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EvidenceReport:RiskofBoneFractureduetoSpaceflight-inducedChangestoBoneHumanResearchProgramExplorationMedicalCapabilitiesElementApprovedforPublicRelease:May12,2017NationalAeronauticsandSpaceAdministrationLyndonB.JohnsonSpaceCenterHouston,Texas

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CURRENTCONTRIBUTINGAUTHORS:JeanD.Sibonga NASAJohnsonSpaceCenter,Houston,TXHarlanJ.Evans KBRwyle,Houston,TXScottA.Smith KBRwyle,Houston,TXElisabethR.Spector KBRwyle,Houston,TXGregYardley KBRwyle,Houston,TXPREVIOUSCONTRIBUTINGAUTHORS:JeanD.Sibonga NASAJohnsonSpaceCenter,Houston,TXJerryMyer NASAGlennResearchCenter,Cleveland,OH

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TableofContentsI. PRDRiskTitle:RiskofBoneFractureduetoSpaceflight-inducedChangestoBone.................................................................................................................................................................4II. Context..................................................................................................................................................4III. ExecutiveSummary....................................................................................................................4IV. Introduction...................................................................................................................................6V. Evidence............................................................................................................................................121. DataObtainedfromSpaceflightMedicalOperations................................................122. DataObtainedfromScientificInvestigationsinFlight............................................132.1 QuantitativeComputedTomography(QCT).........................................................132.2 BoneTurnoverBiomarkers.........................................................................................132.3 EndocrineRegulation....................................................................................................132.4 RiskFactorsforReductionsinBoneStrength......................................................132.5 ProbabilisticRiskAssessments...................................................................................142.6 AnalysisofDatafromLong-DurationMissions(MirandISS).......................15

3. DataObtainedfromGround-BasedStudies..................................................................17VI. Computer-BasedSimulationInformation.....................................................................19VII. RiskinContextofExplorationMissionOperations...................................................22VIII. Gaps................................................................................................................................................25IX. Conclusions.................................................................................................................................25X. References...................................................................................................................................27XI. Team..............................................................................................................................................34XII. ListofAcronyms.......................................................................................................................34

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I. PRDRiskTitle:RiskofBoneFractureduetoSpaceflight-inducedChangestoBone

RiskStatement:Giventhatspaceflightmayinduceadversechangesinboneultimatestrengthwithrespecttomechanicalloadsduringandpost-mission,thereisapossibilityafracturemayoccurforactivitiesotherwiseunlikelytoinducefracturepriortoinitiatingspaceflight.

II. ContextDeclinesinbonemineraldensity(BMD)occurduringspaceflightataveragedlossratesbetween1-1.5%permonthfornormallyweight-bearingskeletalsitesonEarth(e.g.,hip,lumbarspine,lowerlimbsofbody).ThesecalculationsarebasedupontotallossinBMD,asmeasuredbydual-energyX-rayabsorptiometry(DXA)technology,inastronautsbeforeandafteratypical4-6monthlong-durationmission.Currently,therearenodatavalidatingapercentagelossinBMDasapredictorofbonefractureforaterrestrialpopulationrepresentingtheagesofastronautsflyingonlong-durationmissions,butdeclinesinbonemass(ascapturedbyBMD)areclearlyariskfactorforfracture.Itisunclearwhetherbonemineraldensitywillstabilizeatalowerlevel,orcontinuetodiminishforlongerspaceflights.Itisalsounknowniffractionalgravity,presentonthemoonandMars,wouldmitigatetheloss.Thislevelofbonelossdoesnotcreateanunacceptableriskoffracturesformissionsinmicrogravity(ISSandasteroid),butmissionsinafractionalgravityenvironmentormissionsgreaterthan6monthindurationcouldcreatehigherfracturerisk.

Theriskoffractureduringamissioncannotbeestimatedwithanylevelofcertaintyuntiltheprobabilitiesofoverloadingbonesduringthemissionsareunderstood.Ifmission-relateddeclinesinbonestrength(orthefailureloadofbone)cannotbecorrectedbyin-andpost-missionrehabilitation,crewmemberscouldbeatgreaterriskoffracturesafterreturntoEarthoranyotherplanetarybody.Boneparametersthatcontributetobonestrengthandthataccuratelyreflectchangesinbonestrengthduetomicrogravityarenecessarytoframethisrisk.Forvariousspaceflightmissionscenarios,within-missiontasksandpost-missionactivitiesandinthecontextofotherriskfactors,theabilitytoassesstheprobabilityoffracturewillhelpdeterminewhichmitigationstrategiesareoptimalandhowtheyshouldbeemployed.

III. ExecutiveSummarySpaceflight-inducedboneatrophyistargetedtospecificregionsoftheskeleton.Site-specificlossesoccuratnormal(Earth)weight-bearingskeletalareas,suggestingthattheregionsthatexperiencelargerdeficitsinmechanicalloadinginmicrogravityundergothegreaterreductioninbonemass.Collectively,theaveragedecrementofpre-flightarealbonemineraldensity(aBMD)permonthis1-1.5%,althoughthereis

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considerablevariationoflossbetweendifferentskeletalsitesandbetweendifferentcrewmembers.Thetimecourseofboneminerallossduringatypical6-monthlong-durationmissionhasnotbeencharacterized,noraredataavailableforcharacterizationformissiondurationsofover6months.Consequently,itisnotknownifandwhenthelossofbonematrixandbonemineralwilleventuallyplateau,norisitknownifboneatrophycanbemitigatedbythepartialgravityenvironmentsofthemoonandMars.Asdictatedbyterrestrialmedicine,fullunderstandingoftheriskofbonefractureduringamissionandlaterinliferequiresthattheeffectsofspaceflightbeevaluatedwithadditionalmeasurementsthatarebeyondDXAaBMD.Consequently,theoperatingbandsforastronauthealthandperformanceduringamissionarenotfullydefined(NASA2014).Itisunclearwhichadditionalmeasurementsofbonecanfullycapturetheeffectsizeofspaceflight.Itisnotknownhowthespaceflight-inducedchangestoboneaffectsthestrengthofbone,suchastheloadvectorthatbonecanresistbeforefailure,orifbonestrengthcanbefullyrecoveredafterreturntoEarth.Thecomplexityofbonetissuerequiresalevelofevidencethatcannotbemetbybioastronauticsresearchduetotheslowaccumulationofbiomedicaldataandsmallnumberoflong-durationastronauts.Withthelackofclinicalevidencefortheriskandtheaggressiveplanningforfuturespaceexploration,researchtechnologiesandanalysesmayneedtotransitiontotheclinicalarenaundermissionoperationcircumstancestofacilitateriskdefinitionandattemptmitigation.Giventhepaucityofdata,statisticalandcomputationalmodelingmaybeusefultoolstounderstandinghowchangestomusculoskeletalphysiology,tissueandcellularactivitiescaninfluencefractureprobability.TheFactorofRiskindexforfractureevaluatestheratioofappliedloadtothefailureloadofbone.Consequently,theriskforfractureisminimalduringmissionsinlowEarthorbitbecauseappliedloadsassociatedwithfalling,orwithcrushing,areessentiallynon-existentinamicrogravityenvironment;thosethatdoexistcanbesuccessfullymitigatedby“engineeringout”theriskwithhuman-protectivedesign.Mechanicalloadstobone,however,mayincreaseinthegravitationalenvironmentofplanetarysurfaces.Likewise,theriskincreaseswiththeperformanceofmissionactivitiesduringexplorationmissions,suchastheconstructionofhabitats,ambulationinextravehicularsuits,jumpingfromladdersorstructures,conductingvehicleegresses,oroff-nominalspacecraftlandings.Similarly,riskincreasesafterreturntoEarthwiththeresumptionofpre-flightphysicalactivitiesthatmayoverloadskeletalintegritybeforeitisfullyrestored.Theincreasedriskforbonefracturemayalsoexistinlong-termskeletalhealthwiththecumulativeeffectsofagingandofspaceflight-associatedremodeling.Therearemedicalrequirementstomonitortheskeletaleffectsoflong-durationspaceflightwithmeasurementsofaBMDbyDXAandofbiomarkersforboneturnover.Somespecifictypesoffractureshaveonlyrecently(e.g.vertebralcompression)ornotatall(e.g.occultstressfractures)beenassessedinastronautsafterreturn.Structuralevaluationsofbonesusingnewerimagingtechnologieshavenotbeenmeasuredlongitudinallyinthemajorityofastronauts.ThepatternofBMDlossandrecoveryneedstobeevaluatedfurtheronamultifactorial,cross-discipline

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level.Inordertoidentify,understand,anddefinetheriskfactorsforbonefractureoccurringduringandafterspaceflight.Additionally,boneneedstobefullyevaluatedwithspecificandexpandedmeasuresbeyondBMDtocapturechangesto“bonequality.”Thisishighlightedfurtherbythemostmoderndefinitionofosteoporosisas“…askeletaldisordercharacterizedbycompromisedbonestrengthpredisposingapersontoanincreasedriskoffracture.Bonestrengthreflectstheintegrationoftwomainfeatures:bonedensityandbonequality”(NIHConsensusDevelopmentPanelonOsteoporosisPrevention,Diagnosis,andTherapy2001).Tosummarize:

• Bonechangesoccurduringspacetravel.• Multiplefactorsduringspaceflight(physiologicalandenvironmental)can

influencebonechanges• DXA-measuredarealBMDhasbeenshowntobeanincompleteindicatorof

wholebonestrength.• Knowledgecharacterizingchangesinbonestructureandmicrostructureis

incomplete.• Therelativecontributionoftrabecularmicroarchitectureandbonegeometry

towholebonestrengthisnotknownbuttheliteratureindicatesthatitcouldbesubstantial.

