risk of bone fracture due to spaceflight- induced changes ...€¦ · 12/05/2017  · lead to...

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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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X. ReferencesAminS,AchenbachSJ,AtkinsonE,etal(2010)BoneBoneDensityFollowingLong-

DurationSpaceflightandRecovery.

AminS,AchenbachSJ,AtkinsonE,SibongaJ(2011)BoneDensityFollowingThreeYearsofRecoveryfromLong-DurationSpaceFlight.

BeckTJ(2007)ExtendingDXAbeyondbonemineraldensity:understandinghipstructureanalysis.CurrOsteoporosRep5:49–55.

BischoffHA,StähelinHB,DickW,etal(2003)EffectsofvitaminDandcalciumsupplementationonfalls:arandomizedcontrolledtrial.JBoneMinerResOffJAmSocBoneMinerRes18:343–351.doi:10.1359/jbmr.2003.18.2.343

Bischoff-FerrariHA,Dawson-HughesB,WillettWC,etal(2004)EffectofVitaminDonfalls:ameta-analysis.JAMA291:1999–2006.doi:10.1001/jama.291.16.1999

BlackDM,BouxseinML,MarshallLM,etal(2008)ProximalFemoralStructureandthePredictionofHipFractureinMen:ALargeProspectiveStudyUsingQCT.JBoneMinerRes23:1326–1333.doi:10.1359/jbmr.080316

BloombergJJ,MulavaraAP(2003)Changesinwalkingstrategiesafterspaceflight.IEEEEngMedBiolMagQMagEngMedBiolSoc22:58–62.

BonnickSL(2007)HSA:beyondBMDwithDXA.Bone41:S9-12.doi:10.1016/j.bone.2007.03.007

BonnickSL,ShulmanL(2006)Monitoringosteoporosistherapy:bonemineraldensity,boneturnovermarkers,orboth?AmJMed119:S25-31.doi:10.1016/j.amjmed.2005.12.020

BoudreauxR,SibongaJD(2015)SimpleGeometricMeasurementsPredictHipFractureBeyondBoneMineralDensity.TexOrthopJ1:109–122.

CarpenterRD,BeaupréGS,LangTF,etal(2005)NewQCTanalysisapproachshowstheimportanceoffallorientationonfemoralneckstrength.JBoneMinerResOffJAmSocBoneMinerRes20:1533–1542.doi:10.1359/JBMR.050510

ChangG,HonigS,LiuY,etal(2015)7TeslaMRIofbonemicroarchitecturediscriminatesbetweenwomenwithoutandwithfragilityfractureswhodonotdifferbybonemineraldensity.JBoneMinerMetab33:285–293.doi:10.1007/s00774-014-0588-4

28

ChesnutCH,MajumdarS,NewittDC,etal(2005)Effectsofsalmoncalcitoninontrabecularmicroarchitectureasdeterminedbymagneticresonanceimaging:resultsfromtheQUESTstudy.JBoneMinerResOffJAmSocBoneMinerRes20:1548–1561.doi:10.1359/JBMR.050411

CodyDD,GrossGJ,HouFJ,etal(1999)FemoralstrengthisbetterpredictedbyfiniteelementmodelsthanQCTandDXA.JBiomech32:1013–1020.

CourtineG,PozzoT(2004)Recoveryofthelocomotorfunctionafterprolongedmicrogravityexposure.I.Head-trunkmovementandlocomotorequilibriumduringvarioustasks.ExpBrainRes158:86–99.doi:10.1007/s00221-004-1877-2

CummingsSR,BlackDM,ThompsonDE,etal(1998)Effectofalendronateonriskoffractureinwomenwithlowbonedensitybutwithoutvertebralfractures:resultsfromtheFractureInterventionTrial.JAMA280:2077–2082.

CummingsSR,NevittMC,BrownerWS,etal(1995)Riskfactorsforhipfractureinwhitewomen.StudyofOsteoporoticFracturesResearchGroup.NEnglJMed332:767–773.doi:10.1056/NEJM199503233321202

DanaCarpenterR,LeBlancAD,EvansH,etal(2010)Long-termchangesinthedensityandstructureofthehumanhipandspineafterlong-durationspaceflight.ActaAstronaut67:71–81.doi:10.1016/j.actaastro.2010.01.022

DeLaetC,OdénA,JohanssonH,etal(2005)Theimpactoftheuseofmultipleriskindicatorsforfractureoncase-findingstrategies:amathematicalapproach.OsteoporosIntJEstablResultCoopEurFoundOsteoporosNatlOsteoporosFoundUSA16:313–318.doi:10.1007/s00198-004-1689-z

EllmanR,SibongaJ,BouxseinM(2010)Maleastronautshavegreaterbonelossandriskofhipfracturefollowinglongdurationspaceflightsthanfemales.[Abstract1142]PodiumpresentationattheAmericanSocietyofBoneandMineralResearchAnnualMeeting;Toronto,Ontario,Canada,October2010.

