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SpaceflightSpaceflight--induced Bone Loss: induced Bone Loss: Is there a risk for accelerated Is there a risk for accelerated
osteoporosis after return?osteoporosis after return?
Jean D. Sibonga, Ph.D.Jean D. Sibonga, Ph.D.Sr. Research Scientist, USRASr. Research Scientist, USRA
HRP Bone Discipline LeadHRP Bone Discipline Lead
https://ntrs.nasa.gov/search.jsp?R=20080014282 2020-04-03T04:39:22+00:00Z
Recommendations of Institute of Recommendations of Institute of Medicine Medicine –– Safe Passage: Safe Passage: Astronaut Care for Exploration Astronaut Care for Exploration MissionsMissionsDevelop and use an occupational health model for the collection and analysis of astronaut health data, giving priority to the creation and maintenance of a safe work environment
Incorporate an evidence-based risk assessment and communication process into the risk identification and reduction approach
The IOM approach for Bone The IOM approach for Bone Discipline Discipline Evidence Base Reports Evidence Base Reports
4 identified risks of an adverse outcome due to 4 identified risks of an adverse outcome due to space exploration.space exploration.
1.1. Accelerated Osteoporosis Accelerated Osteoporosis Long-term health
2.2. Formation of Renal StonesFormation of Renal Stones3.3. Intervertebral Disc Injury Intervertebral Disc Injury (or Damage)(or Damage)4.4. Bone FractureBone Fracture#2-4 Risk for mission but more evidence required.
OverviewOverviewEvidence Base for #1 Risk of Accelerated
Osteoporosis
Involutional OsteoporosisInvolutional OsteoporosisBone remodeling process Bone remodeling process Skeletal adaptation to spaceSkeletal adaptation to spaceSkeletal changes: space vs. ageingSkeletal changes: space vs. ageing-- Circumstantial EvidenceCircumstantial Evidence
Gaps in our knowledge base Gaps in our knowledge base
Two Risk StatementsTwo Risk Statementsfor Accelerated Osteoporosisfor Accelerated Osteoporosis
EarlierEarlier: Bioastronautics Roadmap: Bioastronautics Roadmap““Osteoporosis associated Osteoporosis associated with agewith age--related bonerelated bone loss may loss may
occur at an earlier age due to occur at an earlier age due to failure to recover bonefailure to recover bone lost lost during spaceflight.”during spaceflight.”
CurrentCurrent: Risk Statement in Human Research Program: Risk Statement in Human Research Program“…(“…(IfIf) mission) mission--related related bone lossbone loss cannot be correctedcannot be corrected by by
postpost--mission rehabilitation; crew members could be at mission rehabilitation; crew members could be at greater riskgreater risk of osteoporosisof osteoporosis--related fractures related fractures in later lifein later life..””
20052005
Is there recovery? Are the changes irreversible? Overlap with involutional changes in bone.
““Involutional” OsteoporosisInvolutional” Osteoporosis
The regressive alterations of a body or its The regressive alterations of a body or its parts characteristic of the ageing processparts characteristic of the ageing process
AgeAge--related bone lossrelated bone loss
Osteoporosis DefinitionsOsteoporosis Definitions
OLDOLD: : “…a reduced amount of bone that is qualitatively normal.” Albright F. Ann Intern Med. 1947
MODERNMODERN::“…a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility with susceptibility to fracture ….”
Am. J. Med.1991
NEWESTNEWEST: : “Osteoporosis is a skeletal disorder characterized by “Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of compromised bone strength predisposing to an increased risk of fracture. Bone strength reflects the fracture. Bone strength reflects the integration of two main features: : bone density and bone quality.” bone density and bone quality.”
JAMA. 2001JAMA. 2001
Classifications of OsteoporosisClassifications of Osteoporosis
Primary Osteoporosis Primary Osteoporosis -- “Involutional Osteoporosis”“Involutional Osteoporosis”MenopauseMenopause--induced Bone Lossinduced Bone Loss “Postmenopausal Osteoporosis” “Postmenopausal Osteoporosis” AgeAge--related Bone Lossrelated Bone Loss “Senile Osteoporosis”“Senile Osteoporosis”
Secondary Osteoporosis Secondary Osteoporosis –– External causesExternal causesGlucocorticoid MedicationGlucocorticoid MedicationAlcoholAlcohol--inducedinducedImmobilizationImmobilizationAntiAnti--seizure drugsseizure drugs
Bone Gain and Loss with Age is SexBone Gain and Loss with Age is Sex-- specificspecific
CP1014192-21
Riggs BL, Melton LJ: Involutional osteoporosisRiggs BL, Melton LJ: Involutional osteoporosisOxford Textbook of Geriatric MedicineOxford Textbook of Geriatric Medicine
Bone massBone mass(g/calcium(g/calcium))
Age (yr)Age (yr)
0
500
1,000
1,500
0 20 40 60 80 100
II
IIII
IIIIII
II
IIIIII
Females
Males
Copyright ©2001 The Endocrine Society
Seeman, E. J Clin Endocrinol Metab 2001;86:4576-4584
Phase I (Bone Gain): Femoral Shaft areal BMD increases with age, but volumetric BMD is independent of age in young males and females.