• Duetothemultiplecontributorstobonestrength,thefullimpactofspaceflightonwholebonestrengthisunknown.

• Thestateofboneloadingfordifferentmissionscenariosisnotfullydefined.Hence,theriskforfracturenecessitatesunderstandingthebiomechanicalrelationshipbetweenappliedloadstoboneandthestrengthofbone.Tothisaim,theresearchgapsandtasksassociatedwiththeRiskforEarlyOnsetOsteoporosisassessestheconditionofbone(includingthetechnologies,themeasurements,theestimationsofbonestrength,andtheinterpretations),whilethegapsandtasksassociatedwiththeRiskforFractureassessesthefactorsthatinfluenceappliedloadsexceedingbonestrengthresultinginfracture.

IV. IntroductionTheprobabilityoffracturesispresumedtobeminimal(<0.1%)duringorafteramissioninlowEarthorbit.Thisperceptionisbasedpredominantlyuponthelowtonoincidenceoffractureinoverfivedecadesofspacetravelofincreasingduration,andlowtonoincidenceoffractureinlong-durationastronauts.Theabilitytomaintainhealthandfitnessinastronautsafterspaceflightsfurtherenforcesthispresumption.Thereareanumberoffactorsthathavecontributedtothisperception,andnotallarebaseduponastrongevidencebase.First,significantdecrementsinBMD,beyondDXAmeasurementerror,havenotbeendetectedformissionsoflessthan90days.Thereareminimalimpactforcestothebodyintheweightlessenvironmentandonplanetarysurfaces,limitingimpactforcesthatcould

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leadtofracture,andNASA’sbonehealthstandardsensuresufficientpre-flightbonemineraldensityforhipandspinetopreventastronautsfromreturningbelowtheminimumpermissibleoutcome(T-score≤-2.0)afterspaceflight.TheavailabilityoftheAdvancedResistiveExerciseDevice(ARED)after2009aswellasadequatenutritionduringflighthavesufficientlyreducedthepreviouslyobserveddeclinesinpost-flightBMDmeasurements(Smithetal.2012).Post-flightrehabilitationprogramsonEarthpromoteskeletalrecoveryandreducethefallrisk,andfracturesinimmediatepost-missionandlong-termhealthperiodshavebeencommonlyattributedtooverloading(trauma)oraging-relatedeffects.Finally,relianceuponastronautself-reportingoffracturesorindicativesymptomatologylikelyleadstounderestimationsoffracture.Thus,itisentirelypossiblethattheassumptionoflowfractureriskandincidencerelatedtolong-durationflightisundersupportedandnotentirelydata-driven.Withexplorationclassmissionsaimingforthemoonandbeyond,theaustereandremoteenvironment,the“unknowns”ofplanetexploration,andthelimitedpoint-of-carecapabilitiesmayincreasetheseverityofevenalowprobabilitymedicaleventsuchasfracture.Theoccurrenceofafractureinacrewmemberwouldnotonlyjeopardizeperformanceofmissionobjectivesduetofunctionalityimpacts,itcouldalsoleadtomedicalcomplicationswhichmightresultinsignificantmorbidityorevenlossoflife.Thedocumentedeffectoftheweightlessenvironmentonbonecellactivitiescouldimpairthehealingprocess,increasetheriskfornon-unionfractures,andexposethecrewmembertoadditionalcomplicationssuchassepsisorthromboembolyticclots.Therefore,itisofparamountimportancetoevaluatethepropensityofacrewmembertofractureaboneundertheconditions,includingmissionlengthandmission-criticaltaskperformance,andeffects,includingadaptivephysiology,ofaspaceflighttoensureappropriatemedicalcapabilitiesareavailable.On-boardcapabilitiesmayincludein-flightinterventionstopreventlong-termhealthfractures,includingprematurefragilityfracturesassociatedwithirreversiblespaceflight-inducedalterations,throughmitigationofdeconditioningorrehabilitationcapabilities.Evaluationoftheprobabilityofabonefractureduringaspaceflightmissionrequiresanassessmentoftherelationshipbetweentwomeasurableparameters:theloadvectorexperiencedbyabone(“AppliedLoad,”whichincludesbothmagnitudeanddirection)andtheabilityofthebonetoresistthatloadvectorwithoutfracturing(“BoneStrength”).Thisrelationshipdeterminesthe“FactorofRisk.”EstimatingaFactorofRiskforbonefractureusestheengineeringapproach,oftenusedinstructuredesign,ofcalculatingthe“FactorofSafety,”wherestructuralfailurelikelyoccurswhentheratioofResistingForce(strength)toDisturbingForce(stress)is<1.FactorofRiskistheinverseratioofFactorofSafety(ortheratioofAppliedLoadtoBoneStrength)wherefracturelikelyoccurswhentheratio>1.AsimpleandaccuratemethodtodeterminingtheFactorofRiskforabonefracturewouldtoquantifytheloadrequiredtofractureabone.Becausethisapproachisneitherpracticalnorethical,RiskforBoneFractureintegratestheresearchgapsandtasks

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withintheRiskforEarlyOnsetOsteoporosisthatdescribetheconditionofboneanditsBoneStrength.AssessmentsofBoneDensityinTerrestrialMedicineAwidelyappliedsurrogatetoreplacethedestructivecalculationofaFactorofRiskisaBMD,measuredbyDXA.DXAisanx-raybasedimagingtechnologywithahighlevelofclinicalutilitybecauseitissafe,available,andaffordable.Becauseofitsclinicalutility,thismeasurementhasbeenappliedtoamultitudeofclinicalstudiessubstantiatingitsabilitytopredictfracture,todetectaneffectsizeofintrinsicriskfactorsincludingmenopauseandaging,togeneratereproducibleresults,andtomonitortheeffectofosteoporosiscountermeasures.Thus,thenoteworthyvalueofaBMDasasurrogateforfractureriskisnotbecauseitprovidesanaccurateassessmentofbonedensity(astruedensityisnotareal),butbecauseoftheabundanceofepidemiologicaldatacorrelatingaBMDwiththeincidentfragilityfractures(fracturesduetoosteoporosis)inpopulation-basedstudies.DXABMDcutoffofaT-scoreoflessthan-2.5wasestablishedfordiagnosingosteoporosisinpostmenopausalwomenbaseduponthedetectionofosteoporosisin~30%ofpostmenopausalwomenatthisscore(Kanisetal.1994).Usingthiscutoff,physicianscanidentifyaclinicallymeaningfulnumberofwomenwhowouldbegoodcandidatesforosteoporosistherapy.Inthiscase,aBMDisausefulindexforstratifyingtherelativeriskforfractureamongstpostmenopausal,Caucasianwomen;however,aBMDaloneisnotagoodpredictorofwhowillfracture(Cummingsetal.1995).Reportsintheliteraturehavehighlightedadisconnectbetweenactualfractureincidenceandcalculatedrelativerisk,asindicatedbyaBMDT-scores(Riggsetal.1990;Cummingsetal.1998;Gutteridgeetal.2002;Schuitetal.2004;Wainwrightetal.2005;Chesnutetal.2005;Sornay-Renduetal.2005).ThedeclineinthespecificityandsensitivityofDXAaBMDforpredictingfragilityfracturesmayberelatedtothefailureofaBMDtoreflectacompletepicturewholebonestrength(NIHConsensusDevelopmentPanelonOsteoporosisPrevention,Diagnosis,andTherapy2001).GiventhenecessitytoexpandmeasurementsbeyondaBMDT-scores,significantworkhasbeenputintothedevelopmentofmoreaccuratemeasurementtools.Ameta-analysisof12cohorts,representing60,000subjectsandmonitoringover250,000person-yearsand5,400fractures,providedthebasisfortheFRAXcalculator(FractureRiskAssessmentTool,UniversityofSheffield,UK)whichusesclinicalriskfactorswithandwithoutfemoralneckBMDtodeterminea10-yearprobabilityoffracture(WorldHealthOrganization2004).However,theFRAXcalculatorisnotrecommendedforuseinhumansunder45yearsofageanddoesnotincludeanimportantastronautriskfactor:theprolongedskeletalunloadinganddisuseofboneduringmicrogravityexposure.Asaresult,theFRAXcalculatorhaslimitedrelevancetoassessingfractureprobabilityinastronautsduetospaceflight.ThelimitationofaBMDasasurrogate,andthelackofabetteralternative,hadalsobeenexpressedinthepreviousevidence-basedBioastronauticsReport(NASA

