ThomasLang,RadiologyandBiomedicalImaging,UCSanFrancisco - PDF document

ThomasLang,RadiologyandBiomedicalImaging,UCSanFrancisco SpaceStationResearchandDevelopmentConference July16,2013 BONELOSSINLONG-DURATION SPACEFLIGHT:MEASUREMENTSAND COUNTERMEASURES ISSTOPDISCOVERIESINMICROGRAVITY BONELOSS:MEASUREMENTSANDCOUNTERMEASURES • ThomasLang, UCSanFrancisco,CTimagingstudies • JoyceKeyakPhD ,UCIrvine,FiniteElementModeling • ScottMSmithPhD ,NASAJSC,NutritionandExercise Countermeasures • AdrianLeBlancPhD ,USRA,ExerciseandPharmacologic Countermeasures • JeanSibongaPhD ,NASAJSC,BoneandMineralLaboratory • PeterCavanaghPhD ,UofWashington,ExerciseandMusculoskeletal Biomechanics MOTIVATION • Bonelossisawell-knownmedicalconsequenceoflong-durationspaceflight, anticipatedlongbeforethefirstspacemissions • Lossofbonemassisassociatedwithlossofbonestrength • Increasedriskoffracture • Inelderlymenandwomen,each10%decreaseinbonemineral densityresultsina2-3foldincreaseinfracturerisk • Amissionrelatedfracturewouldbeapotentiallylife-threateningor mission-compromisingevent • Extensivebonelossduringamissionmaycompromiselong-term bonehealthinthedecadesafterserviceiscomplete • Releaseofcalciumfromskeletonincreasesriskofrenalstonedevelopment EARLYSTUDIESOFBONELOSSINSPACEFLIGHT Skylab (early70’s):metabolicstudies showlossofcalciumandlossofbone fromheelusingearlybone densitometry. Salyut missionsshowedlossofbone inheel MIR (1985-2001):firstsystematicstudyofbonelossusingmodern DXAtechnology.19cosmonautsmeasuredpre-andpost-flightat StarCity. Keyfinding :Cosmonautslost1-1.5%/monthbonedensityin hipand1%/monthfromspine.Lossescomparabletoyearly post-menopausalwomen(LeBlancetalJMuscNeurInt2000) Headdownbedreststudies :90-daybedrestsimulationsof spaceflightshowedbonelosssimilartoMIR.Bonelosswasnot reducedinsubsetofsubjectswhohadacarefullycontrolled moderateexerciseprogram(LeblancJBoneandMinRes1990), andwasonlyreducedbyanintenseprogramofresistanceexercise (ShackefordetalJAppPhys2004) BONELOSSANDCOUNTERMEASURES: NASASUPPORTEDHUMANSTUDIESONTHEISS • Studiesofboneloss: • Previousstudieshadfocusedonbonemass. • Newstudieswouldmovebeyondbonemasstobonearchitecture, boneloadingandstrength • “Subregionalassessmentofbonelossintheaxialskeletoninlong- termspaceflight”(ThomasLang) • “TheEffectofLong-DurationSpaceflightontheBiomechanicsof theProximalFemur”(ThomasLang) • “FootReactionForcesDuringSpaceFlight”(PeterCavanagh) • Countermeasureprescriptions • Combinationofexerciseandnutrition(ScottMSmith,PhD) • Bisphosphonateasacountermeasuretoboneloss(Adrian Leblanc) DUAL-ENERGYX-RAYABSORPTIOMETRY • Pros • Widelyavailable • Inexpensive • Excellentreproducibility • Lowx-rayexposure • Cons • 2-Ddensity(g/cm 2 )atvarioussites • Combinestrabecularandcorticalbone • Doesnotaccountforbonegeometry • Doesnotevaluatebonestrengthperse QCT:IMAGINGTOQUANTIFYBONE ARCHITECTUREANDSTRENGTH • Volumetricbonedensityofcorticalandtrabecularbone EquivalentconcentrationofCaHAing/cm3 • Bonegeometry Cross-sectionalareas Tissuevolumes Bonedimensions • Bonestrengthestimates Simpleestimatesofbendingofcompressivestrength Finiteelementmodeling(FEM) JoyceH.Keyak,PhDUCIrvine SUBREGIONALASSESSMENTOFBONELOSS INTHEAXIALSKELETONINLONG-TERM SPACEFLIGHT • 