Dispelling a Fallacy: NOT BMD, but Bone size increases in growing males.
Being Female is a risk factor for Being Female is a risk factor for osteoporosis. osteoporosis.
Smaller bonesSmaller bonesUndergo two phases of bone loss: an Undergo two phases of bone loss: an earlier rapid phase of loss (menopause earlier rapid phase of loss (menopause induced) followed by a slower phase of induced) followed by a slower phase of loss (induced by ageing) equivalent to the loss (induced by ageing) equivalent to the rate of bone loss in men.rate of bone loss in men.
How does the “Risk for How does the “Risk for Accelerated Osteoporosis” in Accelerated Osteoporosis” in
crew members crew members fit in with Involutional fit in with Involutional
Osteoporosis?Osteoporosis?
Clarifying the “Risk for Accelerated Clarifying the “Risk for Accelerated Osteoporosis.”Osteoporosis.”
1. Accelerated: “to bring about at an earlier time”
2. Osteoporosis: Occurrence of fractures under mechanical loading of normal activities “atraumatic”
3. Evidence: incidence of atraumatic fractures at an earlier age (relative to expected age of occurrence)
4. Evidence: Greater prevalence fractures in the former astronauts compared to peer group.
A STUDY EVALUATING FRACTURE AS THE A STUDY EVALUATING FRACTURE AS THE OUTCOME IN ASTRONAUTS???OUTCOME IN ASTRONAUTS???
0
1,000
2,000
3,000
4,000
Inci
denc
e/10
0,00
0 pe
rson
-yr
Inci
denc
e/10
0,00
0 pe
rson
-yr
35-39 ≥ 85
Age group (yr)Age group (yr)
MenMen WomenWomenHipSpineWrist
HipSpineWrist
35-39 ≥85
AgeAge--Related Fractures : when and how many?Related Fractures : when and how many?
Cooper and Melton, 1992
The influence of endocortical bone loss on # hip fractures in later life.
The influence of cancellous bone loss on wrist and spine fractures.
Measuring surrogates to bone Measuring surrogates to bone strength.strength.
Supplementing DXA measures of Supplementing DXA measures of areal BMD.areal BMD.
But, with which one?But, with which one?
Bone Volume Changes in the Adult Bone Volume Changes in the Adult Skeleton : Skeleton :
The The Bone Remodeling ProcessBone Remodeling Process
Growth Growth -- developing skeleton (BF>BR)
Modeling Modeling -- shaping of shaping of bone (e.g., elongation)
Remodeling Remodeling –– repair, renewal, calcium homeostasis
-- 10% of skeleton/year10% of skeleton/year
Changes in the skeletal tissue occurChanges in the skeletal tissue occurthrough 3 regulated processesthrough 3 regulated processes
Remodeling in Discrete Packets of BoneRemodeling in Discrete Packets of Bone(Bone Remodeling Unit BRU (Bone Remodeling Unit BRU –– Basic Basic MulticellularMulticellular Unit BMU)Unit BMU)
Remodeling at the level of the BRURemodeling at the level of the BRU
Specific sites of bone remodeling.Specific sites of bone remodeling.
Trabecular surface
Intracortical
Endocortical
Cortical Bone
Endocortical
Cancellous Bone
Bone Remodeling of Cancellous BoneBone Remodeling of Cancellous Bone(aka Trabecular Bone)(aka Trabecular Bone)
For normal turnover, bone repair & tissue renewal, mineral For normal turnover, bone repair & tissue renewal, mineral homeostasishomeostasis
Bone Resorption (BR) precedes Bone Formation (BF)Bone Resorption (BR) precedes Bone Formation (BF)
Time for BR < Time for BFTime for BR < Time for BF
Two phases of BF: matrix production and mineralizationTwo phases of BF: matrix production and mineralization
44--6 months6 months
Bone Balance vs. Bone CouplingBone Balance vs. Bone Coupling
Osteoporosis in the adult likely results from a perturbation in Osteoporosis in the adult likely results from a perturbation in the the remodeling process.remodeling process.
