current review heterotopic classification
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126 UNIVERSITYOFPENNSYLVANIAORTHOPAEDICJOURNAL
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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