Bisphosphonates are powerful drugs used for the management of osteoporosis and metastatic bone disease to avoid skeletal-related complications. Side effects are rare but potentially serious such as the bisphosphonate-related osteonecrosis of the jaws (BRONJ). BRONJ impairs the quality of life and can even lead to pathologic fractures of the mandible. Management of BRONJ is difficult per se. If complicated with pathologic mandibular fractures in advanced stages, the treatment options are controversially discussed. This review delineates the epidemiology and pathogenesis of BRONJ to put the various modalities for the treatment of pathologic mandible fractures into perspective.
Methods
Various case reports and case series in the literature were reviewed. Cases were reviewed of patients suffering from pathologic fracture due to bisphosphonate-related osteonecrosis of the jaw treated in the Department of Oral and Maxillofacial Surgery (Ludwig-Maximilians-University of Munich) from 2003 to 2010. Of 140 patients suffering from BRONJ, four were identified with pathologic fracture of the mandible.
Results
Management of pathologic mandibular fractures in patients suffering from BRONJ is an unsolved issue. At present there is a paucity of information to establish reliable therapy guidelines. The published strategies range from conservative treatment to major bone resections with or without internal or external fixation and with or without autogenous reconstruction. There is no evidence for the superiority of a single therapeutic mode, however.
Conclusion
Further understanding of BRONJ is mandatory to establish a sound rationale for the treatment of associated mandibular fractures.
YaromNYahalomRShoshaniYHamedWRegevEEladSOsteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcomeOsteoporos Int2007181363–1370
4.
BerensonJRLichtensteinAPorterL, et al; Myeloma Aredia Study GroupEfficacy of pamidronate in reducing skeletal events in patients with advanced multiple myelomaN Engl J Med1996334488–493
5.
CranneyATugwellPAdachiJ, et al; Osteoporosis Methodology Group and The Osteoporosis Research Advisory GroupMeta-analyses of therapies for postmenopausal osteoporosis. III. Meta-analysis of risedronate for the treatment of postmenopausal osteoporosisEndocr Rev200223517–523
6.
BlackDMCummingsSRKarpfDB, et al; Fracture Intervention Trial Research GroupRandomised trial of effect of alendronate on risk of fracture in women with existing vertebral fracturesLancet19963481535–1541
7.
MehrotraBSafety profile of intravenous bisphosphonatesSemin Oncol200734604S24–S27
8.
MiglioratiCABisphosphanates and oral cavity avascular bone necrosisJ Clin Oncol2003214253–4254
9.
MarxREPamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemicJ Oral Maxillofac Surg2003611115–1117
10.
WangJGoodgerNMPogrelMAOsteonecrosis of the jaws associated with cancer chemotherapyJ Oral Maxillofac Surg2003611104–1107
11.
WalterCAl-NawasBGrötzKA, et al. Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronateEur Urol2008541066–1072
12.
BamiasAKastritisEBamiaC, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factorsJ Clin Oncol2005238580–8587
13.
VahtsevanosKKyrgidisAVerrouE, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jawJ Clin Oncol2009275356–5362
14.
BoonyapakornTSchirmerIReichartPASturmIMassenkeilGBisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignanciesOral Oncol200844857–869
15.
LoJCO'RyanFSGordonNP, et al; Predicting Risk of Osteonecrosis of the Jaw with Oral Bisphosphonate Exposure (PROBE) InvestigatorsPrevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposureJ Oral Maxillofac Surg201068243–253
16.
Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial SurgeonsAmerican Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jawsJ Oral Maxillofac Surg200765369–376
17.
RuggieroSLDodsonTBAssaelLALandesbergRMarxREMehrotraBAmerican Association of Oral and Maxillofacial SurgeonsAmerican Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 updateJ Oral Maxillofac Surg200967 (5, Suppl): 2–12
18.
KhoslaSBurrDCauleyJ, et al; American Society for Bone and Mineral ResearchBisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral ResearchJ Bone Miner Res2007221479–1491
19.
Abu-IdMHAçilYGottschalkJKreuschT[Bisphosphonate-associated osteonecrosis of the jaw]Mund Kiefer Gesichtschir20061073–81
20.
Abu-IdMHWarnkePHGottschalkJ, et al. “Bis-phossy jaws”—high and low risk factors for bisphosphonate-induced osteonecrosis of the jawJ Craniomaxillofac Surg20083695–103
21.
OttoSHafnerSGrötzKAThe role of inferior alveolar nerve involvement in bisphosphonate-related osteonecrosis of the jawJ Oral Maxillofac Surg200967589–592
22.
WongchuensoontornCLiebehenschelNWagnerK, et al. Pathological fractures in patients caused by bisphosphonate-related osteonecrosis of the jaws: report of 3 casesJ Oral Maxillofac Surg2009671311–1316
23.
WangEPKabanLBStrewlerGJRajeNTroulisMJIncidence of osteonecrosis of the jaw in patients with multiple myeloma and breast or prostate cancer on intravenous bisphosphonate therapyJ Oral Maxillofac Surg2007651328–1331
24.
DimopoulosMAKastritisEAnagnostopoulosA, et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acidHaematologica200691968–971
25.
MarxRECilloJEJrUlloaJJOral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatmentJ Oral Maxillofac Surg2007652397–2410
26.
BadrosAWeikelDSalamaA, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factorsJ Clin Oncol200624945–952
27.
DielIJFogelmanIAl-NawasB, et al. Pathophysiology, risk factors and management of bisphosphonate-associated osteonecrosis of the jaw: Is there a diverse relationship of amino- and non-aminobisphosphonates?Crit Rev Oncol Hematol200764198–207
28.