EllmanR,SpatzJ,CloutierA,etal(2013)Partialreductionsinmechanicalloadingyieldproportionalchangesinbonedensity,bonearchitecture,andmusclemass.JBoneMinerResOffJAmSocBoneMinerRes28:875–885.doi:10.1002/jbmr.1814

EspallarguesM,Sampietro-ColomL,EstradaMD,etal(2001)Identifyingbone-mass-relatedriskfactorsforfracturetoguidebonedensitometrymeasurements:asystematicreviewoftheliterature.OsteoporosIntJEstablResultCoopEurFoundOsteoporosNatlOsteoporosFoundUSA12:811–822.doi:10.1007/s001980170031

29

GadomskiBC,LernerZF,BrowningRC,etal(2016)Computationalcharacterizationoffracturehealingunderreducedgravityloadingconditions.JOrthopResOffPublOrthopResSoc34:1206–1215.doi:10.1002/jor.23143

GadomskiBC,McGilvrayKC,EasleyJT,etal(2014a)Aninvivoovinemodelofbonetissuealterationsinsimulatedmicrogravityconditions.JBiomechEng136:21020.doi:10.1115/1.4025854

GadomskiBC,McGilvrayKC,EasleyJT,etal(2014b)Partialgravityunloadinginhibitsbonehealingresponsesinalargeanimalmodel.JBiomech47:2836–2842.doi:10.1016/j.jbiomech.2014.07.031

GarneroP,Sornay-RenduE,DuboeufF,DelmasPD(1999)Markersofboneturnoverpredictpostmenopausalforearmbonelossover4years:theOFELYstudy.JBoneMinerResOffJAmSocBoneMinerRes14:1614–1621.doi:10.1359/jbmr.1999.14.9.1614

GarrawayWM,StaufferRN,KurlandLT,O’FallonWM(1979)Limbfracturesinadefinedpopulation.I.Frequencyanddistribution.MayoClinProc54:701–707.

GutteridgeDH,StewartGO,PrinceRL,etal(2002)Arandomizedtrialofsodiumfluoride(60mg)+/-estrogeninpostmenopausalosteoporoticvertebralfractures:increasedvertebralfracturesandperipheralbonelosswithsodiumfluoride;concurrentestrogenpreventsperipheralloss,butnotvertebralfractures.OsteoporosIntJEstablResultCoopEurFoundOsteoporosNatlOsteoporosFoundUSA13:158–170.doi:10.1007/s001980200008

HansD,BartheN,BoutroyS,etal(2011)CorrelationsBetweenTrabecularBoneScore,MeasuredUsingAnteroposteriorDual-EnergyX-RayAbsorptiometryAcquisition,and3-DimensionalParametersofBoneMicroarchitecture:AnExperimentalStudyonHumanCadaverVertebrae.JClinDensitom14:302–312.doi:10.1016/j.jocd.2011.05.005

HernandezCJ,GuptaA,KeavenyTM(2006)Abiomechanicalanalysisoftheeffectsofresorptioncavitiesoncancellousbonestrength.JBoneMinerResOffJAmSocBoneMinerRes21:1248–1255.doi:10.1359/jbmr.060514

KanisJA,MeltonLJ,ChristiansenC,etal(1994)Thediagnosisofosteoporosis.JBoneMinerResOffJAmSocBoneMinerRes9:1137–1141.doi:10.1002/jbmr.5650090802

30

KanisJA,OdenA,JohnellO,etal(2007)TheuseofclinicalriskfactorsenhancestheperformanceofBMDinthepredictionofhipandosteoporoticfracturesinmenandwomen.OsteoporosIntJEstablResultCoopEurFoundOsteoporosNatlOsteoporosFoundUSA18:1033–1046.doi:10.1007/s00198-007-0343-y

KeavenyTM,KopperdahlDL,MeltonLJ,etal(2010)Age-dependenceoffemoralstrengthinwhitewomenandmen.JBoneMinerResOffJAmSocBoneMinerRes25:994–1001.doi:10.1359/jbmr.091033

KeyakJH,KanekoTS,TehranzadehJ,SkinnerHB(2005)Predictingproximalfemoralstrengthusingstructuralengineeringmodels.ClinOrthop219–228.