16InternationalSpaceStationCrewmemberswithpre- flight,post-flight(within3weeksoflanding)andone yearmeasurements • Datagatheredbetween2001-2005 • DXAofspineandhipatJSC • VolumetricQCToftheproximalfemurandspine performedatMethodistHospital,BaylorCollegeof Medicine QCTIMAGING Imageacquisitions ImageAnalyses Spine Hip 3DFINITEELEMENTMODELING Finiteelementmodel derivedfromQCT scan Mapof material properties 3DfiniteelementmodelofhipderivedfromCTscan JHKeyak Elasticmodulusandstrength derivedforeachQCTvoxel parametricallyfromBMD StanceFall Loading Conditions TotalFemur 39.000 40.000 41.000 42.000 43.000 44.000 45.000 46.000 47.000 48.000 PREPOST12MONTH Visit C o r t . V o l ( c c ) VQCTBONELOSSRESULTS MinimumCSA 11.400 11.500 11.600 11.700 11.800 11.900 12.000 12.100 12.200 PREPOST12MONTH Visit C S A ( c m 2 ) TotalFemur 28.000 29.000 30.000 31.000 32.000 33.000 34.000 35.000 36.000 PREPOST12MONTH Visit I n t . B M C ( g ) TotalFemur 0.110 0.115 0.120 0.125 0.130 0.135 0.140 0.145 0.150 PREPOST12MONTH Visit T r a b . v B M D ( g / c c ) LangetalJBoneandMinerResearch2006 Corticaltissuevolume Trabecularvolumetricdensity TotalBonemass Femoralneckcrosssectionalarea -16.5% -2.3%/mon +8% p.001 vbaseline -8% -1.3%/mon +8% -10.8% -1.6%/mon +8.1% +2.4% p.05 vbaseline +1.0% 405060708090 Pre-Filght Post-Flight 1YearPost-Flight 0 1000 2000 3000 4000 5000 HIPBONESTRENGTH: FALLLOADINGINMEN Astronauts Control Subjects Fracture Subjects HipBoneStrength(N) Age(years) JoyceH.KeyakPhD LOWCORRELATIONSBETWEENDXACHANGES ANDHIPBONESTRENGTHCHANGES . -6.0% -5.0% -4.0% -3.0% -2.0% -1.0% 0.0% 1.0% -2.0%-1.5%-1.0%-0.5%0.0% ChangeinDXATotalFemurArealBMD C h a n g e i n F E S t r e n g t h . Stance Fall Stance,R 2 =0.23Fall,R 2 =0.05 PerMonthDecreaseinFEStrengthvs.DXAAreal BMD JoyceKeyakPhD BONELOSSMEASUREMENTSDISCUSSION • EarlyISScrewshadexperiencedsimilarratesofbonelossto MIRcrew • Trabecularandcorticalbonecompartmentschangedatdifferent rates • Trabboneloss��corticalboneloss • Recoveryofbonemasscompriseschangesinbonestructure • Increaseinbonesize • Impairedrecoveryoftrabecularbone • Hipstructurelooks“older” • HipbonestrengthlosshigherthanpredictedbyDXA • Someindividualslostover30%oftheirhipstrengthoverthe courseofa6monthmission. PROBLEMSWITHCOUNTERMEASURES: EARLYISSMISSIONS • Earlycrewsusedtheinterimresistiveexercisedevice(iRED),atreadmill,andan exercisebicycle • Forbone,crewscarriedoutsquatsanddeadliftsontheiRED • Treadmillrunningusedtensionedloadingdevicestoloadsubjectontotreadmill withgoalof80%ofbodyweight • TheiREDhadlimitedmodesofusage,variableloadoverrangeofmotion,anda maximumloadcapacityof297lbs • “Footreactionforcesinspaceflight”(PI:PeterCavanagh) • 4astronautsonmissionworeleggingsequippedwithinsoleloadmeasurement devicetomeasurefootforcesandestimatelowerextremityloads • Footforcesintreadmillrunningwerelessthanhalfthoseexperiencedonearth • Inresistanceexercise,loadsonlowerextremityrangedfrom0.2-1.3bodyweight • 30%ofprescribedexercisetimeresultedinmeasureableloading • EarlyISScrewsconsumed70-80%oftheirenergyrequirements,resultingin5-10% lossofbodyweight ADVANCEDRESISTANCEEXERCISE/NUTRITION AdvancedResistiveExerciseDevice(aRED) waslaunchedtoorbitin2008 • 600lbmaximumload • Constantloadacrossrangeofmotion • Largerselectionofmotion Exercise/NutritionCountermeasureStudy ScottMSmith,PhD