Multiple Multiple PathophysiologiesPathophysiologies for Osteoporosis: for Osteoporosis: Perturbations to RemodelingPerturbations to Remodeling
Osteoporosis BF BR
Disuse* (“Skeletal unloading”) +
Aging -
Glucocorticoids -
Estrogen Deficiency + ++
Alcohol -
Metabolic diseases of High Bone Turnover + ++
Skeletal Adaptation to SpaceSkeletal Adaptation to Space
Evidence to DateEvidence to Date
Early Missions: Early Missions: Skeletal MeasurementsSkeletal Measurements
Shuttle 1981-present
Mercury 1961-63
Gemini 1965-66
Apollo 1968-72
Skylab 1973-74
Intl Space Station2000-present
• Calcium balance • SPA of heel
and wrist
• SPA Heel,Wrist • Urine, fecal Ca • Ca balance • Urinary OH-Pro • NTX 1998
• DXA • QCT
• x-ray photodensitometry • Ca balance
Soyuz/Salyut
1974-85 Mir
1986-2000 • SPA, DPA Heel • DXA whole body,
regional • CT estimates of
lumbar spine BMD • pQCT
Calcium RegulationCalcium Regulation
SkylabSkylab--Calcium balanceCalcium balance
Bone Ca Loss ~ 250 mg/dBone Ca Gain ~ 100 mg/dRecovery: 2-3 x missionm
g/d
-500
-400
-300
-200
-100
0
100
200
300
Preflight InflightLanding
Postflight2-3mo9d
Calcium Balance
Smith et al., 1999Smith et al., 2005
Slide courtesy of Dr. Scott M. Smith
Spaceflight:↓ Vitamin D stores↓ PTH↓ Active vitamin D↓ Ca absorption
-100
-50
0
50
100
150
% Δ
from
pre
fligh
t
~FD 100Landing
Postflight9d 2-3mo
Calcium Absorption
Smith et al., 1999Smith et al., 2005
Slide courtesy of Dr. Scott M. Smith
SkylabSkylab--BMD of CalcaneusBMD of Calcaneus
Bone Mineral DensityBone Mineral Density
Regional BMD losses MirRegional BMD losses Mir
LeBlanc et al, 2000
Index DXAaBMD g/cm2
%/Month Change +
SDLumbar Spine -1.06+0.63*Femoral Neck -1.15+0.84*Trochanter -1.56+0.99*Total Body -0.35+0.25*Pelvis -1.35+0.54*Arm -0.04+0.88Leg -0.34+0.33*
*p<0.01, n=16-18
Hip1.5% / month
Whole Body0.3% / month
Lumbar Spine1% / month
DXA (Mir) and QCT (ISS) DXA (Mir) and QCT (ISS) LeBlanc, J Musculoskel Neuron Interact, 2000; LeBlanc, J Musculoskel Neuron Interact, 2000;
Lang , J Bone Miner Res, 2004; Vico, The Lancet 2000Lang , J Bone Miner Res, 2004; Vico, The Lancet 2000
Index DXA
%/Month Change + SD
Index QCT
%/Month Change + SD
aBMD Lumbar Spine
1.06+0.63* Integral vBMD Lumbar Spine
0.9+0.5
Trabecular vBMD Lumbar Spine
0.7+0.6
aBMD Femoral Neck
1.15+0.84* Integral vBMD Femoral Neck
1.2+0.7
Trabecular vBMDFemoral Neck
2.7+1.9
aBMD Trochanter
1.56+0.99* Integral vBMD Trochanter
1.5+0.9
*p<0.01, n=16-18
Trabecular vBMD Trochanter
2.2+0.9
T. Lang et al., JBMR 2006.T. Lang et al., JBMR 2006.
BMCFemoral Neck
5.200
5.400
5.600
5.800
6.000
6.200
6.400
6.600
PRE POST 12MONTH
Visit
Int.
BM
C (g
)
Total Femur
28.000
29.000
30.00031.000
32.000
33.00034.000
35.000
36.000
PRE POST 12MONTH
Visit
Int.
BM
C (g
)
**
**
•*: p<0.05 with respect to preflight, postflightLang et al, JBMR 2004, 2006. Losses in vBMD of integral femoral neck but greater % losses In trabecular compartment, significant thinning of cortex at the femoral neck during flight, and periosteal expansionduring 12-month postflight period.