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HumanResearchProgram2016).Thus,theNASAHumanResearchProgram(HRP)supportsinvestigationstosupplementthemeasurementofspaceflighteffectsontheskeleton.Manyrecentandongoingstudiesincludenovelandemergingtechnologyinordertomeasureindicesof“bonequality”andobtainanexpandedreflectionofskeletalintegrityassociatedwithspaceflight,forbetterpredictivecapabilityoftheriskoffractureinlong-duration,explorationmissions.AssessmentofBoneQualityforTerrestrialApplicationsOnelimitationoftheDXAtechnologyinitsmeasurementofaBMDisthattheindexfailstoaccountforthesizeandgeometryofabone.Figure1depictshowthebendingandcompressivestrengthofwholebonearedependentuponitssizeandgeometry,whichcannotbedirectlyevaluatedbyDXA.TherehavebeenrecentattemptstomodifytheuseofDXAtechnologyfortheevaluationofvolumetricorstructuralparametersasindicesofBoneQuality(Prevrhaletal.2004;Beck2007)butthefailuretoachieveabetterunderstandingandassessmentoffractureriskaboveandbeyondDXAmeasurementofaBMD(Bonnick2007;BoudreauxandSibonga2015)haspresumablylimitedtheirutilityintheclinicalarena.

Figure1.MaryBouxsein,Ph.D.,BoneGeometryandSkeletalFragility.May2005BoneQualityMeetingHowever,thereareemergingtechnologiesforthenon-invasiveassessmentsofotherskeletalindicesbesidesaBMD,suchasotherputativeparametersofBoneQualitythatcontributetobonestrength.Inparticular,measurementsoftrue,volumetricBMD(vBMD,measureding/cm3)ofwholeboneandofbonecompartmentscanbeobtainedbyquantitativecomputedtomography(QCT).QCTmeasurementswerevalidatedinarandomizedcontrolledtrialforthepredictionofhipfractureinmenover65yearsold(Blacketal.2008).WhilethemeasurementofvBMDonlymodestlyimprovesfracturepredictionoverDXA-measuredaBMD,QCTenablesadditionalmeasurementsofthefemoralnecktoincreasetheunderstandingofspaceflight-inducedeffectsonfracturerisk(Blacketal.2008);thatis,QCT

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measurementsofthefemoralneck(percentcorticalbonevolume,trabecularvBMD,andminimumcross-sectionalarea)arepredictorsofhipfractureindependentofarealBMD(Blacketal.2008).Thiscapabilityisvitaltounderstandingfractureriskinanunderstudiedastronautpopulation(generallyyoung,healthy,andpredominantlymale)inwhichbonelossisunlikeage-relatedboneloss(Orwolletal.2013).Furthermore,magneticresonanceimaging(MRI)andhigh-resolutionQCTareemergingasnoveltechnologiestoassesschangestotrabecularmicroarchitectureofcancellousboneatperipheralskeletalsites[HR-QCT,Scanco].MRI-basedimagingofhiptrabecularmicroarchitectureandDXA-basedvertebralmicrostructuralanalysesarebeingdevelopedformicrostructuralassessmentsofthehipandspine(Hansetal.2011;MedimapsGroup2015;Changetal.2015).Suchmeasurementsmaybeusedtoreflectthedisruptionoftrabecularconnectivityordegradationofcancellousboneinthebonemarrowcompartmentofbone,asverifiedagainstparameterspreviouslyderivedfrombonehistomorphometry(Parfittetal.1987).Changestomicroarchitecturecaninfluencethemechanicalpropertiesanddistributionsofloadsincancellousbone(vanderLindenetal.2001).Untilrecently,theskeletaleffectsofspaceflightonbonemasshadonlybeendescribedbymeasuringaBMDdeterminedfromDXAscansperformedincrewmembersbeforeandafterthetypicallong-durationspaceflightmissionof6monthsontheInternationalSpaceStation(ISS).Therefore,evaluationofBoneQualityisstillrequiredtosubstantiatethisrisk,asspaceflightrepresentsacollectionofnovelriskfactorsthatcouldlikelyaffectmorethanarealBMD(forexample,radiationeffectsonbonemarrow).Whiletherearemultipleindicesthatcaninfluencethequalityofboneandwholebonestrength,suchasthedegreeofmineralization,microcrackaccumulation,resorptioncavities,andactivationfrequency,HRPneedstobefocusedonmaturetechnologiesinordertomeetitspath-to-riskreductionforanexploration-classmission.Thus,tasksthatareconsideredessentialinclude,first,thedeliveryoftechnologiesandteststhatenablenon-invasivemeasurementsofcrewmembers,particularlyifsuchtechnologieshavebeenpreviouslyvalidatedforclinicalutilityinterrestrialpopulations;andsecond,provisionofknowledgethroughmodelingandanalogvalidationsthatcanbetranslateddirectlytomissionapplications.PossibleRiskFactorsforFallsorInjuryAgeisanindependentriskfactorforfracture.Theprobabilityforfractureinthepostmenopausalwoman,forexample,increasesexponentiallywitheverydecadeover50yearsforagivenmeasurementofaBMD(Figure2).Youngerpersonsdonothavethemetabolicco-morbidities,thenutritionalissues,orthecumulativeexposuretobonelossriskfactorsthatcompoundbonefragilityintheelderlypopulations.OnEarth,youngerindividualsalsodonothavethemuscleloss,theposturalinstability,theimpairedneuromuscularcontrolandpoorvisualacuitythatincreasetheriskforfallinginagedpersons.Theintegrationoftheseclinicalriskfactorsaccountsfortheincreasedprobabilityforfractureinolderpopulationsas

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theselatterriskfactorsincreasethepropensityforfallsand,accordingly,theappliedloadstobone(DeLaetetal.2005).However,thesecontributingfactorsforinjurymayexistinastronautsdeconditionedbyprolongedtransitsbeyondlowEarthorbit.

Figure2.AgeasanIndependentRiskFactorforOsteoporoticFractures.Probabilityoffirstfractureofhip,distalforearm,proximalhumerus,andsymptomaticvertebralfractureinwomenofMalmö,Sweden.WhiletherelativeriskforfracturesmaybethesamebaseduponBMD,theprobabilityoffractureinthe50yearoldislessthantheprobabilityforfractureinthe80yearold.AdaptedfromKanisJAetal.OsteoporosisInt.2001.SlidecourtesyofS.Petak,M.D.ThereisanimprovedabilityofaBMDtopredictfractureswhenconsideredconcurrentlywithclinicalriskfactorspredisposingindividualstoosteoporosis(Kanisetal.2007).Table1outlinesclinicalriskfactorsassociatedwithterrestrialosteoporosis(Espallarguesetal.2001),whicharerarelyobservedinyounger-aged,physicallyhealthypersonsoftheAstronautCorps(<55yearsofage)priortolaunch.However,thereareriskfactorsforosteoporosis,asidentifiedbyCummings(alsopresentedinTable1),thataremorerelevanttocrewmembersafterthetypical6-month,long-durationmissioninspace(Cummingsetal.1995);manyofthesefactorsareevidentincrewmembersduringflightandduringre-adaptationtoagravitationalenvironment.Thisincludestheastronautreturningtotheirpre-flightlevelhighphysicalactivitysoonafterreturntoEarthwithassociatedgaitinstability,imbalance,orvisionimpairmentthatmayincreasethefallingrisksoonafterlanding(CourtineandPozzo2004;Mulavaraetal.2010;Maderetal.2011).VitaminDdeficienciesmayalsobeariskincrewmembersonexplorationmissionsduetoinsufficientsupplementation;VitaminDdeficiencieshavebeenassociatedwithanincreasedriskforfallingduetothevitamin’sbenefittoneuromuscularcoordination(Bischoffetal.2003;Bischoff-Ferrarietal.2004).Giventhepotentialconsequencesofthefracturerisk,rangingfromlossofeffectiveperformancetolossoflife,probabilityriskassessmentsshouldalsoconsiderthepresenceoftheobservedriskfactorsthatinfluencetheriskforfalling.Inaddition,itmaybeofvaluetocollect

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kinematicmeasuresfrommotionanalysisandaccelerometersthatcouldbeusedestimatefallvelocityandfallorientationwhileperformingfunctionaltasksinadeconditionedstate(e.g.,FunctionalTaskTesting).Table1.ClinicalRiskFactorsobservedinosteoporosispatientpopulationandproposedcross-disciplineriskfactorsrelevanttolong-durationcrewmembers(Cummingsetal.1995;Espallarguesetal.2001).

