Spaceflight Skeletal Update:
Is there a need for countermeasures
on Current and Future ISS Missions?
Adrian Leblanc
Division of Space life Sciences, USRA
Aerospace Medicine Grand Rounds
June 26, 2007
Outline
• What we know
– Bone mass
– Strength
– Remodeling
– Renal Stone
– Recovery
• What we don’t know
• Countermeasures
• Answer question
Bone Mass
• Temporal information
• Extent/Location
• Frequency
Skylab-Ca balance
Bone Mass
• Temporal information
• Extent/Location
• Frequency
Change in QCT Trabecular BMD after ISS Flights
(n=14)
20
15
Means
10
% Change / 6 Months
5
0
-5
-10
-15
-20
-25
-30
-35
Lumbar Spine
Data published by T. Lang 2004
Femoral Neck (Hip)
Trochanter (Hip)
Total Hip
Regional nature of bone loss
• DXA
–
–
–
–
Total body/Arm=8
Trochanter/Arm=39
Trochanter/total body=4.5
leg/total body=1
• QCT
– Femur neck trabecular/Femur neck DXA=2
– Femur neck trabecular/DXA total body=8
– Femur neck trabecular/ Spine trabecular=4
Bone Mass
• Temporal information
• Extent/Location
• Frequency
Percentage of Long Duration
Crewmembers
BMD Loss in Long Duration Crewmembers
100
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
%Bone Loss in at Least One Skeletal Region
19
20
21
Outline
• What we know
– Bone mass
– Strength
– Remodeling
– Renal Stone
– Recovery
• What we don’t know
• Countermeasures
• Answer question
Percentage Reduction in Hip Strength
Joyce Keyak-UCSF
Fall
Number of Subjects
Stance
4
4
3
3
2
2
1
1
0
0
0
10
20
% Reduction
30
-10
0
10
20
% Reduction
Perspective on Strength Loss
• Cross-sectional study of Caucasian women
• 128 elderly (70 - 80yr)
• 30 pre-menopausal (35 - 45yr)
Lifetime loss due
to aging, mean
Stance
6.9%
6 mo in space,
median (range)
13%
(4 to 30%)
Fall
24.4%
14%
(0 to 23%)
Outline
• What we know
– Bone mass
– Strength
– Remodeling
– Renal Stone
– Recovery
• What don’t we know
• Countermeasures
• Answer question
Bone Modeling Unit-BMU
Micrograph of Bone
Susan Ott
Skylab
Bone Resorption
N-Telopeptide
% Change from Preflight
250
*
200
150
100
* *
*
*
*
* * *
*
*
*
*
50
0
-50
1
2
3
4
5
6
7
8
Weeks In-flight
9
10
11
12
1
2
3
Weeks
Postflight
Remodeling
Excess Bone Remodeling
• Resorption increased
– Increased activation frequency
– Reduced apoptosis
• Formation unchanged
• Result is loss of bone
– Increased remodeling space
– Uncoupling
• Architectural changes
– Rapid; fracture reduction in osteoporosis; spaceflight
– Reduced trabecular connectivity; increased number and
depth of resorption sites (stress risers); increase in
under-mineralized bone matrix leads to:
– Reduced strength in addition to that calculated from
decreased BMD
Outline
• What we know
– Bone mass
– Strength
– Remodeling
– Renal Stone
– Recovery
• What we don’t know
• Countermeasures
• Answer question
Kidney Stone-General
• Kidney stones occur in 1 in 20 people at some time in
their life.
• The development of the stones is related to decreased
urine volume or increased excretion of stone-forming
components such as calcium, oxalate, urate, cystine,
xanthine, and phosphate.
• The most common type of kidney stone contains calcium
in combination with either oxalate or phosphate.
• The prevalence of kidney stones rises dramatically as we
enter our 40s and continues to rise into our 70s.
• 75% of first-time renal stone formers will have a
reoccurrence within 5 yrs
• Hypercalciuria, is responsible for about 70% of calciumcontaining stones.
Kidney Stones-Spaceflight
• 14 in 12 crew in US program
• Multiple events in Russian program-one
event in-flight
• Postflight all stone formers associated with
elevated postflight urinary Ca-6/10 had
hypercalciuria.