KeyakJH,KoyamaAK,LeBlancA,etal(2009)Reductioninproximalfemoralstrengthduetolong-durationspaceflight.Bone44:449–453.doi:10.1016/j.bone.2008.11.014

KeyakJH,SigurdssonS,KarlsdottirG,etal(2011)Male-femaledifferencesintheassociationbetweenincidenthipfractureandproximalfemoralstrength:afiniteelementanalysisstudy.Bone48:1239–1245.doi:10.1016/j.bone.2011.03.682

KohrtWM,BloomfieldSA,LittleKD,etal(2004)AmericanCollegeofSportsMedicinePositionStand:physicalactivityandbonehealth.MedSciSportsExerc36:1985–1996.

LangT,LeBlancA,EvansH,etal(2004)CorticalandTrabecularBoneMineralLossFromtheSpineandHipinLong-DurationSpaceflight.JBoneMinerRes19:1006–1012.doi:10.1359/JBMR.040307

LangTF(2006)Whatdoweknowaboutfractureriskinlong-durationspaceflight?JMusculoskeletNeuronalInteract6:319–321.

LeBlancA,LinC,ShackelfordL,etal(2000a)Musclevolume,MRIrelaxationtimes(T2),andbodycompositionafterspaceflight.JApplPhysiolBethesdaMd198589:2158–2164.

LeBlancA,SchneiderV,ShackelfordL,etal(2000b)Bonemineralandleantissuelossafterlongdurationspaceflight.JMusculoskeletNeuronalInteract1:157–60.

LeBlancAD,SpectorER,EvansHJ,SibongaJD(2007)Skeletalresponsestospaceflightandthebedrestanalog:areview.JMusculoskeletNeuronalInteract7:33–47.

31

MaderTH,GibsonCR,PassAF,etal(2011)Opticdiscedema,globeflattening,choroidalfolds,andhyperopicshiftsobservedinastronautsafterlong-durationspaceflight.Ophthalmology118:2058–2069.doi:10.1016/j.ophtha.2011.06.021

MedimapsGroup(2015)AdvancedDXAUsingTBSiNsight.

MulavaraAP,FeivesonAH,FiedlerJ,etal(2010)Locomotorfunctionafterlong-durationspaceflight:effectsandmotorlearningduringrecovery.ExpBrainRes202:649–659.doi:10.1007/s00221-010-2171-0

NASA(2014)NASASpaceflightHumanSystemStandards-NASAStandard3001.NationalAeronauticsandSpaceAdministration,NASAJohnsonSpaceCenter

NASAHumanResearchProgram(2016)HumanResearchProgramRoadmap.https://humanresearchroadmap.nasa.gov.

NelsonES,LewandowskiB,LicataA,MyersJG(2009)Developmentandvalidationofapredictivebonefractureriskmodelforastronauts.AnnBiomedEng37:2337–2359.doi:10.1007/s10439-009-9779-x

NewmanDJ,JacksonDK,BloombergJJ(1997)Alteredastronautlowerlimbandmasscenterkinematicsindownwardjumpingfollowingspaceflight.ExpBrainRes117:30–42.

NgAC,DrakeMT,ClarkeBL,etal(2012)Trendsinsubtrochanteric,diaphyseal,anddistalfemurfractures,1984-2007.OsteoporosIntJEstablResultCoopEurFoundOsteoporosNatlOsteoporosFoundUSA23:1721–1726.doi:10.1007/s00198-011-1777-9

NIHConsensusDevelopmentPanelonOsteoporosisPrevention,Diagnosis,andTherapy(2001)Osteoporosisprevention,diagnosis,andtherapy.JAMA285:785–795.

OrwollES,AdlerRA,AminS,etal(2013)Skeletalhealthinlong-durationastronauts:nature,assessment,andmanagementrecommendationsfromtheNASABoneSummit.JBoneMinerResOffJAmSocBoneMinerRes28:1243–1255.doi:10.1002/jbmr.1948

OrwollES,MarshallLM,NielsonCM,etal(2009)Finiteelementanalysisoftheproximalfemurandhipfractureriskinoldermen.JBoneMinerResOffJAmSocBoneMinerRes24:475–483.doi:10.1359/jbmr.081201

ParfittAM,DreznerMK,GlorieuxFH,etal(1987)Bonehistomorphometry:standardizationofnomenclature,symbols,andunits.ReportoftheASBMRHistomorphometryNomenclatureCommittee.JBoneMinerResOffJAmSocBoneMinerRes2:595–610.doi:10.1002/jbmr.5650020617

32

PetersB,BloombergJ,LayneC,etal(1996)Eye,head,andtrunkphaserelationshipsduringtreadmilllocomotionwhileviewingvisualtargetsatdifferentdistances.Soc.Neurosci.Abstr.199622(3):1848.SocNeurosciAbstr22:1848.

