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