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Current Review o Heterotopic Ossifcation

Jason E. Hsu1

Expert Commentary

Mary Ann Keenan1

1 Department of Orthopaedic Surgery,

University of Pennsylvania

Heterotopic ossication, the abnormal development o bone in areas o the body other than skeletal tissue, commonly

occurs in association with traumatic brain injury and spinal cord injury. The prevalence o heterotopic ossication in

those sustaining extremity combat injuries has also been highlighted with the recent rise in the number o overseas

combat injuries. This ectopic bone ormation can have proound eects on the rehabilitation and care o these

patients. This clinical entity is still an enigma among scientists and clinicians, and current preclinical work has made

slow but steady progress in our understanding o the etiology and pathophysiology behind heterotopic bone ormation

This article briefy reviews the most recent concepts regarding the pathophysiology, epidemiology, and treatment oheterotopic ossication.

Heterotopic ossifcation is a condition in

which lamellarbone is ormed innon-ossifedsottissue.ItwasfrstillustratedbyReidelin

1883 and subsequently described by Dejerneand Ceiller during the FirstWorldWar, whenpatients sustaining spinal cord injuries were

observedtoormheterotopicnewbone1.Thiswasollowedbyoneothelandmarkdiscoveries

in orthopaedic research, when Marshall Urist

described the osteoinductive properties obonemorphogeneticprotein(BMP)inectopicareas such as muscle2, 3. Since Urists initial

discovery,multipleBMPshaveadoptedclinicalorthopaedicuses,yetourunderstandingintotheormationonewboneinnon-skeletaltissuehas

notprogressedasrapidly.Clinically,heterotopicossifcationcanhavea

prooundeectonawiderangeopatientswithpredisposingactors suchasneurologic injury,

majorjointsurgery,localextremitytrauma,andsevere burns. Heterotopic bone can limit therangeomotionoanumberodierentjoints,

most commonly the hip, knee, shoulder, andelbow(Figure1).Itcanalsodevelopconcomitant

with sot tissue contractureswhich results ingreatlylimitedjointmobility.Inaddition,certain

populations, particularly those that suerrom neurogenic heterotopic ossifcation, areimpactedbytheinabilitytomaintainpersonal

hygiene, and skinmaceration, pressure ulcers,and intractable pain candevelop. Limitations

in joint range o motion can lead to urthercomplications suchas disuseosteoporosis and

eventualracturesduringtransersoralls.This article aims to review the most

recent advances in our understanding othe pathophysiology behind ectopic boneormation. Recent data on the epidemiology,

clinicalevaluation,andtreatmentoheterotopicossifcationisalsodiscussed.

PathophyioslogyThe precise pathophysiology behind

heterotopic ossifcation is still unclear but isthoughttoberelatedtobothlocalandsystemic

actors causing osteoblastic dierentiation o

pluripotentmesenchymalstemcells.ThemostrecentworkhasocusedonBMPsignalingand

identifcationoprogenitorcellsresponsibleorectopicboneormation.

Muchoourunderstandinghas come rom

the work o Drs. Eileen Shore and FrederickKaplan investigating fbrodysplasia ossifcan

progressiva,araregeneticdiseasecharacterized

byheterotopicbone ormation. PatientswiththiscongenitaldisorderhaveamutationintheACVR1genethatcausesconstitutiveactivation

o BMP type-I receptor activity and ormationoectopicbone4. Inhibitiono transcriptionaactivityoBMPtype-Ireceptorswithantagonist

such as noggin and chordin has been shownto disrupt the osteoblast dierentiation

signalingpathway5,6.Micelackingnogginshowoveractivity o BMP and display exuberan

orthotopic and heterotopic ossifcation. TheroleoBMPsignalingasanimportantregulatoo ectopic bone ormation, along with other

mediatorssuchasplatelet-derivedgrowthacto(PDGF), insulin-like growth actor 1 (IGF-1)

and transorminggrowth actorb-1 (TGFb-1)continuestobetheocusoresearchattempting

toelucidatekeyinitiatorsandregulatorsinthicellularprocess.