Femoral Neck
0.300
0.310
0.320
0.330
0.340
0.350
0.360
0.370
PRE POST 12MONTH
Visit
Intg
. vB
MD
(g/c
c)
Total Femur
0.270
0.280
0.290
0.300
0.310
0.320
0.330
0.340
PRE POST 12MONTH
Visit
Intg
l. vB
MD
(g/c
c)
* **
* **
Minimum CSA
11.40011.500
11.600
11.700
11.800
11.900
12.00012.100
12.200
PRE POST 12MONTH
Visit
CSA
(cm
2)
**
Minimum FN CSA and strength
Bone strength indices
1.000
1.250
1.500
1.750
2.000
2.250
2.500
2.750
3.000
3.250
3.500
1 2 3
Stre
ngth
inde
x
Series1
Series2**
*
*
bending (cm3)compressive (g2/cm4)
vBMD
Pre Post 12 Pre Post 12 Pre Post 12
Pattern of cortical bone thinning as seen in Pattern of cortical bone thinning as seen in beagle after 40 wks of cast immobilization.beagle after 40 wks of cast immobilization.
From J.W.JaworskiSlide Courtesy of D Carter
Copyright ©2001 The Endocrine Society
Seeman, E. J ClinEndocrinol Metab 2001;86:4576-4584
DXA Measurement
Skeletal Response
Use of Imaging Use of Imaging Technology to Technology to evaluate changes in evaluate changes in bone massbone mass
Mary Mary BouxseinBouxsein, Ph.D., Ph.D.
Physiological Changes in Bone GeometryPhysiological Changes in Bone Geometry
Bone Turnover MarkersBone Turnover Markers
Bone Resorption
Bone resorption is increased during flight
Space Flight:↑ Urinary collagen xlinks↑ Urinary Ca↑ Urinary OH-Proline
Smith et al., JCEM, 1998
****
* **
*
*
** * *
N-Telopeptide
% C
hang
e fr
om P
refli
ght
-50 Weeks In-flight Weeks
Postflight
1 2 3 4 5 6 7 8 9 10 11 12 1 2 3
25020015010050
0
Slide courtesy of Dr. Scott M. Smith
Response of Bone BiomarkersResponse of Bone Biomarkers(Smith et al, JBMR 2005)(Smith et al, JBMR 2005)
Bone RecoveryBone Recovery
-25
-20
-15
-10
-5
0
5
10
0 300 600 900 1200 1500
Days-After-Landing
BM
D C
hang
e (%
)
Trochanter
-25
-20
-15
-10
-5
0
5
10
0 300 600 900 1200 1500
Days-After-Landing
BM
D C
hang
e (%
)
Pelvis
-25
-20
-15
-10
-5
0
5
10
0 300 600 900 1200 1500
Days-After-Landing
BM
D C
hang
e (%
)
Lumbar Spine Femoral neck
-25
-20
-15
-10
-5
0
5
10
0 300 600 900 1200 1500
Days-After-Landing
BM
D C
hang
e (%
)
Consistent increase in BMD in Postflight Period
Model for Skeletal RecoveryModel for Skeletal RecoverySkeletal Site Loss (L0) at
landing %
50% Recovery
Time (days)
Femoral Neck 6.8 (5.7, 7.9)
211 (129, 346)
Trochanter 7.8 (6.8, 8.8)
255 (173, 377)
Pelvis 7.7 (6.5, 8.9)
97 (56, 168)
Lumbar Spine 4.9 (3.8, 6.0)
151 (72, 315)
Calcaneus 2.9 (2.0, 3.8)
163 (67, 395)
Sibonga et al BONE 2007Sibonga et al BONE 2007
Spaceflight Bone Loss vs. Spaceflight Bone Loss vs. AgeAge--related Bone Lossrelated Bone Loss
BMD Loss vs. AgeBMD Loss vs. Age--matched Lossmatched Loss
Losses in 6 months in space far exceed 2-year losses on Earth in similarly –age population.
Minimal BMD loss in forearms of males on earth.
Small n for females but suggest losses equivalent to postmenopausal losses on earth.
