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Bonestimulationforfracturehealing:What'sallthefuss?

IndianJOrthop.2009AprJun43(2):117120.

PMCID:PMC2762251

doi:10.4103/00195413.50844

Bonestimulationforfracturehealing:What'sallthefuss?
GalkowskiVictoria,BradPetrisor,BrianDrew,andDavidDick
CenterforBoneHealingandResearch,PerformancePhysiotherapy,Hamilton,Ontario,Canada
Addressforcorrespondence:Dr.GalkowskiVictoria,CenterforBoneHealingandResearch,Hamilton,Ontario,Canada.Email:
vmgalkow@mailservices.uwaterloo.ca
CopyrightIndianJournalofOrthopaedics
ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,
distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.

Abstract
Approximately10%ofthe7.9millionannualfracturepatientsintheUnitedStatesexperiencenonunion
and/ordelayedunions,whichhaveasubstantialeconomicandqualityoflifeimpact.Avarietyofdevicesare
beingmarketedunderthenameofbonegrowthstimulators.Thisarticleprovidesanoverviewofelectrical
andelectromagneticstimulation,ultrasound,andextracorporealshockwaves.Moreresearchisneededfor
knowledgeofappropriatedeviceconfigurations,advancementinthefield,andencouragementinthe
initiationofnewtrials,particularlylargemulticentertrialsandrandomizedcontroltrialsthathave
standardizeddeviceandprotocolmethods.
Keywords:Electricalstimulation,electricalstimulationtherapy,fracturehealing,lowintensitypulsed
ultrasound,pulsedelectromagneticfields
INTRODUCTION
Theeconomicandhealthburdenoffracturesislarge.Fortunately,mostfractureshealwithoutany
complications.However,outoftheestimated7.9millionfracturesthatoccurannuallyintheUnitedStates,
510%ofthemdevelopnonunionsand/ordelayedunions,whicharemajorsourcesofcomplicationsinthe
treatmentofbonefractures.1Fracturehealingisacomplicatedmetabolicprocessandrequirestheinteraction
ofmanyfactors,includingtherecruitmentofreparativecellsandgenes.Ifthesefactorsareinadequateor
interrupted,healingisdelayedorimpaired,resultinginanonunionofthebone.2
Thecauseofnonunionsanddelayedhealingsoffracturesisusuallyunknown.Theknownreasonsof
delayedorimpairedunionsincludeproblemswithoperativeandnonoperativeinterventions,comprising
inadequatemobilizationofthefracture,distractionoffracturefragmentsbyfixationdevicesortraction,
repeatedmanipulationsorexcessiveearlymotionofafracture,excessiveperiostealstripping,anddamageto
othersofttissuesduringoperativeexposure.Otherrisksforimpairedfracturehealingincludecontamination
atthetimeofinjuryoroperation,smoking,diabetes,andtheskeletallocationoftheinjury.3
Bonehealingmaybemanipulatedbyexternal(biomechanical)andinternal(biological)stimuli.Theability
forfracturehealingtobeenhancedinthepercentageofpatientswithimpairedfracturehealingwouldhavea
greateconomicimpact,aswellasenhancethephysicalandmentalwellbeingofthesepatients.Avarietyof
biological,mechanical,andphysicalinterventionshavebeendevelopedtoenhancefracturehealing.This
articlefocusesontherangeofphysicalmethodstostimulatebonehealingincludingelectricalstimulators,
lowintensitypulsedultrasound,andextracorporealshockwaves.Thesemodalitiesarelessinvasiveto
patientsandthecostorcomplicationsrelatedtoharvestinganautograftareeliminated.3
HISTORICAL PERSPECTIVES
Therehavebeencasereportsofsuccessusingelectricalstimulationasearlyas1841,4buttheuseofthis
methodoftreatmentdidnotprogressuntilthe1950s.In1953,Yasudaappliedcontinuouscurrenttoarabbit
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femurforthreeweeksanddemonstratednewboneformationinthevicinityofthecathode.5Itbecame
knownthatthereareelectricalpotentialsinbone,includingstressgeneratedpotentials5andbioelectricor
steadystatepotentials.3Stressgeneratedpotentialsoccurwhenaportionofboneissubjectedtoabending
loadandthatportionbecomeselectronegative,whileothertensilepartsbecomeelectropositive.Bioelectric
potentialsareelectronegativepotentialsthatoccurinnonstressedboneinareasofactivegrowthandrepair.
Investigatorsaroundtheworldbegantostudytheeffectsofelectricityonboneandcartilage,andby1976,at
least119articlesappearedintheworldliteraturedescribingtheeffectsofdifferentformsofelectricityon
bonegrowthandrepair.3Avarietyofelectricalstimulationdeviceshavenowbeendeveloped.
Anotherphysicalstimulusthatisofneweruseintheenhancementofbonehealingissound.Thebenefitsof
ultrasoundaredeterminedbyintensity.Diagnosticuseofultrasoundrequiresverylowintensities(milliwatts
persquarecentimeter)toavoidexcessiveheatingofthetissues.Nevertheless,ultrasonicintensitiesofoneto
threewattspersquarecentimeterhavebeenreportedtoreducejointstiffness,pain,musclespasm,improve
muscularmobility,andmorerecentlyenhancethegrowthandhealingofbones.3Areportoflowintensity
ultrasoundsplayingaroleinbonegrowthandfreshfracturehealingofrabbitswaspublishedin19836,and
thefirstclinicalapplicationofultrasoundsonthetreatmentofnonunionswasreadattheAnnualMeetingof
TheAmericanAcademyofOrthopaedicSurgeonsin1987byDuarteandXavier.3Throughoutthe
subsequentyears,lowintensitypulsedultrasoundshavebeenshowntobeeffectiveinthetreatmentofupper
andlowerextremityfractures.Thus,in1994,theFoodandDrugAdministration(FDA)approvedthe
marketingofultrasoundsforthehealingoffreshfractures.7
Anevenmorerecentmethod,nowbeingstudiedforthetreatmentofbonefractures,isextracorporealshock
waves(ESWT).Thismethodrequireshigherfrequenciesandenergiesandhasbeenusedasastandardfor
thetreatmentofureterstones.Inrecentyears,investigatorshavebecomeinterestedinESWTabsorption
throughbonestructures.Onlyafewstudieshavebeenpublishedsofaronthemechanismsandeffectiveness
ofthistherapy.8
Atthistime,thevariousbonestimulationdevicesarebeingproducedandmarketedunderthecommon
names,externalbonegrowthstimulatorsandimplantablebonegrowthstimulators.Someofthecommon
companiesincludeBiometIncorporated,SmithandNephewIncorporated,DJOIncorporated,DepuySpine,
OrthofixIncorporated,andVQOrthoCare.
BONESTIMULATORS:HOWDO THEYWORK?
Electricalstimulation