ClinicalRiskFactorsforOsteoporosis(Espallargues2001)

PutativeandIdentifiedRiskFactorsRelevanttoLong-DurationandExplorationCrewmembers(Cummings1995)

Aging(>70y)LowbodyweightWeightlossPhysicalinactivityCorticosteroidsAnticonvulsantdrugsPrimaryhyperparathyroidismDiabetesmellitus(TypeI)GastrectomyPerniciousanemiaAnorexianervosaPriorosteoporoticfracture

OnFeet≤4hoursperDay(reducedgroundreactionforces)Can’tRiseFromChairWithoutUsingArmsLowestQuartileDepthPerceptionLowestQuartileContrastSensitivityFair,PoororVeryPoorHealthVitaminDdeficiencyWeightLosstoBWatAge25BalanceinstabilityGaitimpairmentsSarcopeniaLowsunlightexposureLowcalciumabsorption

Anincreasedriskforfracturewillbesubstantiatedwhenmoredataarecollectedanduncertaintycanbereduced.ThisreportwillsummarizethecurrentevidencefrommeasurementsofriskfactorsthatinfluenceBoneStrengthandwillhighlighttheknowledgerequirements(gapsinknowledgebase)inordertocalculateandassesstheprobabilityforfractureduringexplorationmissionsperaNASA-developedprobabilisticfractureriskassessmenttool,theBoneFractureRiskModule(Nelsonetal.2009).

V. Evidence1. DataObtainedfromSpaceflightMedicalOperationsTodate,theDXAmeasurementsconductedpre-andpost-flightinlong-durationcrewmembershavecharacterizeddeficitsinaBMDforweight-bearingskeletalsites,withlosses,averagedpermonth,thataregreaterthanthelossesdetectedinperyearincomparablesitesinelderlypersons(Orwolletal.2013)andexceedtheexpectedratepredictedbyanalgorithmderivedfromtheapopulationcohort,basedonserialBMDmeasurementsof150menand150womenwithagescomparable(20-50years)totheastronautcohort(Aminetal.2010,2011).WhiledeclinesinaBMDareariskfactorforbonefragility,theNASAtestsforbonehealtharebaseduponBMDT-scoresandnotonpercentagelossinBMD.Moreover,T-scoresassessarelativeriskforfragilityfractures,notfromfracturesfromthebiomechanicaloverloadingofbones,acharacteroffracturesthataremoretypicalofyounger-agedpersons(Garrawayetal.1979;Ngetal.2012).Themedicaltestingfor

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riskoffragilityfractures(Sibonga2017,figure9)doesnotrevealanyincreasedriskforfragilityfracturesinastronauts.Anon-clinicalBMD(forexample,BMDforhip,spine,forearm)may“mask”aweakenedbonethatmaystrongenoughtoresistthemechanicalloadswithphysicalactivitiesperformedbeforespaceflight.

2. DataObtainedfromScientificInvestigationsinFlightAlthoughtheassessmentofboneintegrityisincomplete,therearedataintheevidencebasethatextendskeletalevaluationbeyondDXAaBMD.Whiletheseadditionalmeasurementsarenotpredictorsoffractureperse,thesemeasuresaddtothecharacterizationofspaceflighteffectsthatmayhelptodefinetherisk.Thesignificanceofthesedataissummarizedinsections2.1-2.6below.

2.1 QuantitativeComputedTomography(QCT)TheapplicationofQCTtechnologyprovidesmeasurementsofvBMDsforwholeboneandforseparatebonecompartments(corticalbone,cancellousbone,andcombined)andthree-dimensionalgeometryofwholebone,whichcanbeusedtoassesstheimpactofspaceflightonwholebonestrengthbyapplyingafiniteelementanalysis(Keyaketal.2005;Hernandezetal.2006).ThedatafromQCTscansconductedinlong-durationcrewmemberscharacterizedhowtheseparatecompartmentsofthehipadapttospacedifferently.Asdescribedlaterinthisreport,thesedatawereusedtoestimateaFactorofRiskforhipfractureonMars,moon,andafterreturntoEarth(Lang2006).

2.2 BoneTurnoverBiomarkersMonitoringthechangesinboneturnovermarkersisreportedtobepredictiveforchangesinbonemassandfracture(Garneroetal.1999;BonnickandShulman2006).Biologicalspecimens(urineandblood)collectedbefore,during,andafterflightwereevaluatedaftersamplereturntoEarth.Thedatasuggestthatboneadaptationinspaceisdrivenbyapredominatingboneresorptionthatisuncoupledtoboneformation(Smithetal.2005,2015).Thisperturbedboneremodelinginspacesuggeststhatthereisanetlossinbonemass,albeitabiomarkerforchangesovertheentireskeleton.

2.3 EndocrineRegulationThehumanskeletonservesasmineralreservoirformaintainingcalciumbalance,whichcouldbeagreaterissuethanfracturesforexplorationmissionsexceedingayear.Studiesoncalcium-regulatinghormonesdemonstratedhowtheendocrineregulationofcalciumhomeostasiscanbeinfluencedbytheboneatrophyanddemineralizationthatoccursinspace(Smithetal.1999,2005;Sibonga2017;Smithetal.2015).

2.4 RiskFactorsforReductionsinBoneStrengthMultipleriskfactorshavebeenidentifiedwithregardstoreductionsinBoneStrength.Thesefactorsincludethefollowing.

• ReducedaBMDatweight-bearingsites,anetincreaseinboneresorptionfortheentireskeleton,geometricalchangesintheproximalfemur,andarapidrateofboneminerallosscollectivelysuggestthatbonesoftheskeletonmay

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havedeclineinstrength(LeBlancetal.2000a;Langetal.2004;Smithetal.2005).

• Reducedcorticalthicknessandcompartment-specificreductionsinvolumetricBMDincorticalandcancellousboneofhipareassociatedwithreductionsincompressiveandbendingstrength(Langetal.2004)andareindependentpredictorsofhipfractureinagedmales(Blacketal.2008).

• EstimationsofloadcapacitywereassessedbyanalysisofmodelsgeneratedfromQCThipscans,performedbeforeandafterspaceflight.Significantreductionswerenotedinboneloadcapacities(minimumforcetocausefracture)forappliedloadingwithone-leggedstanceandposterolateralfalls(Keyaketal.2009).

• Preferentiallossesintrabecularboneobservedincrewmembersmaydisrupttrabecularconnectivityorreducetrabecularthickness,bothofwhichcouldaffectbiomechanicalstrengthofbone(vanderLindenetal.2001;Hernandezetal.2006).

• PersistentdeficitsintrabecularvBMDofthehipandoflumbarspine(L1,L2)in8ISScrewmembersinwhomafourthscanwasperformedbetween2-4yearsafterreturn(DanaCarpenteretal.2010)mayaddtoage-relateddeclinesandinduceprematurefragility.

• DeficienciesinvitaminDobservedinlong-durationcrewmembersafterapproximately6-monthspaceflightsmayinducesimilarimpairmentsinneuromuscularcoordinationandincreasedriskforfallingasdocumentedintheelderly(Bischoffetal.2003;Bischoff-Ferrarietal.2004)ifin-flightsupplementationforspaceflightmissionsbeyondlowEarthorbitcannotbemaintained.