• 39% of studied crew (n=329) had postflight
hypercalciuria
• Prediction of which astronauts will develop
renal stone is currently impossible
Pietrzyk, Jones et al. ASEM 2007
Outline
• What we know
– Bone mass
– Strength
– Remodeling
– Renal Stone
– Recovery
• What we don’t know
• Countermeasures
• Answer question
BMD-Femoral Neck
Loss0=6.9%
Recovery Half-life=221 d
BMD deficit (% Loss)
10
5
0
-5
-10
-15
-20
-25
0
300
600
900
Days-After-Landing
1200
1500
QCT Extension Study (n=8)
Total Femur Region
1.16
1.14
1.12
1.1
QCT simulated DXA
1.08
Series1
1.06
Series2
1.04
DXA
1.02
1
0.98
PRE
POST
1YEAR
EXT
Hip BMD has a 6% loss (p<0.001) during the flight and slowly
recovers. DXA and QCT simulated total femur a BMD are
1-3% below preflight values, but the difference is not statistically
significant
QCT extension Study (n=8)
Cortical BMD in hip
0.545
0.54
0.535
Series1
0.53
0.525
0.52
0.515
PRE
POST
1YEAR
EXT
Cortical parameters show a 2-3% during the mission and
show no statistically significant differences from pre-flight
at 2-4 years
QCT extension study (n=8)
Trabecular BMD in hip
0.16
0.15
0.14
0.13
Series2
0.12
0.11
0.1
PRE
POST
1YEAR
EXT
Hip trabecular BMD is lost at 2-3% per month during
the flight and does not appear to show a long term recovery
Changes in bone size during recovery
Integral Volume
Cortical Volume
Femoral Neck
Femoral Neck
*
19.000
18.500
18.000
17.500
*
10.000
9.800
Cort. Vol (cc)
In t . V o l ( c c )
19.500
17.000
9.600
9.200
9.000
Minimum CSA
8.800
**
8.600
PRE
POST
12MONTH
12.200
8.400
PRE
Visit
POST
Total Femur
Total Femur
*
114.000
112.000
Cort. Vol (cc)
110.000
48.000
47.000
46.000
108.000
106.000
104.000
102.000
100.000
PRE
POST
12MONTH
12.100
12MONTH
12.000
CSA (cm2)
Visit
Int. Vol (cc)
Minimum CSA
*
9.400
11.900
11.800
11.700
11.600
*
11.500
11.400
PRE
POST
12MONTH
Visit
45.000
44.000
43.000
*
42.000
41.000
40.000
39.000
PRE
Visit
POST
12MONTH
Visit
* *: p<0.05 with respect to preflight, postflight
Cortical volume decreased over the the flight, but recovered to the preflight
value. Integral volume increased during the recovery period and showed a
Trend (NS) to be 5-7% larger than at pre-flight. Minimum CSA also increased in
the recovery period and was 3% larger at 12 months than at preflight (p<0.05)
Strength Recovery
bending (cm3)
Compressive (g2/cm4)
Bone strength indices
3.500
3.250
3.000
Strength index
2.750
*
***
2.500
2.250
2.000
1.750
***
1.500
***
1.250
1.000
1
2
3
* : p<0.05 ***: p<0.001 with respect to preflight
The bending strength and axial compressive strength indices
both decreased sharply over flight, but only the bending strength
index showed a trend towards recovery
Recovery summary
• Recovery of integral BMD or DXA occurs slowly
in most crewmembers.
• Some evidence that recovery is in cortical bone
and not necessarily in trabecular bone
• There are geometric changes of unknown
consequence
• There are significant decreases in bone strength
that remains at least out to 12 months post flight
Outline
• What we know
– Bone mass
– Remodeling
– Strength
– Renal Stone
– Recovery
• What we don’t know
• Countermeasures
• Answer question
What we don’t know
• Temporal relationship of loss
• Full extent of loss
• Consequence of geometric changes not
understood
• Risk of extended elevation of remodeling rate
– Microscopic architectural changes
• Bone microenvironment consequences of long
duration atrophy
• Quantitative risk of renal stone incidence during
flight
– could ruin an expensive mission
– could impact astronaut mission selection.
• Fracture risk during and after flight, working on
planetary surfaces; long term post flight
consequences
Outline
• What we know
– Bone mass
– Strength
– Remodeling
– Renal Stone
– Recovery
• What don’t we know
• Potential countermeasures
• Summary
Potential Countermeasures
• Exercise
• Pharmacologic
– Antiresorptive
• Bisphosphonates-Fosamax, zoledronic acid
• AMG 162
– Anabolic
• Fluoride
• PTH
• Other
– vibration
TRL levels of current Systems
• Exercise
• Bisphosphonates
• AMG 162
• Vibration
Exercise
Treadmill running
0.6 g via bungee cord
Cycling
Squats on iRED
Advantages of Exercise
• Theoretical. If you perform exercise of sufficient
duration and/or intensity, net bone loss will be
effectively prevented.
• High intensity resistive exercise during BR was
able to achieve macroscopic bone balance, but
the remodeling rate was still elevated.
• Potentially improve many systems
• Astronauts want to exercise
• Psychological benefit
Disadvantages of Exercise
• Does not prevent bone loss with current
prescription; continued increased remodeling
• Requires periodic equipment repair. After 2010
equipment repair will be limited, significant need
for spare parts; William Gerstenmaier “Build and
Burn”
• If trying to protect bone with high force resistive
exercise: Risk of sprain, muscle damage, stress
fracture-ARED is capable of inputting large
loads-600Ibs; BR subject ruptured pectoral
tendon during strength testing before BR
• Requires considerable crew time
• Requires considerable weight & space -ARED vs
shoebox
Bisphosphonate Countermeasure
• Fosamax (pill, once/wk) zoledronic acid (IV
preflight) used clinically for treatment of
resorption related bone loss. Fosamax:
2Million pts/yr; 20million prescriptions/yr in
2006
• Have been shown to inhibit resorption and
decrease bone loss, fracture risk and renal
stone risk in ground-based disuse studies.
