The Critical Role of Physical Activity
in Skeletal Development and
Maintenance
Dennis R. Carter, PhD
Stanford University
USRA/DSLS Bioastronautics Seminar Series
March 29, 2007
Limb Skeletal Pattern Formation
(courtesy of Cliff Tabin, Harvard)
Bone forms by endochondral and perichondral ossification
Periosteum
Simon et al., 2003
Osteoblasts
Osteoclasts
resorb bone
create bone
Bone
Time
Osteoblast
Osteoclast
Local mechanical forces created by
physical activity regulate osteoblast
and osteoclast activity
Mechanical cues regulate skeletal
development and adaptation to
different physical activities and
environments-----Throughout life
Newborn Human Tibia and Fibula
Normal
Hypokinetic
X-section size is
determined mostly by
The loading magnitude
Long bone cross sectional shape and size are
determined by osteoblast/osteoclast activity on
periosteal and endosteal surfaces
• Size--Influenced by intracortical stresses/strains
created in the mineralized tissue (measured by strain
gages)
– The “sensors” are probably the osteocytes and/or cells lining
the bone surfaces
• Shape---Influenced by “small” local forces normal to
the shaft
– Tension causes bone deposition (e.g. ridges at muscle
insertion sites)
– Compression (e.g. contraction of muscle bellies) inhibits
bone deposition
Muscle belly
Mid Lower Leg
tension
com
p re
ssi o
X-section shape is
determined mostly by
transverse pressures
And tension
n
X-section size is
determined mostly by
The intracortical forces
and moments
Interosseous membrane
Fleckenstein and Tranum-Jensen, 2001
Strain gage rosettes bonded
to cortical bone
• Metal foil elements change
resistance when stretched.
Resistance change is related
to strain in the direction of
the element
• 3 “stacked” elements
measure strain in 3
directions- necessary for fully
determining strain state at a
point on a surface
Should we use high forces (that create
high tissue stresses and strains) or a lot
of loading cycles to maintain bone mass?
ΨAS (MPa/day)
5000
4000
70
60
50
40
50
30
m = 4 slope from
human exercise studies
30
2500
2000
1500
20
1000
rooster ulna
bone maintenance
10
500
400
turkey ulna
bone maintenance
300
4
200
2
human tibia
normal walking
1
1
2
4
10
100
1,000
Number of Daily Load Cycles
10,000
100
Daily stress or strain stimulus
ψ = [∑ niσ ]
m 1/ m
i
day
ξ = [∑ ni εi ]
m 1/ m
day
ψ = Daily stress stimulus
ξ = Daily strain stimulus
i = Index of loading type
n = Number of loading cycles
σ = Maximum cyclic energy stress
ε = Maximum cyclic energy strain
m = Empirical weighting constant (~ 4)
Should we use high forces or a lot of
loading cycles to maintain bone mass?
It seems, from thought experiments, animal
studies, and human clinical studies that the
value of “m” is large--between 4 and 10
This means that the magnitude of the forces is
much more important than the number of
cycles in regulating bone density
Y AS - w
0
rdrift
rdrift
Tissue
Y AS
Stress Stimulus
Y AS + w
Ψ
(MPa/day)
Z
a
Y
L
L−ΔL
L+DL
X
a
σ zz = M y / I xx
M = (Ixx / y)σ zz
Surface strains regulate bone
apposition/resorption at the
periosteal and endosteal
surfaces
t=0
Initial Geometry
Apply Daily Load History
(Fig. 4.10)
Calculate Stress StimulusΨ at
Periosteum and Endosteum
Compare Y with Attractor Stess
Stimulus to find Modeling Error
Determine Surface Modeling Rate
(rm ) from Rate Law (Fig. 4.7)
Add Baseline Biologic Rate r(b )
to Periosteal Rate (Fig. 4.6)
Integrate Modeling Rate to find
New Inner and Outer Radii
t = t + Dt
A
Scale: 10 mm
0
2
6-60 years
B
0
2
6
18
60 years
16
14
12
10
8
6
4
2
0
0
10
20
30
Periosteum
Simulation
McCammon
Smith & Walker
Martin & Atkinson
Endosteum
Simulation
Martin & Atkinson
40
50
Age (years)
60
Femora cross section projected bone
mineral content and bone diameter
can be measure using DXA
From these measures, bone linear
density (g/mm) and section modulus
can be calculated
100
95 kg
adult
80
70 kg
adult
60
45 kg
adult
40
20
8
12
16
20
Age (yr)
24
28
5.0
4.0
3.0
Experimental Data
Male
Female
Analytical Models
45 kg adult
70 kg adult
95 kg adult
2.0
1.0
0.0
A
10
15
20
Age (years)
25
B
30
40
50
60
70
Body Mass (kg)
80
90
100
Going to Mars
Pattern of Bone Loss in Disuse
Adult beagle humeri (bilateral) after 40 weeks of immunization in a plaster cast
Courtesy of J.W.Jaworski
Being raised on Mars
Unilateral cast for 32 wks
during development
Unilateral cast for 60 wks
during development
Unilateral cast for 32 wks
during development followed
by recovery for 28 wks w/o
cast
From Uhtoff and Jaworski
Cancellous Bone
From Bell and Einhorn,
2001
Cancellous vs. Compact
Bone
The primary difference is in the degree of porosity
Dense compact bone has a porosity of about 5%
and an
“apparent density of about 1.9 g/cc
Cancellous bone porosity varies considerably but
is often between 60% and 95% with “apparent
density” of 0.8 and 0.1 g/cc
Bone Apparent Strength vs. Apparent Density
From Carter and Hayes 1976
Bone strength is proportional to the “apparent density” squared
“Apparent stress” and “true stress”
σ = ( ρ t / ρ ) σ app
2
ρ
ρt
= apparent density
= true density of mineralized tissue
Calculate the daily stress
stimulus from the “true stress”
ψ = [∑ niσ ]
m 1/ m
i
day
Y AS - w
0
rdrift
rdrift
Tissue
Y AS
Y AS + w
Stress Stimulus
Ψ
(MPa/day)
Bone Architecture of the Proximal Femur
Adaptations to Altered Loading
Skeletal changes in different
gravitational fields
Bone mineral loss after 4-6 months on the
International Space Station
Lang et al. 2004 JBMR
• 13 males 1 female, 40-55 years
– Considerable variation in individual bone loss
– No report of exercise activity
– QCT images revealed endosteal resorption of
cortical bone and increase in cancellous bone
porosity
• Average bone mineral loss in the Hip
– 1.2-1.5% per month
• Average bone mineral loss in the Spine
– 0.9% per month
Can we learn from observations on Earth?