2.5 ProbabilisticRiskAssessmentsCalculatingtheFactorofRiskforfractureisonlyasaccurateastheestimationsofbonestrengthandofappliedloads.Likewise,theassessmentoffractureprobabilityisdependentuponthenumberoffactorsthatinfluencetheprobabilityofanoverloadingeventoccurring,suchasthedurationofthemission,thetotalnumberofEVAsconducted,thefrequencyofEVAs,thetypesofmechanically-loadedevent(forexample,fallimpactswithhighenergy(suchasafallwhilecycling),orlowenergy(suchasasimpletripandfall)events).Estimationsofappliedloadtoboneareclearlynotperfect.Forinstance,somereportedalgorithmstocalculateloadsincurredbythehiponEartharebaseduponbodyweight;height,velocity,andorientationoffalls;anddampeningofforcebyfatpadding(Robinovitchetal.1991;Carpenteretal.2005;Riggsetal.2006).BothQCTandDXAdatacanstrengthentheestimationsbyincludingmeasurementsofsofttissuethicknessoverthehip(Riggsetal.2006;Ellmanetal.2010).Inaddition,thefactorofriskforexplorationmissionsonaplanetarysurfacerequiringintegratingtheeffectofpartialgravityonappliedloadsinfractionalgravityenvironment.Theseestimationsmaybeunderestimatedbecauseofthedifficultyinquantifyingthemulti-systemdeconditioningoftheastronauts,includingfactorssuchasvision

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impairment,muscleatrophy,reducedphysicalfitness,andpoorneuromuscularcoordination.EvenfactorssuchasrepetitivefallingduetoacumbersomeEVAsuitor“loping”toambulateinanEVAsuitwillincreasethehazardtofractures.Otherchallengesmayincludefractionalgravityinfluencingaproportionaldeclineinbonemass,(Ellmanetal.2013;Swiftetal.2013)ordeclinesinfallloadsbecauseofslowervelocitiesandlowerenergyoffallimpacts.Preliminarydata,includingestimationsofbonestrengthfromtheanalysisoffiniteelementmodels(Keyaketal.2009),supportthefractureriskandhavebeenpresentedinaseparateEvidenceBaseReportonEarlyOnsetOsteoporosis(Sibonga2017).Collectively,theriskforbonesbeingoverloadedinastronautsismorelikelyduetoanincreasedprobabilityofencounteringatraumaticloadbecauseofvisionimpairment,lossofneuromuscularcoordination,muscleatrophy,mobilityissuesandpossiblyreducedcognitionorpoorjudgment.Riskissimilarlyelevatedwithphysicalactivityinanunfamiliar,atypicalenvironment,suchasexplorationactivitiesonplanetarysurfaceswithpartialgravity,aswellasareturntotypicalpre-flightphysicalactivities,beforerestorationtopre-flightbonestrength,afterlandingonEarth.Tomanagethisriskofoverloadingbones,computermodelingisusedtoassesstheprobabilityofcrewmembersencounteringmechanicalloadsduringthelengthofanexplorationmissionwhileperformingmissiontasks(Nelsonetal.2009);suchmodelingmayalsobeusefulforassessingriskinastronautsafterreturntoEarth.

2.6 AnalysisofDatafromLong-DurationMissions(MirandISS)ThereisamedicalrequirementtoperformDXAmeasurementsofaBMDinthehip,lumbarspine,wholebody,forearm,andcalcaneusinlong-durationcrewmemberstoevaluatetheeffectsofspaceflight.DXAscanswereperformedwithin45dayspriortolaunchandwithinapproximately5daysoflanding.Recoveryofbonemass,asindexedbyaBMD,takesconsiderablylongerthanthetimetoincurtheloss(Vicoetal.2000;Sibongaetal.2007).Recoverycanbeinfluencedbymultiplefactorssuchasage,nutritionalintake,andpost-flightactivity,whichmayaccountfortherestorationofBMDtopre-flightstatusasearlyas6monthsafterreturn.Duetothecomplexityofbonetissueandthemulti-factorialnatureofboneloss,thereisrecognizedvariabilityinskeletalmeasurementsinEarth-basedpopulations.Likewise,itisnotunexpectedtoobservehighlyvariableresponsesbetweenskeletalsiteswithinonecrewmemberandbetweencrewmembers.Thisvariabilityisalsoevidentinassaysofboneturnovermarkerswhichareperformedinlong-durationcrewmembersatsimilartimepointsbeforeandafterspaceflightmissions.Biomarkersforboneresorptionarereportedtoincreaseearlyinflightwheretheyremainelevateduntiltheirrestorationtopre-flightlevelssoonafterreturn(Smithetal.2005).Biomarkersforboneformationarenotasprofoundlyinfluencedbyspaceflightandareeitherunchangedordecreasedduringspaceflight;circulatinglevels,however,areincreasedapproximately1monthafterlanding(Smithetal.2005).

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BasedupontheDXAmeasurementofaBMDandtheWorldHealthOrganizationGuidelinesforOsteoporosisDiagnosis(WHO1994),therearenodatatoindicateadiagnosisinastronautsafteralong-durationmission(Figure3).Inotherwords,nolong-durationastronauthasreturnedwitha“non-permissibleoutcome,”definedasaT-scoreof≤-2.0forthefemoralneck,trochanter,orspine(NASA2014).However,theseguidelinesweredevelopedforcliniciansconsideringinterventionsforperimenopausalandpostmenopausalwomenormenovertheageof50,atargetpopulationconsideredtobeatriskforage-relatedfractures.Althoughuseful,thecurrentaBMD-basedfracturestandardsforriskassessmentareprobablynotsufficientforassessingriskinastronautswhoarelosingbonemassbyadifferentimpactonboneremodeling(Orwolletal.2013).

Figure3.T-scoresbaseduponpre-flightandpost-flightmeasurementsofBMDandreferencesbacktoyoungwhitesex-matchedpopulation.Nolong-durationcrewmemberhasreturnedfromthetypical6-monthmissioninlowEarthorbitwithadiagnosisofosteoporosisaccordingto1994WorldHealthorganizationguidelines(WHO1994).Moreimportantly,asreportedintheEvidenceReportforEarlyOnsetOsteoporosis(Sibonga2017),theaveragemonthlyBMDloss(LeBlancetal.2000a,2007;Sibonga2017)increwmembersisalmostequivalenttotheannuallossofaBMDlossincomparablesitesofelderlypersons(Orwolletal.2013).ThiscomparisonofbonelossrateswasalsodemonstratedinTable2,whichdisplaysacomparisonbetweentheobservedlossesinBMDinlong-durationastronautstoapredictedlossbyamathematicalalgorithmdevelopedfromtheRochesterBoneHealthStudy(TheMayoClinic,Rochester).TheBMDdeclineinastronautswaspredictedbyaformuladerivedfromapopulationcohort(n~800)composedofsubjectsspanningtheage

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of19-97years(Aminetal.2010).Asmentionedabove,changesinaBMDovertimewerederivedfromserialBMDmeasurements,whichincludedmeasurementsin150menand150womenofagesthatspantheastronautagerange(20-50years),perhapstheonlypopulationstudyofbonehealththatincludesyounger-agedsubjects(Aminetal.2010,2011).Thegreater,calculatedmonthlyrateofBMDlossintheyounger-agedcrewmembersisreminiscentofaggressive,osteoclast-drivenboneresorptionobservedinpostmenopausalwomen.Ifresorptioncavitiesonthesurfaceofcancellous(trabecular)bonearetargetedtositesofincreasedstress,thencancellousbonestrengthandstiffnesscanbeinfluencedregardlessofthechangesinvBMDinthecancellousbonecompartment(Hernandezetal.2006).Thedepthandlocationofresorptioncavitiescannotbedeterminednon-invasively,butcouldbeconfirmedwithresearchintooptionssuchasinvitroanalyses,includinghistologyandmicro-CT,ofbonesamples.Table2.ComparisonbetweenobservedBMDchangesinmalelong-durationastronautsvs.predictedchanges,immediatelyandapproximately3yearsafterreturn(Aminetal.2010,2011).

Inadditiontotheriskofbonevolumeloss,clinicalriskfactorsthatinfluencethepropensityforfallinghavebeenobservedincrewmembersafterreturntoEarthfromlong-durationmissions.Lossesinposturalmusclemassareacontributingfactortoposturalinstability,whileassessmentsofhead-trunkcoordinationsuggestinstabilityduringstandingandambulation(LeBlancetal.2000b,a;CourtineandPozzo2004).Actualimpairmentsingait(BloombergandMulavara2003;Mulavaraetal.2010),jumping(Newmanetal.1997),anddecrementsindynamicvisualacuity(Petersetal.1996;Maderetal.2011)areevidentafterlong-durationmissionsinspace.