Circumstantial Evidence: Parallels Circumstantial Evidence: Parallels Menopause vs. SF Menopause vs. SF
1.1. Reduction Reduction TbNTbN, loss of , loss of connectivity in connectivity in postmenopausal women postmenopausal women ((KleerekoperKleerekoper, 1985), 1985)
2.2. Preferential cancellous bone Preferential cancellous bone loss (Riggs refs.)loss (Riggs refs.)
3.3. BMD losses 2BMD losses 2--3%/yr (Riggs 3%/yr (Riggs refs)refs)
4.4. Resorption on inside surface Resorption on inside surface (endocortical) of cortex.(endocortical) of cortex.
5.5. Activation Frequency Activation Frequency highhigh in in postmenopausal women postmenopausal women ((ReckerRecker, 2004), 2004)
1.1. Biopsies after 120 days bed Biopsies after 120 days bed rest. rest. TbNTbN reduced reduced ((ThompsenThompsen, , 2005)2005)
2.2. Preferential cancellous bone Preferential cancellous bone loss in proximal femur loss in proximal femur (Lang, (Lang, 2004)2004)
3.3. Range BMD losses (3Range BMD losses (3--9%) per 9%) per ~6 months~6 months
4.4. Cortical thinning at femoral Cortical thinning at femoral neck from endocortical neck from endocortical surface.surface.
5.5. Not quantifiedNot quantified
Given the preferential loss in trabecular bone compartment and tGiven the preferential loss in trabecular bone compartment and the rapid rate of he rapid rate of loss in crew members, loss in crew members, suspectsuspect that the impact on microarchitecture is at the very that the impact on microarchitecture is at the very least equivalent to postmenopausal women.least equivalent to postmenopausal women.
Turnover in CrewmembersTurnover in CrewmembersLoss in crewmembers at faster rate than Loss in crewmembers at faster rate than postmenopausal females (months vs. years)postmenopausal females (months vs. years)High turnover with menopause leads to High turnover with menopause leads to perforations of trabecular struts.perforations of trabecular struts.At what time point with SF does irreversible At what time point with SF does irreversible perforation occur?perforation occur?
Normal vs. High Bone TurnoverNormal vs. High Bone Turnover
Are crewmembers restored to Are crewmembers restored to preflight skeletal status? Recover preflight skeletal status? Recover
bone that was lost in space?bone that was lost in space?
DXA: Restoration of areal BMD within ~ 3 DXA: Restoration of areal BMD within ~ 3 years but cannot assess structure.years but cannot assess structure.QCT: QCT: IncompleteIncomplete recovery of recovery of vBMDvBMD at 12 at 12 months postflightmonths postflightGeometrical changes at femoral neck Geometrical changes at femoral neck indicate early onset of ageindicate early onset of age--related related changes changes (Riggs, JBMR 2004; 2008)(Riggs, JBMR 2004; 2008)
Histomorphometry of Bone Biopsies Histomorphometry of Bone Biopsies (Bed Rest Flight Analog) (Bed Rest Flight Analog)
VicoVico (1987) a (1987) a reduced mineralizationreduced mineralization, no change in , no change in matrix formation and increased resorption of bone matrix formation and increased resorption of bone (osteoclast parameters)(osteoclast parameters)Arnaud (1992) Arnaud (1992) suppressed bone formation ratesuppressed bone formation rate and and reduced osteoblast activity in as short as 7 d reduced osteoblast activity in as short as 7 d experiment experiment ZerwekhZerwekh (1998) mild (1998) mild decrement in bonedecrement in bone--forming forming osteoblastsosteoblasts concurrent with concurrent with increased bone increased bone resorptionresorption in 12 wk studyin 12 wk studyThomsen ( 2006) deterioration of trabecular Thomsen ( 2006) deterioration of trabecular microarchitecture 120 d suggestive of aggressive microarchitecture 120 d suggestive of aggressive resorptionresorption
AgeAge--related Bone Lossrelated Bone Loss
20 30 40 50 60 70 80
0.5
1.0
1.5
2.0
Trabecular NumberMale
Age (Years)Tr
abec
ular
Num
ber (
mm
1)
P=0.02R=-0.35
Sibonga et al, manuscript
Bone Gain and Loss with Age is SexBone Gain and Loss with Age is Sex-- specificspecific
CP1014192-21
Riggs BL, Melton LJ: Involutional osteoporosisRiggs BL, Melton LJ: Involutional osteoporosisOxford Textbook of Geriatric MedicineOxford Textbook of Geriatric Medicine
Bone massBone mass(g/calcium(g/calcium))
Age (yr)Age (yr)
0
500
1,000
1,500
0 20 40 60 80 100
II
IIII
IIIIII
II
IIIIII
Females
Males
Incidence of Limb FracturesIncidence of Limb Fractures
CP1014563-1
Incidence/Incidence/100,000 p100,000 p--yy
Age group (yr)Age group (yr)
0
800
1,600
2,400
3,200
4,000
0-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 ≥85
FemalesFemales
MalesMales
The influence of previous bone loss on fractures in later life.