Electricalandelectromagnetic(EM)fieldsareassumedtoplayaroleinbonehealingthroughthesame
principlesasmechanicalstressapplications.Whenmechanicalloadisappliedtobone,astraingradient
develops.4Subsequentpressuregradientsintheinterstitialfluiddrivefluidthroughthecanaliculifrom
regionsofhightolowpressureandexposeosteocytemembranestoflowrelatedshearstress,aswellasto
electricalpotentialssubsequenttothestreamingprocess.4ApplicationofEMtothefracturesiteismeantto
mimictheeffectofmechanicalstressonbone.
AvarietyofinstrumentshavebeendevelopedtobedeliveredtoelectricalandEMfieldstofracturesites,
eachbeingcategorizedintooneofthreetypes:invasivedirectcurrent(DC)stimulators,noninvasive
capacitivecoupling(CC)stimulators,andnoninvasiveinductivecoupling(IC)stimulatorsproducedby
pulsedelectromagneticfields(PEMF).
However,theeffectsofEMoncellularprocessesarenotwellunderstood.4Aaronetal.,9reviewedaseries
ofpreclinicalandclinicalstudiesonelectricalandelectromagneticenergyonbones.ApplicationsofPEMF
andtheirroleonregulationofstructuralECMproteinshavebeenexploredinmoredetailsthantheothertwo
electricalstimulationtechniques.Preclinicalstudies,bothinvitroandinvivo,havedemonstratedthatEM
stimulatesthesynthesisofstructuralextracellularmatrix(ECM)proteinsandinitiatescascadeeventsinthe
productionofproteinsthathavearoleingeneregulationandsignaltransductionofelectricalpotentials.10
ManystudieshaveobservedtheupregulationofmRNAlevelsandproteinsynthesisforgrowthfactor,which
enhancescellularrepairandthesynthesisofECMproteins.4Ithasbeendemonstratedthattheamplification
oftheelectricalandelectromagneticfieldsareprobablyduetotransmembranereceptors(includingPTH,
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insulin,IL2,transferrin,LDL,IGF2,calcitonin,andadenosineA2A).10Electricalstimulatorshavealso
beenusedandstudiedclinically,specifically,fortheirefficacyinfreshfracturesandosteotomies,spine
fusions,anddelayedandnonunionoffractures.Thereisnostandardonconfigurationanddoseofelectricor
electromagneticinput,andthesespecificsettingsmaydeterminewhichtransmembranesignaling
mechanismsareactivated.10
DirectcurrentstimulatorsdeliverEMthougheitherimplantedorpercutaneouslyappliedinsulated
electrodes.11Insurgicallyimplantedelectrodes,thecathodeisplacedintothesiteofbonerepair,whilethe
anodeisplacedinnearbysofttissues.Thepowersourcesandgeneratingunitscanbeexternalorimplanted.
Thecurrentisappliedconstantlybythepowergeneratorsforseveralmonths,andosteogenesisisstimulated
atthecathodeatcurrentsof5100A.9InDCstimulation,adoseresponsecurvehasbeenshownwhere
currentsbelowacertainthresholdleadtoboneformation,whilethoseaboveacertainthresholdshow
cellularnecrosis.3
StimulationviaCCdevicesusuallyappliespotentialsof110Vatfrequenciesof20200kHz.Theresulting
electricalfieldsinthetissuearearound1100mV/cm.Thesedevicesarenoninvasiveandtheelectrodesare
placedontheskinonoppositesidesofthefracturesite.9
ThethirdtechniquethathasbecomequitepopularisICstimulation,whichisalsoappliedexternally(asthe
CCtechnique),anditproduceselectricalfieldsinbonewithvaryingorpulsedelectromagneticfields(hence
thistechniqueisalsoreferredtoasPEMF).9Thecurrentisproducedbyasingleordoublecoil,drivenbyan
externalfieldgenerator.Theoutcomeisasecondaryelectricalfieldproducedinthebone.Boththe
characteristicsoftheappliedmagneticfieldsandthebiologicalpropertiesofthetissuesinfluencetheinduced
secondaryfield.Inpractice,theconfigurationsoftheappliedmagneticfieldshavevariedbyamplitude,
frequencysinglepulseorpulseburst(aseriousofpulseswithfrequenciesof1to100bursts/second)and
waveform.Varyingconfigurationshaveproducedmagneticfieldsof0.120G,whichhaveproduced
voltagegradientsof1100mV/cm.9
Theadvantagesofelectricalstimulationmaybethelowcomplicationratesascomparedtootherinvasive
methods.ImplantableformsoftheDCstimulatorshavetheadvantageofprovidingconstantstimulationof
bonedirectlyatthefracturesiteaswellasincreasedpatientcompliance.However,theinvasiveDCmethod
maycausemoreinfectionrates,havethepotentialforapainfulimplant,andthecommonstressassociated
withoperativeprocedures.11Thereisagreatneedforthoroughexplorationsofsuccessratesandcost
effectivenessofelectricalstimulationmethodscomparedtoperforminganothersurgeryonpatientswith
nonunionormalunion).
Lowintensitypulsedultrasound