Traumaandsottissueinjuryisaconsistent

eature o heterotopic ossifcation, and manyinvestigators have sought to elucidate the

cellular and molecular mechanisms that linktraumatizedsottissuetoectopicboneormation

Jackson et al recently identifed and isolateda population o multilineage mesenchyma

progenitorcellswithosteogenicpotentialthatwerelocalizedprimarilyintraumatizedtissue7

Subsequent studies have shown that these

mesenchymal progenitor cells isolated romtraumatizedmusclehadthepotentialtoservea

osteoprogenitorcellsintheormationoectopicboneaterinjury8.Lounevetalsuggestedthatcellsresponsibleorheterotopicossifcationare

romtheendotheliumothelocalvasculature9

By using two mouse models o dysregulated

Corresponding Author:Jason E. Hsu, MDDepartment of Orthopaedic SurgeryUniversity of Pennsylvania3400 Spruce Street, 2 SilversteinPhiladelphia, PA 19104Jason.Hsu@uphs.upenn.edu

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BMP signaling andheterotopic ossifcation, they were abletoidentiyprogenitorcellsthatcontributetodierentstages

o the heterotopic endochondral anlagen. Progenitor cellswith markers consistentwith endothelial precursorswerepresent inall stages o the endochondral anlagen, whereas

skeletaland smoothmuscle progenitorshadminimal tonocontributionatanystage9.Resultsothisstudysuggestthat,in

asettingochronicallystimulatedBMPactivity,muscleinjuryandassociatedinammationsufcientlytriggersheterotopic

boneormationandthatcellsovascularoriginareessentialto construction o ectopic bone. This cell lineage, alongwithstimulatingactorssuchasBMPthatcreatethecorrect

environment or bone ormation, could be targets or thedevelopmentotherapeuticinterventionstotreatheterotopic

ossifcation.

Prevalence and Risk FactorsThese recent advances in ourunderstandingo ectopic

boneormationaretimely,asmultiplestudieshaverecently

reportedonthehighincidenceoheterotopicossifcationin

soldierssustainingextremitywarinjuries.Increaseduseoexplosiveweaponryhasresultedinarisingnumberoblast

type injuries. Furthermore, advancements in resuscitativemedical care, hemostatic measures, and damage control

surgeryhaveresultedinincreasedsurvivalromotherwisedeadly injuries10. A recentretrospective studybyForsberg

etaloutotheNationalNavalMedicalCentershowedthatthemajorityopatients(65%)whosustainedextremitywarinjurieshaddevelopedradiographicallyapparentheterotopic

ossifcation11. Associated risk actors or development oheterotopic ossifcation included lower extremity trauma,

amputated limb, and multiple extremity injuries. Theseresultsare inconcordancewitha recentstudybyPotteret

al12

,whichsupportedtheroleoheterotopicossifcationasa causeo painin the residual limbsomilitary amputees(Figure 2). This group reported a similar prevalence o

heterotopic ossifcation (63%) as Forsberg et al. Sevenpercent o amputees required operative excision o bone

at an average o 8.2months ater the initial injury. Theseresults highlight the increased prevalence o heterotopic

ossifcationinwar-woundedpatientswhencomparedtothecivilianpopulationandurthersupporttheneedorresearchidentiyingandtargetingsignalsthatstimulateectopicbone

ormationaterlocalsottissuetrauma.Historically,heterotopicossifcation ismoreotenknown

toaectpatientssustainingtraumaticbraininjuryandspinal

cordinjury13.Theratesoheterotopicossifcationarereportedtobeapproximately11%inTBIand20%inSCI14,15andmostotendevelopsinthespasticlimbsothesepatients.Similarto those patientswith fbrodysplasia ossifcans progressiva,

neurologicallyimpairedpatientshaveagreatlyincreasedrateoheterotopicossifcationwhentheysustainlocaltraumaor

with orcible passive movement16. Post-traumatic racturesanddislocationsareotencomplicatedbyheterotopicbone,

and the incidence o heterotopic ossifcation ater surgicaltreatment o acetabular ractures has been reported to be

about25%17.Itisalsooneothemostrequentcomplications

ollowingtotalhiparthroplasty,althoughectopicboneinthi

settingisnotalwaysoclinicallysignifcance18.