VitaminDdoseof800IU/day Foodfrequencyquestionaire(FFQ)wasemployedtorecordintakeofbasicdietary components:energy,protein,water,sodium,calcium,iron,andpotassium. FivesubjectsexercisingonaRED,andhavingoptimizednutritionalintakewere comparedto12iREDexercisersandMIRcosmonauts Bonedensity,bodymass,leanmass,boneformationandresorptionmarkers, andvitaminDlevelsweremonitored JBoneandMinerRes2012 ComparisonofhipbonedensitychangesinMIR crew,iREDusersandaREDusers In5aREDexercisers,datasuggestlower rateofbonelossthanMIRoriRED Allgroupsshowedincreasedratesofbone resorption aREDexercisersreturnedwithhigher leanmassandlowerfatmass aREDusersmaintainedhigherenergy intake,greater%requiredenergy intakeandhigherintakeofprotein Acrossallsubjects,inflightenergyand proteinintakewereinverselycorrelated withbonelossinhipandpelvis BISPHOSPHONATESASACOUNTERMEASURE TOBONELOSS Bisphosphonates,suchasalendronate(FOSAMAX TM )havebeenusedsincethe mid90’stotreatosteoporosis,showing30-50%reductionoffracturerates Bisphosphonatesinhibittheactionofosteoclaststhatresorbboneandwhich showincreasedactivityindisuse Alendronateattenuatedbonelossinaearlierbedreststudy(LeBlancetal,JBone andMinerResearch1999) NASAprojecttoevaluateuseofalendronatetoreduceorpreventbonelossin ISScrew(PI:AdrianLeBlanc) SevenISScrewmembersfromNASAandJAXAtook70mgalendronate/wk starting3weekspriortolaunchandcontinuingthroughflight.Allsubjects exercisedonaRED SubjectsimagedwithDXAandQCTpreandpost-flight.QCTimagesanalyzed withbonedensityandFEMsoftware LeBlancetalOsteoporosisInternat2013 StanceStrength(%)(SD) FallStrength(%)(SD) Pre-aRED BIS+aRED COUNTERMEASUREKEYPOINTS • Highintensityresistanceexerciseappearstoreducelossofbonedensity, althoughboneturnoverisstillelevated • Datasupportimportanceoffulfillingrequiredenergyandproteinintakefor reducingboneloss • BisphosphonatestudyshowedthatevenwithaREDexercise,statistically significanthipbonelossoccurs • Alendronate,combinedwithaRED,preventedbonelossatthehip,as documentedbyDXA,QCTandFEM. • Overall,datadocumentthatitispossibletopreventboneloss,mitigating changesinhipstructurethatmaycompromisebonehealthinlaterlife TRANSLATINGFINDINGSTOMEDICAL OPERATIONSINEXPLORATIONERA • Smallerspacecraftanddifferentmissionprofilesimplylogisticalconstraints • Optimalcombinationofdrugandexercisetoreducedrugdoseandexercise dose • Emergingosteoporosismedicationsmayofferreducedgastrointestinalside effectscomparedtobisphosponates • Combinationofdrugsandexercisetoreduceloadsandriskofinjury • Developstateoftheartbonehealthstandardsthatincorporatenew quantitativemethodssuchasFiniteElementModeling(JeanSibonga,PhD) • FiniteElementCutPointTaskGroup:Panelofleadingcliniciansare helpingtodevelopnewguidelinesforusingQCTandFEMdatato assistflightphysiciansinassessmentofastronautskeletalhealth • Evidence–basedrecommendationsrecentlypublishedinkeybone journal(Orwolletal,JBoneandMinerRes2013) ACKNOWLEDGMENTS • IsraSaeedMD • JohnKornakPhD • YingLuPhD • AlainKoyama • AliceYu • WenjunLi • TadashiKaneko • T.Matsumoto • H.Evans • L.Shackelford • E.Spector • R.Ploutz-Snyder • J.Jones • J.Shapiro • T.Nakamura • K.Kohri • H.Oshima • L.Ploutz-Snyder • M.Heer • S.Zwart BoneLossStudies(QCT/FEM) NASANNJ04HC7SAandNNJ04HF78G CountermeasureStudies NASAJSCHumanResearchProgram