Bone loss after spinal cord injury (SCI)
• Immediate acute loss rate (Kiratli, 1989)
– 1-2% in the hip
– 0% in the spine
• Bone loss stabilized in 2 years, except in femoral
shaft. (Biering-Sorensen, 1990)
– 40-50% total reduction in femoral bone
– 60-70% total reduction in tibial bone
• Clinical observations--”paraplegic fractures” in about
2% per year with SCI--Twice as many fractures as
normal age matched controls (Vestergaard et al.
1998)
Boss loss 1-12
months after stroke
From Ramnemark et al 1999
Risk of Hip Fracture
May be as high as 4x normal
(Ramnemark et al. 2000)
•Reduced bone strength
•More falls
Recovery of bone mineral and
strength after return to Earth
Bone Mineral Content vs Bone Strength Changes
100%
90%
Cancellous bone
80%
Strength Loss
70%
60%
50%
40%
30%
Compact Bone in
tension / compression
20%
10%
0%
Bone shaft in
bending / torsion
10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Bone Mineral Loss
Kourtis and Carter, 2007
Maximum Compressive Principal Strains Measured in Extreme Physical
Activities (from Rubin et al., 1994).
Bone
Activity
Peak Strain x 10-6 (microstrain )
---------------------------------------------------------------------------------------------------Horse radius
Trotting
-2800
Horse tibia
Galloping
-3200
Horse metacarpal Accelerating
-3000
Dog radius
Trotting
-2400
Dog tibia
Galloping
-2100
Goose humerus
Flying
-2800
Cockerel ulna
Flapping
-2100
Sheep femur
Trotting
-2200
Sheep humerus
Trotting
-2200
Sheep radius
Galloping
-2300
Sheep tibia
Trotting
-2100
Pig radiusTrotting
-2400
Fish hypural
Swimming
-3000
Monkey mandible Biting
-2400
Turkey tibia
Running
-2350
3000 microstrain = strain of .003mm/mm = 0.3%
Poor fatigue resistance of cortical
bone
Strain control
Bone tensile strains on the
tibia on Earth prior to flight
• Walking ~400 microstrain
• Jogging ~800 microstrain
• Rigorous activity~2500microstrain
– Creates significant fatigue microdamage
Bone tensile yield strain~6000microstrain
Bone strains after return to Earth will
increased in proportion to loss in bone
strength
For example a FULL ADAPTATION to the gravitation field of Mars
would cause a with a 60 % loss in tibia bone strength (a 36%
loss in cancellous bone density)
•
Walking 1000 microstrain (up from 400)
•
Jogging 2000 microstrain (up from 800)
– fatigue microdamage?
•
Rigorous activity 6250 microstrain (up from 2500)
– FRACTURE after a very short time
Average recovery of proximal femur bone
1 year after long-duration space flight
Lang et al. 2006 JBMR
•
Sixteen crew members of International space station making flights of
4.5-6 months
– Considerable individual variation
– Residual loss of cancellous bone density
– Apposition of new bone on periosteal surface causing increase in
bone size
•
Total bone mass (g)
– After flight -12.5% with one year recovery still -2%
Cortical Bone mass(g)
– After flight -14%with on year recovery still -4%
Cancellous bone density (g/cc)
– After flight -15% with one year recovery still -9%
•
•
Bone recovery after return from
space flight
• Immediately--there is an increase risk of bone
fracture that is directly related to the bone
mineral deficient
• Fatigue microdamage can accumulate and
lead to fatigue fracture
• Meanwhile, bone mass will increase in
response to the high bone strains and (some)
strength will be restored.
– We have a race between fatigue fracture and
bone restoration
Acknowledgements
Gary S. Beaupre
Dave Fyhrie
Rob Whalen
Tracy Orr
Marjolein van der Meulen
Dana Carpenter
Lampros Kourtis
Supported in large measure by the VA Rehabilitation R& D Service
16
Periosteum
12
8
Normal
Endosteum
↓Load in
development
↓Load in
adulthood
Normal loading
40% normal
4
0
16
Periosteum
12
8
Endosteum
Normal loading
40% normal at age 20
4
0
16
Periosteum
Same
Section Modulus
12
8
Endosteum
Normal loading
125% normal at age 20
4
0
0
10
20
30
40
Age (years)
50
60