surg  2003; 61 (9):1115–7.2. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated withcancer chemotherapy.  J Oral Maxillofac Surg   2003; 61 (9):1104–7.3. 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