3. DataObtainedfromGround-BasedStudiesTherearenoground-basedspaceflightanalogsthathaveevaluatedFactorofRiskforbonefractureinhumansubjects.Therearenumerousanimalmodels(rodents,dogs,non-humanprimates)thatimmobilizeorskeletallyunloadlimbsorwholebodiesasameanstoinduce“disuseosteoporosis.”Theseanimalmodelsarevaluableresourceswithwhichtocharacterizethecellularandtissueeffectsofmechanicalunloadingunderwell-controlledexperimentalconditions(Turner2000).Thesemodelscanbefurtherappliedtoevaluatetheefficacyof

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pharmacologicalandmechanicalcountermeasuresusingmechanicalstrengthtesting(fracturingbonesunderdefinedloads)toquantifybonestrengthdirectly.However,aspreviouslydiscussed,therearemultiplephysiologicalandbiologicalmeasuresthatcaninfluencewholebonestrengthinhumans;asaresult,thehumanskeletaleffectsofdisusemightnotbecompletelymodeledbyanysinglespeciesmodel.Recently,HRPfundedthedevelopmentofananimalmodeltostudyfracturehealingandtotestarehabilitativeloadingprotocoltopromotehealinginthehypogravityenvironment.Aseriesofpublishedreportsdescribedanovine(sheep)modelforfracturehealingthatinducedtheskeletaleffectsofsimulatedmicrogravityonthetissueofthemetatarsal(Gadomskietal.2014a)displayeddelayedhealingundersimulatedmicrogravityonasurgicalexcision(osteotomy)ofthemetatarsal(Gadomskietal.2014b),andusedfiniteelementmodelstoassesstheinfluenceoflocalizedmechanicalloadingat0.25Gand1Gonfracturehealing(Gadomskietal.2016).Theinvestigations,conductedatColoradoStateUniversity,wereabletodescribestatisticallysignificanttissuedecrementsassociatedwithadaptationtomicrogravity,includingalossofbonemineraldensityof29.0%,areductioninbendingmodulusof25%,andadeclineinfailureloadof28%.Therewerealsodecrementsinparametersofbonehistomorphometry(bonevolume,trabecularthickness,trabecularnumber,formationratesandosteoblastnumberalldeclinedwhileosteoclastnumberincreased).Collectively,thesedatasubstantiatetheoverallfidelityofthesheepmodeltomimictheskeletaltissueeffectsofhumansinspaceaswellasdemonstratingtheutilityofanexternalfixationdevicetosimulateskeletalunloadingonthemetatarsal(Gadomskietal.2014a).Thesamemodelwasusedtoacquiredatathatsuggeststhatlocallyreducingmechanicalloadingbyvaryinghydrostaticpressureandstainpromotesintramembranousboneformation(asopposedtoendochondralossification),whichcouldaccountforthedelayedhealingandreducedintegrityofhealedfracturesinadisuseenvironment(Gadomskietal.2016).Thereisanaggressivepath-to-riskreductionforfuturemannedspaceflight;inthiscontext,modelsforprobabilisticriskassessments(PRA)mayberequiredinlieuofdatathatdirectlyquantifiesfractureoutcomes.OneNASAPRAtoolhastakenabiomechanicalapproachtoassessingfractureriskbyestimatingtheprobabilityofoverloadingtheskeletalbonesofanastronaut.ThisPRAmaybeindividualizedforaspecificbodyweightandheightandforcertainphysicalactivitiestypicalforthegivenastronaut.Tothisaim,theDigitalAstronautProject,conductedatNASAGlennResearchCenter,performsaserviceusingbiomechanicalalgorithmstoestimatethemechanicalloadstotheastronautduringpost-missionactivities.Inessence,thismodelingcouldbeusedtopredicttheabilityofadeconditionedbonetoresistloadsincurredduringperformanceofexplorationmissionobjectivesorafterreturntoEarth’sgravityenvironment.Anincreasedfractureriskdoesnotrequireabonewithosteoporosis;rather,anastronautmaybepredisposedtofracturebecauseoftheasymptomaticnatureofbonelossandasub-clinicalreductioninboneintegrity.The

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medicaltest,DXA2d-measurementofaBMDT-scores,doesnotquantifythisdeclineinstrength.

VI. Computer-BasedSimulationInformationAspreviouslydiscussed,theFactorofRiskforfractureistheratioofAppliedLoadstoFailureLoads,wherefractureislikelytooccurwhentheratiois>1.Theprobabilityoffracture,ontheotherhand,isdependentuponmultiplefactorsorvariables.TwoapproacheshavebeenusedtocalculatetheFactorofRiskforBoneFractureincrewmembersduringandafterlong-durationmissions.OnecalculationofFactorofRiskappliesfiniteelementanalysistofiniteelementmodelsdevelopedfromQCTscansofthehip(Keyaketal.2005).ThisapproachhasbeenusedtodeterminetheFailureLoadofbone(orBoneStrength)afterlong-durationspaceflight;forexample,estimatesforhipstrengthweredeterminedfortwoloadingorientationsanddeterminedfor11crewmembersscannedatthehipbyQCT(Keyaketal.2005;Lang2006).Inrecentyears,mergingdatafromterrestrialcohortsofagingpopulationsindicatethatfiniteelementmodelestimatesofhipstrengthmayberelatedtofracturerisk(Orwolletal.2009;Keavenyetal.2010;Keyaketal.2011),especiallyincombinationwithaBMD.Finiteelementmodelestimatesofhipfailureloadquantifytheabilityofthehiptoresistfractureforaspecificloadvector.Thisindexmaybethesinglebestexistingcompositeassessmentofbonestrengthbecauseofitsabilitytointegrateappliedloadswithgeometryanddistributionofmaterialproperties,suchasBMD,elasticmodulus,andyieldstrength,in3-Dbonestructure(Keyaketal.2005).WhilemodelestimationofstrengthonlymodestlypredictsfragilityfractureoveraBMD,thefinitemodeldoesintegratemultiplebonedeterminantsofbonestrength(Keyaketal.2005).This,inconjunctionwiththesingleaBMDsurrogateforbonestrength,mayenhancetheassessmentoffractureprobabilityineachastronautforindividualizedclinicaldecisions.ThisindividualizedapproachisdiscussedfurtherintheEvidenceReportforEarlyOnsetOsteoporosis(Sibonga2017).TheotherapproachwasdevelopedaspartoftheIntegratedMedicalModel(IMM),aMonteCarlosimulationapproachtospaceflightmissionsthatexplorestheeventspaceformedicalconcernsduringagivenreferencemission.TheIMMwasdesignedtobeaprobabilisticmodelsystemanddatabaseofsupportingmedicalconditionsusedtoprovidetherelativerisk,includinglikelihoodandseverityofoutcomes,forthelistofmedicalconditions.TheassociatedBoneFractureRiskModule(BFxRM)wasdevelopedattheNASAGlennResearchCenter(Nelsonetal.2009),designedtoestimatebonefractureprobabilitybyintegratingthefrequencyofevents,whereappliedloadsexceedsbonestrength,withphysicalactivitiesofhighorlowenergy.Specifically,themodulecanprovideadistributionofloadstothehipbaseduponafallwhileengaginginarangeofmostlikelyperformanceactivitiesoverthedurationofaspacemissionorintheimmediatepost-missiontimeperiod.Topredicttheprobabilityoffracture,theBFxRMtakesintoaccountthefollowingparameters:

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• Specificcrewmemberdata(forexample,age,height,bodymass,initialbonemass,jointandhipfatpadstiffness,anddampingcharacteristics)

• Thedurationoflow-gravityexposureatanygiventimeduringthemission,• TheattenuationcharacteristicsoftheEVAsuittoabsorbtheenergyof

impact(Sulkowskietal.2011)• Thedeflectivestrategiesoftheastronaut(forexample,armbracing)to

protectthemselvesbyenergyreductionandlimitingsubsequentinjuryfromafall

• Thespecificmissionparameters,includingdurationandtransittime,andmissiontasksthatwouldleadtohighlevelsofskeletalloading,

• Thenumberoftimesthatafracture-riskevent(suchasafallduringEVA,impactwithequipment)couldoccurduringamissionandthedetailsofsuchanevent,includingheightortranslationvelocity

• ThechangeinbonestrengthasafunctionofaBMDchange(LeBlancetal.2000a).