Patient EvaluationEarlyidentifcationopatientswithheterotopicossifcation

can be difcult. The natural history o heterotopic boneormationisnotwelldefnedanddependslargelyonetiology

Usually, heterotopicbonewill begin limiting joint range omotioninthefrsttwomonthsaterinjuryorsurgerybutcan

alsofrstpresentoverayearateroriginalinsult.Themostcommon clinical signs are airly nonspecifc, such as pain

erythema,swelling,andwarmthotheaectedjoint.Becausemanyothesepatientshavesueredneurologicinsult,theicognition may be impaired, urther obscuring the clinica

diagnosis.Inpatientswithimpairedlevelsoconsciousness,the clinician isotenobligated to rule outotherdiagnoses

such as inection, deep vein thrombosis, and osteomyelitisNonetheless,thediagnosisoheterotopicossifcationshould

beconsideredinthosepatientswithknownriskactorsordevelopment.

Radiographically,plainflmstakenatthetimeoonsetosymptoms are seldom useul, as the maturation o ectopicbone doesnot become evident until weeks ater onset o

clinicalsymptoms.Three-phasebonescintigraphyisauseulimagingmodalityorearlydiagnosis,andMRIhasbeenshown

Figure 2. Extensive heterotopic ossication in a residual lower limb.

Figure 1. Heterotopic ossication of the posterior elbow (A) and medial knee (B).

A B

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todetectormationoectopicboneweeksbeoreevidenceon

x-ray.Laboratorystudiessuchasserumalkalinephosphataselevelmaypotentiallybetheonlyhelpulobjectivemeasure

inmaking the diagnosis in thesepatientsduringthis initialphase.Althoughsensitive,itisnotspecifc,andalterationsin

serumlevelscanbedependentonhepaticandrenalunction.Becauseothelackosimpleobjectivemeasuresindetectingheterotopicboneormation,thediagnosisisotenmissedin

theearlystages,leadingtodelaysintreatment.Asectopicbonematuresandappearsonplainflms, the

eect o substantial jointcontracturesand rangeomotionlimitationswillbecomemoreevident.Patientswithankylosed

joints orneurologic sequelae due to ectopic bonemay beconsideredsurgicalcandidates.Incertaincases,aCTscancanbeahelpuladjuncttoplainflmsindefningthepresenceo

intra-articularlesionsaswellastheextentoossifcationanddisuseosteopenia(Figure3).Theseactorscanbepredictive

ocomplicationssuchasintra-operativeractureandlossorangeomotion19.

Treatment StrategiesMedical Management and Radiotherapy

Withaconstellationoappropriateclinicalsignsinapatientand an appropriate workup to rule out DVT or inection,

earlydiagnosisoheterotopicossifcationcanbemadeandisotenkeytostartingappropriatetherapy.Earlyinitiationothesevarious therapiesmayimproveclinical outcomes and

preservejointmobility.Heterotopicossifcationidentifedintheearlyphasescanbeaddressedwithearlyphysiotherapy

and medically with bisphosphonates or nonsteroidal anti-inammatories(NSAIDs).Treatmentotenbeginswithgentle

physiotherapyandterminalresistancetrainingthroughapain-reerangeomotion.NSAIDs,particularlyindomethacin,have

showntobeobeneft,buttreatmentcannotbeusedincertainpatientpopulationsduetoassociatedrenal, gastrointestinal,

and bleeding complications. Bisphosphonates, such a

etidtronate,bindtohydroxyapatitecrystalsandmayinhibimineralization and calcifcation o sot tissue. However

clinical evidence supporting the use obisphosphonates ilimited.Radiationtherapyhasshownvalueintheprevention

o urther ormationandmaturation oectopic bone. Thimodality,however,islimitedbylogisticaldifculties,andotenitisdifculttopredicttheeventualsiteoheterotopicbon

ormation,particularlyinpatientssustainingheadinjuries.The optimal prophylactic treatment or preventing o

minimizing ectopic bone ormation is controversial. Most othe literature has been related to prophylaxis ater total hip

arthroplasty and post-traumatic heterotopic ossifcation, suchaspost-fxationoacetabular ractures20. Evidencecomparingthe roleo NSAIDs and radiation therapy is limited regarding

neurogenicheterotopicossifcationandnon-existentregardingthetreatmentotrauma-relatedamputations.Moststudieshav

concludednodierenceinrecurrenceorincomplicationswitheithertreatmentmodality21,whileotherstudieshavesupported

a synergestic eect o both modalities used simultaneously

Unortunately, the majority o studies in the literature areretrospective innatureandlack controlgroups. Theprimary

beneftoNSAIDsoverradiationiscost,withrecentstudiesusingMedicaredata reportingtheaveragecost oNSAID treatmen