Invitrostudiessuggestthatultrasonicstimulationenhancesbonehealingbyincreasingtheincorporationof
calciumionsinculturesofcartilageandbonecellsandstimulatetheexpressionofnumerousgenes
(includinggenesforAggrecan,IGF,andTGF)involvedinthehealingprocess.4Themostimportanteffect
thatultrasoundhasonbonehealingmaybeonchondrocytepopulation,assuggestedbystudiesthat
demonstrateanincreaseintheformationofsoftcallusandearlyonsetofendochondralossificationafter
ultrasonicapplications.4Manypreclinicalandclinicalstudieshavedemonstratedpromisingresultsusing
lowintensitypulsedultrasoundsforhealingfreshfracturesandtreatmentofdelayedunionornonunions.
Theultrasonicintensityrequiredtohealfracturesislower(notexceeding30W/cm2)thanthatcurrentlyused
byphysiotherapists(spatialaveragedtemporalaveragedintensitiesrangingfrom2to100W/cm2).Although
ultrasoundhasbeenusedforhealingpurposes,manytextbooks,includingreviewsonfracturemanagement,
butspecificallyoccupationaltherapyandphysiotherapytexts,continuetomisclassifytheuseofultrasound
forthetreatmentoffracturesasacontraindication.Thesenotionsarelargelybasedonmuchhigherintensity
ultrasound(100W/cm2)usingthephysiotherapyliteraturedamagetotissueshasbeendemonstratedbythe
useofhighintensityultrasonography.12
Extracorporealshockwaves

Extracorporealshockwaves(ESWT)haveveryrecentlystartedbeinginvestigated,andthemechanismsof
actionarenotwellknownorresearched.Thetherapyisnotcurrentlyusedasastandardtreatmentforbone
8