Summary: Spaceflight EvidenceSummary: Spaceflight Evidence
Negative calcium balance, reduced absorption and downNegative calcium balance, reduced absorption and down--regulated regulated calcitropiccalcitropic hormoneshormones
Deficits in Deficits in aBMDaBMD at weightat weight--bearing sites, bearing sites, vBMDvBMD cancellous cancellous bone, thinning of cortical bonebone, thinning of cortical bone
Increased bone resorption markers>formation markersIncreased bone resorption markers>formation markers
Reductions in hip bone strength estimated by FEA, also in Reductions in hip bone strength estimated by FEA, also in compressive and bending strengths at femoral neck after compressive and bending strengths at femoral neck after returnreturn
Delayed and possibly incomplete restoration of preflight hip Delayed and possibly incomplete restoration of preflight hip bone integrity.*bone integrity.*
Summary/ConclusionsSummary/Conclusions
The evidenceThe evidence--toto--date suggests that the rapid rate of sitedate suggests that the rapid rate of site--specific specific bone loss in space, due to the unbalanced stimulation of bone bone loss in space, due to the unbalanced stimulation of bone resorption, may predispose crew members to irreversible changes resorption, may predispose crew members to irreversible changes in bone structure and microarchitecture.in bone structure and microarchitecture.No analyses conducted in the postflight period to assess No analyses conducted in the postflight period to assess microarchitecturalmicroarchitectural changes.changes.There is no complete analysis of skeletal recovery in the postflThere is no complete analysis of skeletal recovery in the postflight ight period to evaluate the structural changes that accompany period to evaluate the structural changes that accompany increases in DXA increases in DXA aBMDaBMD. . Postflight analyses based upon QCT scans performed on Postflight analyses based upon QCT scans performed on limitedlimitedcrew members indicate reductions in hip bone strength and crew members indicate reductions in hip bone strength and incomplete recovery at 1 year.incomplete recovery at 1 year.No recovery of trabecular No recovery of trabecular vBMDvBMD after 1 year return (HRP IWG).after 1 year return (HRP IWG).Time course of bone loss in space unknown.Time course of bone loss in space unknown.
Thank you.Thank you.
Crew dataCrew dataLang T, LeBlanc A, Evans H, Lu Y, Lang T, LeBlanc A, Evans H, Lu Y, GenantGenant h, Yu A. 2004 Cortical and trabecular h, Yu A. 2004 Cortical and trabecular bone mineral loss from the spine and hip in longbone mineral loss from the spine and hip in long--duration spaceflight. J Bone duration spaceflight. J Bone Miner Res 19(6):1006Miner Res 19(6):1006--1012.LeBlanc A, 1012.LeBlanc A, Lang TF, LeBlanc AD, Evans HJ, Lu Y. The effect of longLang TF, LeBlanc AD, Evans HJ, Lu Y. The effect of long--duration spaceflight on duration spaceflight on the density, mass and geometry of the hip bone Submitted manuscrthe density, mass and geometry of the hip bone Submitted manuscript. 2006.ipt. 2006.Schneider V, Shackelford L, West S, Schneider V, Shackelford L, West S, OganovOganov V, V, BakulinBakulin A, A, VoroninVoronin L. 2000 Bone L. 2000 Bone mineral and lean tissue loss after long duration space flight. mineral and lean tissue loss after long duration space flight. J J MusculoskeletMusculoskeletNeuronal Interact 1(2):157Neuronal Interact 1(2):157--160.160.VicoVico L, L, ColletCollet P, P, GuignandonGuignandon A, A, LafageLafage--ProustProust M, Thomas T, M, Thomas T, RehailiaRehailia M, M, AlexandreAlexandre C 2000 Effects of longC 2000 Effects of long--term microgravity exposure on cancellous and term microgravity exposure on cancellous and cortical weightcortical weight--bearing bones of cosmonauts. The Lancet 355:1607bearing bones of cosmonauts. The Lancet 355:1607--1611.1611.VicoVico L, L, ChappardChappard D, D, AlexandreAlexandre C, C, PallePalle S, S, MinaireMinaire P, P, RiffatRiffat G, et al. Effects of a G, et al. Effects of a 120 day period of bed120 day period of bed--rest on bone mass and bone cell activities in man: attempts rest on bone mass and bone cell activities in man: attempts at countermeasure. Bone Miner. 1987;2(5):383at countermeasure. Bone Miner. 1987;2(5):383--94.94.Sibonga JD, Evans HJ, Sibonga JD, Evans HJ, SpectorSpector ER, ER, OganovOganov, , BakulinBakulin, Shackelford LC, et al. , Shackelford LC, et al. Skeletal recovery following longSkeletal recovery following long--duration missions as predicted by preflight and duration missions as predicted by preflight and postflight dualpostflight dual--energy xenergy x--ray absorptiometry (DXA) scans of 45 crewmembers ray absorptiometry (DXA) scans of 45 crewmembers BONE. 2007BONE. 2007