($20)asbeing45times less than that oradiation treatmen($899)22. However, administering NSAIDs to all patients a

riskorheterotopicossifcationisdifcultto rationalizewhenconsideringthecomplicationsassociatedwithitsuse.

Theuseoradiationtherapyinthepreventionoheterotopi

ossifcationstemslargelyromthetotalhipliterature.Adoseo 700 to 800 cGy o local radiation in thefrst ourpost

operativedaysiscommonlyusedtopreventHOormationinhigh-risktotalhippatients.AstudybySchaeerandSosne

utilizeda totaldoseo20Gyin10 ractionstotwopatientwithincreasingserumalkalinephosphataseassociatedwithclinicalsignsoheterotopicboneormation23.Bothpatients

had complete pain relie and improvement in joint rangeomotion.Morerecentstudiesemployingalargernumber

opatients have ailedto show the same results. Ciprianoetalshowedthatthestandardsingle700cGydoseoloca

radiationwithinthefrstourpost-operativedaysaterectopicboneexcisionwasnoteectiveinpatientswithneurogenicheterotopicossifcation24.Furtherstudieswithhigherdose

oradiationtherapymaybewarranted.Because o the side eects and logistical problems

associated with current prophylactic options, other more

selectiveagentsarebeingstudied.Shimonoetalreporttheuseoselectiveretinoicacidreceptoragonistintheinhibitiono ectopic bone ormation, suggesting its possible role inthe treatment o heterotopic ossifcation25. Isotretinoin, a

nonselective retinoic acid receptor agonist, was previouslytestedasatreatmentinpatientswithfbrodysplasiaossifcans

progressiva,andalthoughadecreasedincidenceoHOwasobservedcomparedtocontrols,anumberosignifcantsid

eectswerenoted26.

Figure 3. 3D CT reconstruction demonstrating heterotopic ossication of the hip.

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Surgical Intervention

Surgical excision is oten necessary in the treatmento

severe heterotopic ossifcation limitingmobility or causingneurologicproblemsandcansignifcantlyimproverangeo

motionandqualityolie.Controversyoverearlyversuslateresectionexists,especiallyregardingexcisiono neurogenicheterotopicossifcation.Someexpertsbelievethatossifcation

is less likely torecuratera prolongedobservationperiod,whichallowsorresolutionotheacuteinammatoryphase

and maturation obone. Othershave suggested that earlyexcisionallowsorincreasedrangeomotion,thepreventionosot-tissuecontractureandmuscleatrophy,andprevention

ointra-articularankylosis27.Optimaltimingosurgerymaybedependent onetiology or example, the ormationo

heterotopicbonecanoccurlaterintraumaticbraininjurythaninspinalcordinjury28.Thecurrentliteraturedoesnotsupport

thetheorythatearlyexcisiontriggerslaterrecurrence29.

Many studies have investigated timing o excision oheterotopicboneromtheelbow,andorthemostpart,have

supportedearlyexcision30,31.Mostretrospectivecaseserieshavereportedgoodresultsaterexcisionoheterotopicossifcation

otheknee32,33(Figure4),andexcisionoheterotopicboneater traumatic amputation has been shown to have low

recurrenceandcomplicationrates12.Heterotopicossifcationothehip,however,canbeassociatedwithnumerousperioperative complications, especially iatrogenic emoral neck

ractures and inection. Recent studies on excision ohipheterotopicossifcationhaveidentifedriskactorsassociated

withcomplications,andassociationbetweendelayedexcisionand peri-operative complications have been established19

Patientsinwhichexcisionwasdelayeduntiljointankylosishavehigherratesointra-operativeiatrogenicracture,likelysecondarytoseverelydecreasedbonedensity.Intra-articular

pathologyandosteoporosis,whichdevelopmorecommonlyinpatientsinwhichexcisionisdelayed,areassociatedwitha

higherchanceoiatrogenicemoralneckracture.Inaddition,delayinsurgeryotenresultsinineriorunctionaloutcome

intermsojointrangeomotion.