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fractures.8
CURRENT EVIDENCEFORBONESTIMULATORS
Theeffectofelectricalstimulatorsontheenhancementoffreshfracturehealingremainsinconclusive.
Researchershavehadmixedresultsinansweringwhethertheuseofelectricalstimulatorsenhancesthe
healingofslowtohealfractures.11Mostofthestudies,however,havenotbeenofhighmethodological
quality.Metaanalysesontheefficacyofelectricalstimulatorsonbonerepairhavebeendifficulttoperform
becauseoftheheterogeneityofstudydesignsandoutcomemeasurementsandinabilitytopoolthedataof
variousstudies.
Arecentmetaanalysisofelectricalstimulationforlongbonefractures13identified11studies(ofvariable
methods,deviceadministration,andquality)foranalysis.Althoughconclusionswerelimited,theauthors
reportedthatelectromagneticstimulationresultedinashorttermincreaseinscintimetrichealingactivityonin
nonoperativelytreatedCollesfractures,bonedensityisimprovedinpatientsundergoingfemoral
intertrochantericosteotomy,andbonedensityisvariablyimpactedinlengtheningproceduresofthelower
limb.
Lowintensitypulsedultrasound,ontheotherhand,hasafairlyextensiveevidencebasederivedfrom
randomizedtrials.Inparticular,onemetaanalysisof3studieswasconductedtoexploretheeffectoflow
intensitypulsedultrasoundtherapyontimetofracturehealing.12Thestudiesthatwerepooledhadonegroup
ofpatientsreceivinglowintensityultrasoundtreatmentandonecontrolgroupinexaminingthetreatmentof
scaphoid,distalradial,andtibialshaftfractures.Thepooledresultsforthestudiesshowedthatthetimeof
healingintheultrasoundgroupwassignificantlyshorterthaninthecontrolgroup(theweighedaverage
effectsizebeing6.41with95%confidenceintervalof1.0111.81)themeandifferenceinhealingtimewas
calculatedtobe64days.Thesefindingssuggestthatultrasoundmayhavesubstantialbenefitstobothquality
oflifeandcosteffectivenessinfracturehealing.
CurrentTrendsinBoneStimulationUse
Themostcommonlyusedbonestimulatorsarethelowintensitypulsedultrasoundsandelectricalstimulation
devices.FrostandSullivanmarketresearchspecialistsreportthatsalesofthesedevices,especially
noninvasivespinalfusionstimulators,areclimbing.14Pulseelectromagneticfield(PEMF)stimulatorsarethe
mostcommonlyusedtypeofnoninvasivebonegrowthandspinalfusionstimulators.
InNorthAmerica,thereisaratherwideuseofbonestimulationtherapiesfortibialshaftfractures,themost
commonofalllongbonefractures.Busseetal.,15conductedasurveytoexplorecurrentmanagementof
tibialshaftfracturesamongCanadianorthopedicsurgeons.Mostsurveyrespondentshadbeeninpracticefor
morethan10years,managingmostlyclosedtibialshaftfractures,andresultsarelimitedtogeneralizationto
surgeonswithintheCanadianOrthopaedicAssociation.Mostrespondents(80%)consideredareductionin
tibialshaftfracturehealingtimeof6weekstobeaclinicallyimportantreduction.Althoughevidencefor
effectivenessofthesetherapiesismixed,almosthalfoftherespondentscurrentlymakeuseofbone
stimulatorsaspartoftheirmanagementofcomplicatedclosedfracturesandcomplicatedopenfractures(45
and43%ofrespondents,respectively)complicatedbeingdefinedasdisplayingnonunion,delayedunion,
ormalunion.Theseorthopedicsurgeonshadanequalpreferenceforelectricalstimulatorsandlowintensity
pulsedultrasound.3%favoredotherbonestimulators.Basedonthissurvey,Mollonetal.,13arguedthat
thecurrentevidenceontheeffectivenessofelectromagneticstimulationdoesnotsupportitsratherhigh
clinicaluseamongthissampleofCanadianorthopedicsurgeons.However,theauthorsdidmentionthat
thereisalotofheterogeneityinstudies,andmorequalitystudiesneedtobeconductedforstrongermeta
analysesandconclusionstobemadeontheuseofelectromagneticstimulationtherapies.
BusseandBhandari16administeredasmallersurveyofbeliefsandpractices,regardingtheuseofultrasound
forbonehealing,amongorthopedicsurgeons,seniorphysiotherapy(PT)students,andseniororthopedic
surgeryresidentsataCanadianUniversity.Ultrasounduseamongthisgroupwasrare,andmanyclinicians
perceivedthatthereisalackofevidenceandavailabilityforitsuse,inadditiontothebeliefthatultrasoundis
contraindicatedforthetreatmentoffractures(consistentwithsomeresearchandmostPTtexts).
DO WEHAVEENOUGHDATAONBONESTIMULATORS?
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Althoughmultiplerandomizedtrialsexisttosupportthevarietyofbonestimulationmodalities,allaresmall
andlimitedtoprimarilyradiologicendpoints.Thereremainsaneedtoconduct,large,anddefinitivetrialsthat
usepatientimportantoutcomesbeforewidespread(anduniversal)acceptanceofsuchmodalitieswilloccur.
Footnotes
SourceofSupport:Nil
ConflictofInterest:None.

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