Todate,BFxRMestimatesadistributionofappliedloading,specifictothehip,perdesignreferencemissions;however,thismodelcouldbemodifiedtoassessoverloadingprobabilitiesforotherskeletalsites.Twoprimaryvariablesarecalculatedinthisriskanalysis,includingtheFactorofRiskforfracture(theratioofAppliedLoadtoBoneStrength)andtheprobabilitythattheFactorofRiskexceeds1(inotherwords,afractureoccurs)duringawiderangeofphysicalactivities.Toassesstheprobabilityoffracture,thefrequencyofoverloadingeventsandtheFactorofRisk(>1)arecombinedandconvertedtoaprobabilitythatistermedthe“FractureRiskIndex.”ThefrequencyandtypesofloadingeventsweregeneratedbyobservingApolloEVAfilmsthatdocumentedarangeofphysicalactivitiesaswellascross-referencingastronautreports.TheFactorofFractureRiskisconvertedtoaprobabilityoffracturefromalogisticregressionofactualfracturesandfromassumptionsfromtheliteraturegoverningtheFactorofRiskforfracturethreshold.Thisconversionisaccomplishedbyselectingrandomcombinationsofthefactorsandattributesdescribedabove,modelingviaMonteCarlosimulation,andgeneratingaprobabilisticdistributionformechanicalloads(kN)tothehipforISS,lunar,andMartianmissionsandduringpost-flightactivitiesonEarth(Nelsonetal.2009).IntheIMM,theprobabilisticmodelingapproachprovidesagroupmeanestimateoffractureprobabilitytothewrist,hipandlumbarspine;eachofthesesiteswaspreviouslyidentifiedbytheIMMtobeathigherriskthanotherbonylocationsforoverloadingandriskoffracture(Nelsonetal.2009).Equallyimportant,itprovidesboundariesoftheuncertaintyinthisPRAbyusingdataandprevailingassumptionsreportedintheliterature.Themodel’smetric,theprobabilityoffractureoccurrence,canbeusedindecision-makingandplanningforexploration-classmissionsandforcomparisonacrossalltheotherrisksinthemissioncontext.

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TheFactorofRisklevelsformaleastronautsduringaspecificEVAmissionscenarioonMarsandlunarmissionsaredisplayedinTable3.Forthisreport(Nelsonetal.2009),theFactorofRiskusedaBMDdataasthesurrogateforbonestrength.Table3.MissionaverageFactorofRisklevelsforseveraldifferentmissionscenariosforamaleastronautonExtravehicularActivities(Nelsonetal.2009).

Activityorevent Missionlocation

Missionduration

MeanFactorofRisk Std

FemoralNeckFractureFalltoside Moon Short 0.09 0.07Falltoside Moon Long 0.10 0.08Falltoside Mars Short 0.23 0.16Falltoside Mars Long 0.28 0.20LumbarSpineFracture45ºtrunkflexion,holdingaload Moon Short 0.12 0.0390ºtrunkflexion,holdingaload Moon Short 0.08 0.03Fallfrom1m,landingontwofeet Moon Short 0.30 0.05Fallfrom2m,landingontwofeet Moon Short 0.46 0.1045ºtrunkflexion,holdingaload Moon Long 0.12 0.0390ºtrunkflexion,holdingaload Moon Long 0.08 0.03Fallfrom1m,landingontwofeet Moon Long 0.31 0.06Fallfrom2m,landingontwofeet Moon Long 0.48 0.1045ºtrunkflexion,holdingaload Mars Short 0.29 0.0890ºtrunkflexion,holdingaload Mars Short 0.20 0.06Fallfrom1m,landingontwofeet Mars Short 0.56 0.12Fallfrom2m,landingontwofeet Mars Short 0.77 0.1645ºtrunkflexion,holdingaload Mars Long 0.34 0.1190ºtrunkflexion,holdingaload Mars Long 0.23 0.08Fallfrom1m,landingontwofeet Mars Long 0.64 0.17Fallfrom2m,landingontwofeet Mars Long 0.88 0.24

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Takingintoaccountavailabledatatodate,theFactorofRisklevelsatthefemoralneckareaveragedandprovidedforseveraldifferentactivitiesduringseveralspecificmissionscenarios.WhilenoFactorofRiskforfractureexceeds1(indicatingcertainriskoffracture)foranysingleevent,theprobabilityoffracturewillincreaseasthefrequencyofaneventincreases.NewspaceflightaBMDdatahavebecomeavailablesince2009withtheuseoftheAREDexercisecountermeasureontheISS.TheAREDprovidesweight-bearingexerciseswithupto600pound-forceresistancewhichmorecloselysimulatestheliftingoffreeweightsonEarth.Thiscapabilityprovidesthe2-3xbodyweightresistancetypicallyrequiredtomaintainbonemass(Kohrtetal.2004).PrevioustoARED,only300pound-forcewasprovidedbytheinterimResistiveExerciseDevice(iRED).Consequently,resistanceexercisewithAREDreducedthetotalchangeinaBMDinISSastronautsfollowingspaceflight.CalculatedratesofBMDloss(n=11astronautsasofsummer2012)aredisplayedinTable4.Table4.CalculatedmonthlylossinBMDbefore(LeBlancetal.2000a)andafterAREDuseonISS.Trochanter

RateofBMDLoss(%/mo)Pre-AREDUse

RateofBMDLoss(%/mo)WithAREDUse

Mean -1.56 -0.5StandardDeviation 0.99 0.4Minimum -0.01 -0.07Maximum -3.0 -1.34LumbarSpine

RateofBMDLoss(%/mo)Pre-AREDUse

RateofBMDLoss(%/mo)WithAREDUse

Mean -1.06 -0.32StandardDeviation 0.63 0.44Minimum 0 -0.16Maximum -2.0 -1.35VII. RiskinContextofExplorationMissionOperationsSpecificexplorationmissionscenariosaredefinedaccordingtothedurationofthetimeinspace(Table5).TheBFxRMwasappliedtoeachofthesemissionscenariostodeterminetheprobabilityofbonefractureduringtheperformanceofspecificmissionactivitiesandthedurationofthespecificmission(includinghabitationandtransittime).

Table5.DefinitionofExplorationMissionScenariosbyDuration

Duration Destination Transit Time to destination (days)

Length of Stay (days)

Transit Time to Earth (days)

Short Moon 3 8 3 Long Moon 5 170 5 Short Mars 162 40 162 Long Mars 189 540 189

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Figure4providesagraphicalillustrationoftheprobabilityofbonefractureoccurrenceformaleastronautsduringvariousactivitiesoreventsofalunarorMartianmission.Loadingeventsincludeafalltotheside,a45degreebendfromthewaist,a90degreebendfromthewaist,adropjumpfrom1meter,andadropjumpfrom2meters.Figure4showsthattheprobabilityoffractureisless(<0.2%)duringshort-durationmissionstothemoon,mostlikelyduetodecreasedexposuretimeinspace.Itispresumedthattheseverityofbonelossvariesasafunctionoftime,althoughitisunknownifbonelossisalinearoranexponentialdecline.GiventhattherecoveryofBMDafterreturntoEarthisasymptotic(Sibongaetal.2007),speculationisthatthedeclineinBMDfollowsasimilarpatternofdecline.Oftheactivitiesevaluated,theprobabilityoffractureisgreaterforfallstothesideandfordropsfrom2metersheight.Itcanbepresumedthatthelowergravitationallevel(roughlyone-sixthofEarthgravity)onthemoonwillmitigatebonelosslikelyproportionallywithfractionalgravity,asinarodentmodelforpartialweight-bearing(Ellmanetal.2013;Swiftetal.2013).Theprobabilityforfractureincreasesasthemissionsbecomelonger(0.02%moonto2.0%Mars)andinthehighergravityenvironmentoftheMartiansurface(roughlyone-thirdofEarthgravity).