• Requires little (Fosamax) or no space
(zoledronic acid)
• Use as adjunct to exercise or backup
countermeasure in case of equipment
failure or crew cannot exercise for an
extended period of time.
Bisphosphonate Risks
• Fosamax
– Esophageal irritation
– ONJ; no cases reported in 17000 pts, controlled
studies; 1/250000
– Effect on fetus unknown
• Zoledronic Acid
– ONJ; <1%
– Renal toxicity
– Possible flu like symptoms for 12-48 hrs
– Transient decrease in ionized Ca
– May cause slight increase in frequency (50vs20) of
serious atrial fibrillation; no difference overall; NEJM,
2007
– Effect on fetus unknown
AMG 162 Countermeasure
• Human monoclonal antibody
• Blocks the RANKL receptor reducing
osteogenesis (resorption)
• Phase 3 clinical trials for treatment of
osteoporosis-TRL of 5 or 6
• Subcutaneus injection
• Long residency time like zoledronic acid-6
months
• Does not incorporate into bone and therefore
thought to be good countermeasure candidate
Potential AMG162 Risks
• Large scale clinical safety data is lacking
• Potential for generation of antibodies to AMG162
that could react with endogenous OPG
• Hypocalcemia
• Effect on fetus is unknown
• Possible effect on tissues other than bone ,e.g.,
immune system or cardiovascular; blockade of
dendritic cell function and survival?
Afrin
• Mild stomach upset, trouble sleeping, dizziness,
lightheadedness, headache, nervousness, fast
heartbeat, loss of appetite, shaking, or unusual
sweating may occur.
• This product may reduce blood flow to your hands and
feet, causing them to feel cold.
• Unlikely but serious side effects: fast irregular
heartbeat, severe/uncontrolled shaking, difficulty
urinating, decreased sexual ability.
• Rare but very serious side effects: chest pain, seizures,
mental/mood changes (e.g., anxiety, panic, unusual
thoughts/behavior).
• A very serious allergic reaction to this drug is unlikely.
Symptoms of a serious allergic reaction may include:
rash, itching, swelling, severe dizziness, trouble
breathing.
Would you recommend an effective
skeletal countermeasure be used on
ISS Missions ?
• Scenario #1
• 45 yr female with T score of -1.5 (osteopenic) who is to
participate in 6 month flight where she might:
– Might lose 20-30% bone mass in critical sites
– Will Increase her remodeling rate by 100-150%
– Will Lose bone strength-could be considerably greater
than we currently recognize (mass and architecture)
– Might experience permanent changes in structure of
bone of unknown long term consequence
– Will experience hypercalciuria increasing risk of a
renal stone during or after flight
– Will require several years to recover, but may not
completely recover.
Would you recommend an effective
skeletal countermeasure be used
on ISS Missions ?
• Scenario #2
• NASA management decides to send crew
to ISS for 12 month missions (e.g., move
ISS to synchronous orbit around Moon to
support Moon exploration)
• Are we ready ?????
Historical Accomplishments
• Apollo
– Bone loss might be a problem
• Skylab
– Initiation of loss is rapid; whole body loss potentially significant
– Loss is continuous for many months
– Loss is not uniform throughout skeleton
• MIR and Shuttle MIR
– Regional mapping of bone loss
– Heterogeneity among bone sites
– Herterogeneity among individuals
• ISS
–
–
–
–
–
Trabecular and cortical contributions to loss
Critical bone regions
Recovery post flight
Geometric changes
Countermeasure testing
Partial List of Contributors
•
•
•
•
•
•
•
•
•
•
•
•
John Vogel
Paul Rambaut
Carolyn Huntoon
Victor Schneider
Don Whedon
Chris Cann
Sarah Arnaud
Linda Shackelford
Scott Smith
Charley Pak
Victor Oganov
Tom Lang
•
•
•
•
•
•
•
•
•
•
•
•
Jay Shapiro
Helen Lane
Y Watanabe
Toshio Matsumoto
OG Gazenko
C Alexandre
Harlan Evans
Elisabeth Spector
GP Stupakov
S Rakhmanov
Emily Holton
Russ Turner
Astronaut and Cosmonaut
Volunteers/Pioneers
•
•
•
•
•
Apollo 14-17 astronauts
Crewmembers of Skylab
MIR cosmonauts
7 astronauts of Shuttle/MIR
ISS astronauts
Thank you
leblanc@dsls.usra.edu