PrevrhalS,MetaM,GenantHK(2004)TwonewregionsofinteresttoevaluateseparatelycorticalandtrabecularBMDintheproximalfemurusingDXA.OsteoporosIntJEstablResultCoopEurFoundOsteoporosNatlOsteoporosFoundUSA15:12–19.doi:10.1007/s00198-003-1500-6

RiggsBL,HodgsonSF,O’FallonWM,etal(1990)Effectoffluoridetreatmentonthefracturerateinpostmenopausalwomenwithosteoporosis.NEnglJMed322:802–809.doi:10.1056/NEJM199003223221203

RiggsBL,MeltonLJ,RobbRA,etal(2006)Population-basedanalysisoftherelationshipofwholebonestrengthindicesandfall-relatedloadstoage-andsex-specificpatternsofhipandwristfractures.JBoneMinerResOffJAmSocBoneMinerRes21:315–323.doi:10.1359/JBMR.051022

RobinovitchSN,HayesWC,McMahonTA(1991)Predictionoffemoralimpactforcesinfallsonthehip.JBiomechEng113:366–374.

SchuitSCE,vanderKliftM,WeelAEAM,etal(2004)Fractureincidenceandassociationwithbonemineraldensityinelderlymenandwomen:theRotterdamStudy.Bone34:195–202.doi:10.1016/j.bone.2003.10.001

SibongaJ(2017)RiskofAcceleratedOsteoporosis.NationalAeronauticsandSpaceAdministration,NASAJohnsonSpaceCenter.HumanResearchProgramEvidenceReportMay9,2017,availableat:https://humanresearchroadmap.nasa.gov/Evidence/

SibongaJD,EvansHJ,SungHG,etal(2007)Recoveryofspaceflight-inducedboneloss:bonemineraldensityafterlong-durationmissionsasfittedwithanexponentialfunction.Bone41:973–978.doi:10.1016/j.bone.2007.08.022

SmithSM,HeerM,ShackelfordLC,etal(2015)BonemetabolismandrenalstoneriskduringInternationalSpaceStationmissions.Bone81:712–720.doi:10.1016/j.bone.2015.10.002

SmithSM,HeerMA,ShackelfordLC,etal(2012)Benefitsforbonefromresistanceexerciseandnutritioninlong-durationspaceflight:Evidencefrombiochemistryanddensitometry.JBoneMinerResOffJAmSocBoneMinerRes27:1896–1906.doi:10.1002/jbmr.1647

SmithSM,WastneyME,MorukovBV,etal(1999)Calciummetabolismbefore,during,andaftera3-mospaceflight:kineticandbiochemicalchanges.AmJPhysiol277:R1-10.

33

SmithSM,WastneyME,O’BrienKO,etal(2005)Bonemarkers,calciummetabolism,andcalciumkineticsduringextended-durationspaceflightonthemirspacestation.JBoneMinerResOffJAmSocBoneMinerRes20:208–218.doi:10.1359/JBMR.041105

Sornay-RenduE,MunozF,GarneroP,etal(2005)IdentificationofOsteopenicWomenatHighRiskofFracture:TheOFELYStudy.JBoneMinerRes20:1813–1819.doi:10.1359/JBMR.050609

SulkowskiCM,GilkeyKM,LewandowskiBE,etal(2011)Anextravehicularsuitimpactloadattenuationstudytoimproveastronautbonefractureprediction.AviatSpaceEnvironMed82:455–462.

SwiftJM,LimaF,MaciasBR,etal(2013)Partialweightbearingdoesnotpreventmusculoskeletallossesassociatedwithdisuse.MedSciSportsExerc45:2052–2060.doi:10.1249/MSS.0b013e318299c614

TurnerRT(2000)Invitedreview:whatdoweknowabouttheeffectsofspaceflightonbone?JApplPhysiolBethesdaMd198589:840–847.

vanderLindenJC,HommingaJ,VerhaarJA,WeinansH(2001)Mechanicalconsequencesofbonelossincancellousbone.JBoneMinerResOffJAmSocBoneMinerRes16:457–465.doi:10.1359/jbmr.2001.16.3.457

VicoL,ColletP,GuignandonA,etal(2000)Effectsoflong-termmicrogravityexposureoncancellousandcorticalweight-bearingbonesofcosmonauts.LancetLondEngl355:1607–1611.

WainwrightSA,MarshallLM,EnsrudKE,etal(2005)HipFractureinWomenwithoutOsteoporosis.JClinEndocrinolMetab90:2787–2793.doi:10.1210/jc.2004-1568

WorldHealthOrganization(2004)WHOScientificGroupontheAssessmentofOsteoporosisatPrimaryHealthCareLevel.SummaryMeetingReport.Brussels,Belgium,May5-7,2004.WorldHealthOrganization,Brussels,Belgium

WorldHealthOrganization(1994)Assessmentoffractureriskanditsapplicationtoscreeningforpostmenopausalosteoporosis.ReportofaWHOStudyGroup.WorldHealthOrganTechRepSer843:1–129.

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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