Bed rest citationsBed rest citations
Arnaud SA, Arnaud SA, SherrardSherrard DJ, Maloney N, Whalen RT, Fung P. Effects DJ, Maloney N, Whalen RT, Fung P. Effects of 1of 1--week headweek head--down tilt bed rest on bone formation and the down tilt bed rest on bone formation and the calcium endocrine system. Aviation, Space and Environmental calcium endocrine system. Aviation, Space and Environmental Med. 1992 64:14Med. 1992 64:14--20.20.ZerwekhZerwekh JE, JE, RumlRuml LA , Gottschalk F, Pak CY. The effects of LA , Gottschalk F, Pak CY. The effects of twelve weeks of bed rest on bone histology, biochemical markers twelve weeks of bed rest on bone histology, biochemical markers of bone turnover, and calcium homeostasis in eleven normal of bone turnover, and calcium homeostasis in eleven normal subjects JBMR. 1998;13 (10):1594subjects JBMR. 1998;13 (10):1594--601.601.Thomsen JS, Thomsen JS, MorukovMorukov BV, BV, VicoVico L, L, AlexandreAlexandre C, C, SaparinSaparin PI, PI, GowinGowin W. Cancellous bone structure of iliac crest biopsies W. Cancellous bone structure of iliac crest biopsies following 370 days of headfollowing 370 days of head--down bed rest Aviation, Space, and down bed rest Aviation, Space, and Environmental Medicine 2005;76 (10):915Environmental Medicine 2005;76 (10):915--22.22.MinaireMinaire P, P, MeunierMeunier P, P, EdouardEdouard C, Bernard J, C, Bernard J, CourpronCourpron P, P, BourretBourretJ Quantitative histological data on disuse osteoporosis. J Quantitative histological data on disuse osteoporosis. CalcifCalcifTissTiss Res 1974;17:57Res 1974;17:57--73. 73.
Backup slidesBackup slides
““Osteoporosis is a skeletal disorder characterized by compromisedOsteoporosis is a skeletal disorder characterized by compromisedbone strength predisposing to an increased risk of fracture. Bobone strength predisposing to an increased risk of fracture. Bone ne strength reflects the strength reflects the integration of two main features: bone density : bone density and bone quality.”and bone quality.”
JAMA. 2001JAMA. 2001
“…“….Bone quality, in turn, is stated to refer to .Bone quality, in turn, is stated to refer to architecture, turnover, damage accumulation, (e.g., architecture, turnover, damage accumulation, (e.g.,
microfracturesmicrofractures) and mineralization….”) and mineralization….”
Osteoporosis Int. 2002Osteoporosis Int. 2002
BMD TBMD T--Score Values by Area Score Values by Area Expeditions 1Expeditions 1--13 (n=16)13 (n=16)
Comparison to Population Comparison to Population NormalsNormals
Normal
Osteopenia
Osteoporosis-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
T-Sc
ore
Pre-Lumbar Spine
Post-Lumbar Spine
Pre-FemoralNeck
Post-FemoralNeck
Pre-Trochanter
Post-Trochanter
Russian DataRussian Data
0.90.9--19.8% losses in calcaneus after 7519.8% losses in calcaneus after 75--84d 84d missions (missions (StupakovStupakov, 1984), 1984)CT scans SalyutCT scans Salyut--7 crew (57 crew (5--7 months) 7 months) ((OganovOganov 1990) document vertebral BMD 1990) document vertebral BMD losses of 0.3, 2.3, 6.2 and 10.8% losses of 0.3, 2.3, 6.2 and 10.8% Highlighted the variability in losses between Highlighted the variability in losses between crew members (as with Apollo missions)crew members (as with Apollo missions)Losses did not correlate with flight durationLosses did not correlate with flight duration
Correlations of SpaceflightCorrelations of Spaceflight--induced Changes (%) induced Changes (%) in DXA BMD to DXA Lean Muscle Massin DXA BMD to DXA Lean Muscle Mass
Correlation BMD with Lean Muscle Mass
R2 p value
Pelvis vs. Leg Lean Mass 0.295 <0.05 Total Hip vs. Leg Lean Mass 0.053 <0.05 Trochanter vs. Leg Lean Mass 0.210 <0.05 Femoral neck vs. Leg Lean Mass
0.006 NS
Leg BMD vs. Leg Lean Mass 0.139 <0.01 Lumbar Spine vs. Trunk Lean 0.248 NS Arm vs. Arm Lean Mass 0.041 NS
Note: A weak but significant correlation of hip BMD with area of muscle group attached to hip, as measured in CT scans in women without fracture compared to women with hip fracture. (Personal communication with T. Lang)
“Every change in the function of a bone is followed by certain definite changes in internal architecture and external conformation in accordance with mathematical principles"
J Wolff (1886)J Wolff (1886)
The Law of Bone Remodelling. (1892) translated by Maquet P and Furlong R. New York, NY: Springer-Verlag; 1986.