Figure4.ProbabilityofbonefractureformaleastronautsduringreferencemissionstothemoonandMars(Nelsonetal.2009).Aspreviouslymentioned,aFactorofRiskhadbeencalculatedtoaddresstheimpactofaMarsmissionforfractureriskafterreturntoEarth(Sibonga2017).ThisestimationwasbasedupontheQCTscansofthehipperformedinISScrewmembers(Lang2006).Thepre-andpost-flightQCTdatafromelevenISSsubjectswereanalyzedbyfiniteelementmodelingtodeterminehipfractureloadsbeforeandafterspaceflight(Keyaketal.2009).ThesedatawereusedtocalculateaFactorofRiskforfractureatthetimeoflaunch(pre-flight)andafterreturntoEarth(post-flightMarsLongmission),asprovidedbelowinTable6.TheseestimationsindicatedthatcrewmembersthatreturnedbacktoEarthfromaMarsmissionwouldhaveacomparableriskoffractureonEarthtoanelderlypostmenopausalfemale,particularlyforaloadingconditionassociatedwithaposterolateralfallbutnotforforcesassociatedwithposturalstance(Sibonga2017).Again,theelderlyarelikely

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tohaveadditionalriskfactorsandskeletalchangesthatareassociatedwithadvancedagecontributingtotheirpropensitytofractureoverayounger-agedperson.Table6.EstimatedFactorofRisksbaseduponFiniteElementAnalysisofFractureLoad FactorofRisk:

EstimatedAppliedLoad/FractureLoadRatio*Astronautpre-flight 0.89+0.21AstronautonEarthafterMarsmission 1.07+0.30Women,70-80yearsofage 1.04+0.37AstronautsonMars(0.38G) 0.66+0.15*aratio>1indicatesthattheappliedloadexceedsthefractureload(strengthofthebone)andfracturewilloccurThefollowingassumptionsweremadeinthesecalculationsofFactorofRisk.First,theonlyappliedforceswerefromgravityfields.Notonlydoesthisassumptionunderestimatefracturerisk,butitalsodoesnotaddressapotentialprotectiveeffectofanexoskeleton(EVAsuit).Theappliedloadsonskeletonduetosuitdesign,EVAactivities,ortasksperformedonplanetarysurfacesarenotknown.Further,itwasassumedthattherewasaconsistentlossinbonemassduringspacetraveltoandfromMarsbaseduponanestimatedmonthlylossofBMD,whichpresumesaconstantloss,forweight-bearingsites.Theactualtimecourseofboneminerallossisnotknown.Further,themodelassumesthatnofurtherbonelossoccursduringexposureto1/6(lunar)or1/3(Martian)gravity.Wedonotcurrentlyknowtheextent,ifany,thatthesepartialgravityfieldswillmitigateboneatrophy.Rodentstudiesinground-basedmodelsofpartialweight-bearingsuggestthatpartialweight-bearingloadsdonotprevent(Swiftetal.2013),orproportionallyreduce(Ellmanetal.2013)musculoskeletaldeclines.SimilarcalculationsofFactorofRiskcanbeperformedforothermissionscenariosaspresentedinTable5.Calculationswillhavelessuncertaintyasmoredatareflectingchangestoadditionalboneparameters,suchasbonestructure,arebetterdefined.Bonedataacquiredbyothermodalitiesandanalysesmayimprovetheprobabilisticriskassessmentsforfracture(Codyetal.1999).WhentherateofBMDlosswaschangedwithintheBFxRMtoreflecttheaBMDdataofcrewmemberswithaccesstoARED,withallotherfactorswithintheBFxRMremainingthesame,therewasminimalchangeintheprobabilityofbonefractureforthesixreferencemissions.Thereasonfortheminimalchangemaybeduetothefollowing:

• TheBFxRMisnotsensitivetochangesinaBMD.aBMDbyDXAaccountsforonly50-70%ofactualbonestrength,soasmallchangeinaBMDtranslatestoasmallchangeinbonestrengthfollowingAREDaccess,evenoverthecourseoflongMartianmissions.USastronautshavesubstantialpre-flightbonemass,withaBMDT-scoresgreaterthanaverageBMDofyounghealthypersons,andthelossofbonemassduringspaceflight,thoughstillevidentevenwithresistiveexerciseonARED,issmallrelativetotheabsolutemass.

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• ThelowergravitationalenvironmentsonmoonandMarsreducethevelocityofafalland,subsequently,appliedloadstothehipduringafallonaplanetarysurface.

• ThereismuchvariabilitywithratesofaBMDlossrenderingtheBRxFMinsensitivetochangesinaBMDinducedbybisphosphonatesorAREDexercise.ThemostsensitiveparameterwithintheBFxRMis“thenumberoftimesduringamissionthataneventoccursthatcouldresultinafracture.”However,itischallengingtoestimatehowmanytimesanastronautmightaccidentlyfall.

Inaddition,theprobabilityofwristfractureremainsunchangedfrompre-AREDimplementationbecausethechangeinBMDatthewristduringthemissioniszeroandwasnotalteredbyuseoftheARED.Therefore,withallotherfactorsremainingthesame,thechangeinbonelossrateafterAREDbecameavailableon-orbithadverylittleeffectonthecalculated,overallbonefractureprobability.ThissuggeststhattheBRxFMusingaBMDforbonestrengthmaynotbeusefulasatoolbecauseitcannotevaluatetheeffectofacountermeasure.Tothisaim,finiteelementmodelingtoestimatechangesinBoneStrengthwillbeinvestigatedintheBFxRMtoimproveourabilitytoestimatefractureprobability.

VIII. GapsAtthetimeofwriting,3researchknowledgegapshavebeenidentifiedthataredirectlyrelatedtotheRiskofBoneFracture.Theseare:

• Fracture1:Wedon’tunderstandhowthespaceflightenvironmentaffectsbonefracturehealingin-flight.

• Fracture2:Weneedtocharacterizetheloadsappliedtoboneforstandardin-missionactivities.

• Fracture3:WeneedavalidatedmethodtoestimatetheRiskofFracturebyevaluatingtheratioofappliedloadstobonefractureloadsforexpectedmechanicallyloadedactivitiesduringamission.

IX. ConclusionsAhighriskforfractureisacharacteristicofosteoporosis,whichisaconsequenceofthelossesinbonemassandinstructuraldeterioration.ThedistinctionbetweentheincreasedbonefractureriskinpersonswithosteoporosisandtheincreasedriskforfracturesduringaspaceflightmissionisbaseduponaFactorofRisk.Osteoporoticpersonsfractureunderscenariosofminimalornoloadingduetothefragilityofboneitself.Fragilityfracturesarecharacteristicoffracturesoccurringundertheloadingofnormalactivities(forexample,standing,coughing,rollingoverinbed)orwithfallsfromastandingheight.Tothebestofourdata-miningcapabilities,thereisnoevidenceforincreasedriskoffragilityfracturesinlong-durationcrewmembers,noristhereadiagnosisofosteoporosisinthesecrewmembersbyclinicallyacceptedguidelines.However,thecurrentT-scorebasedcriteriaforriskassessment,

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originallydevelopedforolderwomen,areprobablynotsufficientforassessingriskinalownumberofastronautswhoarepredominantlyyoung,healthymalesexposedtoskeletalassaultthatisunlikeage-relatedboneloss.Parametersofbonemicro-andmacrostructurecontributetothestrengthofboneandcanbequantifiedbynon-invasivetechnologies.Uncertaintyrelatedtospaceflighteffectsonbonemorphologyandonbonestrengthexistbecausetechnologies,includingQCTscanningandFEA,toassesssuchchangeshavecurrentlybeenassessedonlyonalownumberofvolunteers.Changestothehumanskeletonwhenexposedtoamicrogravityorfractionalgravityenvironmentremainunknown.Lowsubjectnumbersanddelayedaccumulationofdataarelargeconstraintstoassessingfractureprobabilityfordecision-makingandmissionplanning.WithanincreasedunderstandingofspaceflighteffectsandimprovedmeasurementcapabilitiesbeyondDXAaBMD,wemaybeabletoprovideabetterassessmentoffracturerisktofuturecrew.Additionaldatacouldincludethetemporalpatternofbonelossformissionsgreaterthan6monthsandthemorphologicalchangesthataccompanyskeletaladaptationtospace,includingbothmicrogravityandpartialgravityenvironments.Documentedreductionsinbonemassandstructuralchangessuggestdeclinesinwholebonestrengthsuchthatadeconditionedpersonwithboneatrophyissusceptibletofractureatloadsthatmayhavebeentolerablebeforespaceflight.Amultifactorialanalysisofcross-disciplinaryriskfactorsforfractureisalsowarranted.Finally,modelingtheFactorofRiskforfractureduringaspaceflightmissionrequiresafullunderstandingofthechangesinbonemassandinbonequalityatspecificsitesaswellashowthesesiteswillbemechanicallyloadedbyactivitiesduringaspaceflightmission.

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XI. TeamNASAJohnsonSpaceCenter,Houston,TXJeanSibonga,Ph.D.HarlanJ.Evans,Ph.D.ElisabethSpector,B.S.ScottA.Smith,M.S.,(CBDT)GregYardley,M.S.NASAGlennResearchCenter,Cleveland,OHJerryG.Myers,Ph.D.BethE.Lewandowski,Ph.D.

XII. ListofAcronymsaBMD:arealbonemineraldensityBFxRM:BoneFractureRiskModelBMD:BonemineraldensityDXA:dual-energyX-rayabsorptiometryEVA:ExtravehicularactivityHRP:HumanResearchProgramIMM:IntegratedMedicalModeliRED:interimresistiveexercisedeviceISS:InternationalSpaceStationMRI:magneticresonanceimagingPRA:probabilisticriskassessmentQCT:quantitativecomputedtomographyvBMD:volumetricbonemineraldensity