ConclusionNumerous risk actors are known tobe associatedwith

theormationoectopicbone,butthemechanismsbehindwhichthesechangesoccurarepoorlyunderstood.Curren

preclinicalworkhasmadeslowbut steady progress inouunderstanding o the etiology and pathophysiologybehind

heterotopicboneormation.Identifcationopatientsintheearlyphasesoheterotopicossifcationcanbedifcultbutisimportantintimelyinitiationovariousormsoprophylactic

therapy. Surgical excision can oten provide symptomaticrelie and improvedmobility, butoptimal timing o surgery

canbedifculttoestablish.Hopeully,currentlaboratoryandclinical investigationswillhelpusunderstand thispuzzling

clinicalentity,andleadtonewpreventativeand therapeuticmeasuresinthemanagementothisdebilitatingproblem.

Figure 4. (A) Heterotopic ossication of the medial knee causing a knee exion

contracture. (B) Excision of ectopic bone from the medial knee.

A B

Ask the ExpertMary Ann Keenan, MD

University o Pennsylvania

What parameters and patient actors do you prioritize

in deciding when to perorm surgical excision o

heterotopic ossifcation?

I excise the heterotopic ossifcation when there is a clearcortex visible on plain radiographs. This indicates that there

is sufcient maturity to localize the extent o the heterotopic

ossifcation during surgery. It also decreases the more

extensive bleeding that occurs when attempting to excise

actively growing heterotopic bone with its associated intense

inammatory response. The ectopic bone becomes well-

defned radiographically within a ew months. This allows

the patient to be mobilized airly quickly ollowing the

inciting injury. Prolonged joint immobilization also causes

atrophy o the articular cartilage. To my knowledge there

is no clear evidence that the rate o recurrent heterotopic

ossifcation is related to the maturity o the process.

What is your current preerence or prophylaxis?

There are no clear studies showing that prophylaxis ater

surgical excision o heterotopic ossifcation has any eec

on recurrence. Use o NSAIDs is oten not possible because

o bleeding concerns or gastrointestinal side eects. We

recently completed a retrospective study showing that 700

gy o radiation given on the frst post-operative day was

not eective in preventing recurrence. That being said, I no

longer use radiation but I do use Indocin when there are

no contra-indications. Using treatments or the prevention

o heterotopic ossifcation ater trauma is less well-studied

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Approximately 20% o brain injury or spinal cord injured

patients develop heterotopic ossifcation. The problem has

always been that we have no way to know which patients are

at risk or heterotopic ossifcation. It doesnt seem reasonable

to treat everyone prophylactically, especially when the long

term eects o low dose radiation are unknown and the risk

o NSAIDs can be clinically signifcant.

Do you ever recommend bisphosphonate medicaltherapy or patients with established HO?

No. The only studies I am aware o are in spinal cord

injured patients. I the patient has clinical evidence o HO

ormation with a hot bone scan and negative radiographs,

then immediate IV Didronel seemed to help. Once there were

any calcifcations seen on radiographs, no eect o Didronel

was noted. It is almost impossible to catch a patient at the

correct time.

Are there any treatment or rehabilitation strategie

or amputees in whom prosthetic use is limited by the

development o heterotopic ossifcation?

Occasionally the heterotopic ossifcation in the residua

limb does not interere with prosthetic ftting. Most timesheterotopic ossifcation limits the use o a prosthesis since al

prosthetic designs or lower extremity amputees require end

weight bearing. When there is extensive skin scarring or spli

thickness skin grats o the residual limb, then the patien

cannot tolerate any heterotopic ossifcation. I have also had

to remove heterotopic ossifcation rom the posterior knee o

through-knee amputees to allow or adequate knee ROM.

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