Age is an Independent Risk FactorAge is an Independent Risk Factorfor Osteoporotic Fracturesfor Osteoporotic Fractures
Adapted from:Kanis JA et al. Osteoporosis Int. 2001;12:989-995.
0
10
20
30
40
50
1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0
Femoral Neck T-score
Ten Year Fracture
Probability (%)
Age
8070
60
50
Probability of first fracture of hip, distal forearm, proximal humerus, and symptomatic vertebral fracture in women of Malmö, Sweden.
Bone Qualities: Indices that Bone Qualities: Indices that influence bone strength.influence bone strength.
Goldstein, “BoneGoldstein, “Bone Quality: A Biomechanical PerspectiveQuality: A Biomechanical Perspective” May 2005” May 2005
Hip Bone Strength: Use of Hip Bone Strength: Use of modelingmodeling
Loading ConditionsLoading ConditionsFinite Element Models of Finite Element Models of Left Proximal FemurLeft Proximal Femur
KeyakKeyak et al, 1998, et al, 1998, 2001, 20052001, 2005
Results Results –– Hip StrengthHip Strength
Loading Loading ConditionCondition
Mean (SD)Mean (SD)PrePre--flightflight
Mean (SD)Mean (SD)PostPost--flightflight pp
StanceStance 13,200 N13,200 N(2300 N)(2300 N)
11,200 N11,200 N(2400 N)(2400 N)
2,280 N2,280 N(590 N)(590 N)
<0.001<0.001
FallFall 2,580 N2,580 N(560 N)(560 N)
0.0030.003
N=11 crewmembers
2.2% loss/month2.2% loss/month
1.01.0--1.5% BMD loss /month1.5% BMD loss /month
1.9% loss/month1.9% loss/month
Percentage Reduction in Hip StrengthPercentage Reduction in Hip Strength
4
3
2
1
0
Stance
0 10 20 30% Reduction
Num
ber o
f Sub
ject
s
Fall
-10 0 10 20% Reduction
4
3
2
1
0
Slide Courtesy of J. Keyak
Activation Frequency requires Bone Activation Frequency requires Bone HistomorphometryHistomorphometry
W.Th=Average thickness of BSUW.Th=Average thickness of BSU
MineralizationMineralization
SecretionSecretion
MAR =Interlabel distance
Label interval
MARMAR =Interlabel distance
Label interval Label interval
Average time that takes for a new remodeling cycle to begin on any point on a cancellous surface – an index for the rate of bone remodeling.
Not practical for site-specific bone remodeling see with mechanical unloading.
Bone HistologyBone Histology
GAPS: Factors Related GAPS: Factors Related to Fracture Risk Besides Bone Massto Fracture Risk Besides Bone Mass
1.1. Energy released by fall or “Energy released by fall or “injury”injury”(need(need to to identify tasks to be performed; perform modeling to predict*)identify tasks to be performed; perform modeling to predict*)
2.2. Neuromuscular protection of bone Neuromuscular protection of bone (need to (need to preserve postural muscle mass and motor coordination)preserve postural muscle mass and motor coordination)
3.3. Energy absorbed by soft tissue Energy absorbed by soft tissue (need to (need to provide adequate “protective padding,” evaluate putative provide adequate “protective padding,” evaluate putative osteoprotectiveosteoprotective effect of EVA suit and partial gravity)effect of EVA suit and partial gravity)
4.4. Bone Strength: Quantity & Quality Bone Strength: Quantity & Quality (need (need supplement DXA bone mass measurements)supplement DXA bone mass measurements)
*Carpenter JBMR, 2005*Carpenter JBMR, 2005
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