HoffAOTothBBAltundagK, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonatesJ Bone Miner Res200823826–836
29.
HessLMJeterJMBenham-HutchinsMAlbertsDSFactors associated with osteonecrosis of the jaw among bisphosphonate usersAm J Med2008121475–483.e3
30.
AllenMRBurrDBThe pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few dataJ Oral Maxillofac Surg200967 (5, Suppl): 61–70
31.
AllenMRBisphosphonates and osteonecrosis of the jaw: moving from the bedside to the benchCells Tissues Organs2009189289–294
32.
RodanGAFleischHABisphosphonates: mechanisms of actionJ Clin Invest1996972692–2696
33.
ScavelliCDi PietroGCirulliT, et al. Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myelomaMol Cancer Ther2007612 Pt 13256–3262
34.
HansenTKunkelMWeberAJames KirkpatrickCOsteonecrosis of the jaws in patients treated with bisphosphonates—histomorphologic analysis in comparison with infected osteoradionecrosisJ Oral Pathol Med200635155–160
35.
ReidIRBollandMJGreyABIs bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity?Bone200741318–320
36.
OttoSHafnerSMastG, et al. Bisphosphonate-related osteonecrosis of the jaw: is pH the missing part in the pathogenesis puzzle?J Oral Maxillofac Surg2010681158–1161
37.
RussellRGWattsNBEbetinoFHRogersMJMechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacyOsteoporos Int200819733–759
38.
SatoMGrasserWEndoN, et al. Bisphosphonate action. Alendronate localization in rat bone and effects on osteoclast ultrastructureJ Clin Invest1991882095–2105
39.
OttoSPautkeCOpelzC, et al. Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanismJ Oral Maxillofac Surg2010682837–2845
40.
AgisHBleiJWatzekGGruberRIs zoledronate toxic to human periodontal fibroblasts?J Dent Res20108940–45
41.
NancollasGHTangRPhippsRJ, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatiteBone200638617–627
42.
HoffmannTJohnMKerschbaumTMicheelsWPotthoffPReichEReisUReiterFSchiffnerUSchroederEOral epidemiology In: MicheelisWSchiffnerU, eds. Institute of German Dentists: Fourth German Oral Health Study (DMS IV)Cologne, GermanyDeutscher Zahnärzte Verlag DÄV2006
43.
RuggieroSLFantasiaJCarlsonEBisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and managementOral Surg Oral Med Oral Pathol Oral Radiol Endod2006102433–441
44.
MontebugnoliLFelicettiLGissiDBPizzigalloAPelliccioniGAMarchettiCBiphosphonate-associated osteonecrosis can be controlled by nonsurgical managementOral Surg Oral Med Oral Pathol Oral Radiol Endod2007104473–477
45.
BadrosATerposEKatodritouE, et al. Natural history of osteonecrosis of the jaw in patients with multiple myelomaJ Clin Oncol2008265904–5909
46.
Van den WyngaertTClaeysTHuizingMTVermorkenJBFossionEInitial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcomeAnn Oncol200920331–336
47.
StantonDCBalasanianEOutcome of surgical management of bisphosphonate-related osteonecrosis of the jaws: review of 33 surgical casesJ Oral Maxillofac Surg200967943–950
48.
PautkeCBauerFOttoS, et al. Fluorescence-guided bone resection in bisphosphonate-related osteonecrosis of the jaws: first clinical results of a prospective pilot studyJ Oral Maxillofac Surg20116984–91
49.
MarkoseGMackenzieFRCurrieWJHislopWSBisphosphonate osteonecrosis: a protocol for surgical managementBr J Oral Maxillofac Surg200947294–297
50.
CarlsonERBasileJDThe role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jawsJ Oral Maxillofac Surg200967 (5, Suppl): 85–95
51.
VescoviPManfrediMMerigoEMeletiMEarly surgical approach preferable to medical therapy for bisphosphonate-related osteonecrosis of the jawsJ Oral Maxillofac Surg200866831–832
52.
PautkeCBauerFBissingerO, et al. Tetracycline bone fluorescence: a valuable marker for the osteonecrosis characterization and therapyJ Oral Maxillofac Surg201068125–129
53.
PautkeCBauerFTischerT, et al. Fluorescence-guided bone resection in bisphosphonate-associated osteonecrosis of the jawsJ Oral Maxillofac Surg200967471–476
54.
FleisherKEDotySKottalSPhelanJNormanRGGlickmanRSTetracycline-guided debridement and cone beam computed tomography for the treatment of bisphosphonate-related osteonecrosis of the jaw: a technical noteJ Oral Maxillofac Surg2008662646–2653
55.
Abu-IdMHWarnkePHGottschalkJ, et al. “Bis-phossy jaws”—high and low risk factors for bisphosphonate-induced osteonecrosis of the jawJ Craniomaxillofac Surg20083695–103
56.
MarxREReconstruction of defects caused by bisphosphonate-induced osteonecrosis of the jawsJ Oral Maxillofac Surg200967 (5, Suppl): 107–119
57.
EngroffSLKimDDTreating bisphosphonate osteonecrosis of the jaws: is there a role for resection and vascularized reconstruction?J Oral Maxillofac Surg2007652374–2385
58.
CorneliusCPAugustinJBSailerLKExternal pin fixation for stabilization of the mandible—comeback of a method: historical review and first experiences with the ‘mandible external fixator.’Oral Maxillofac Surg2009131–14
59.
MückeTHaarmannSWolffKDHölzleFBisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstructionJ Craniomaxillofac Surg200937291–297
