Fragility Fractures - Pathogenesis-Biomechanical View

1. 1
Pathogenesis of Fragility Fractures:
A Biomechanical View
A.Arputha Selvaraj-APMP – IIM C

2. 2
Outline
• Pathogenesis of fractures and determinants of bone
strength
• Age-related changes that contribute to skeletal fragility
• Interaction between skeletal loading and bone strength
• Non-invasive assessment of bone strength

3. 3
Design of a structure
• Consider what loads it must
sustain
• Design options to achieve
desired function
– Overall geometry
– Building materials
– Architectural details

4. 4
Determinants of whole bone strength
• Geometry
– Gross morphology (size & shape)
– Microarchitecture
• Properties of Bone Material / Bone Matrix
– Mineralization
– Collagen characteristics
– Microdamage

5. 5
Hierarchical nature of bone structure
Macrostructure
Microstructure
Matrix Properties
Cellular Composition and
Activity
Seeman & Delmas
N Engl J Med 2006; 354:2250-61

6. 6
Biomechanical approach to fractures
Fall traits
Protective responses
Bending, lifting
Loads applied
to the bone
FRACTURE?
Bone Mass
Geometry
Material properties
Factor of
risk
Bone strength
Applied load
Bone strength
Hayes et al. Radiol Clin N Amer. 1991; 29:85-96
Bouxsein et al. J Bone Miner Res. 2006; 21:1475-82
>1
fracture

7. 7
Pathogenesis of fragility fractures
Age-related changes that contribute to fragility fractures:
1) Decreased bone strength
2) Increased propensity to fall

8. 8
Assessing bone
biomechanical properties
Structural
Properties
Material
Properties
Force
Deformation

9. Biomechanical testing
Key properties
Failure load
Force
Stiffness
Energy absorbed
Displacement

10. Review of the relevant material & geometric
properties vs loading mode
Material:
Elastic modulus
Ultimate strength
compression
bending
E ∝ (density)a
S ∝ (density)b
Cross-sect area, A ∝ r2
Axial rigidity, E•A
Moment of inertia, I ∝ r4
Section modulus, Z ∝ r3
Bending rigidity, E•I
10

11. 11
Effect of cross-sectional geometry on
long bone strength
aBMD (by DXA)
=
=
↓
Compressive strength
=
↑
↑
Bending strength
=
↑↑
↑↑↑
Bouxsein, Osteoporos Int, 2001

12. 12
Bone strength
SIZE & SHAPE
macroarchitecture
microarchitecture
MATERIAL
tissue composition
matrix properties
BONE REMODELING
formation / resorption
OSTEOPOROSIS DRUGS
Bouxsein. Best Practice Res Clin Rheumatol, 2005; 19:897-911

13. 13
Outline
• Determinants of bone strength
• Age-related changes that contribute to skeletal fragility

14. 14
Age-related changes in mechanical properties
of bone tissue
Cortical bone
% loss 30-80 yrs
Cancellous bone
% loss 30-80 yrs
Elastic modulus, E
-8%
-64%
Ultimate strength, S
-11%
-68%
Toughness
-34%
-70%
Bouxsein & Jepsen, Atlas of Osteoporosis, 2003

15. 15
Whole bone strength (Newtons)
Whole bone strength declines
dramatically with age
10000
Femoral neck
(sideways fall)
8000
6000
4000
10000
Lumbar vertebrae
(compression)
8000
young
6000
old
2000
0
Courtney et al. J Bone Joint Surg Am. 1995; 77:387-95
Mosekilde. Technology and Health Care 1998; 6:287-97
4000
2000
0
young
old

16. Age-related changes in geometry
Adaptation to maintain whole bone strength
16

17. Age-related changes in femoral neck vBMD,
geometry, and strength indices
% Change, ages 20-90 yrs
Men
Women
F vs M
(P-value)
Trabecular vBMD
Cortical vBMD
- 56**
- 24**
- 45**
- 13**
<0.001
<0.001
Total area
MOIap
Axial rigidity
Bending rigidity
13**
-1
- 39**
- 25**
7*
- 21**
- 31**
- 24**
ns
ns
ns
ns
For age regressions: *P<0.05, **P<0.005
368 women, 320 men, aged 20-97
Riggs et al. J Bone Miner Res. 2004; 19:1945-54
Riggs et al. J Bone Miner Res. 2006; 21(2):315-23
17

18. 18
Age-related changes in trabecular
microarchitecture
• Decreased bone volume,
trabecular thickness and
number
• Decreased connectivity
• Decreased mechanical
strength
Image courtesy of David Dempster

19. 19
Microarchitectural changes that influence
bone strength
Force required to cause a slender
column to buckle:
• Directly proportional to
– Column material
– Cross-sectional geometry
• Inversely proportional to
– (Length of column)2
www.du.edu/~jcalvert/tech/machines/buckling.htm

20. Theoretical effect of crossstruts on buckling strength
# Horizontal
Trabeculae
Effective
Length
Buckling
Strength
0
L
S
1
1/2 L
4xS
Bouxsein. Best Practice Res Clin Rheumatol, 2005; 19:897-911
20

21. 21
Cortical porosity increases with age
15
(41 iliac biopsies, age 19-90)
r = 0.78
P < 0.001
12
(%)
4-fold increase in
cortical porosity from
age 20 to 80
9
6
Increased heterogeneity
with age
3
0
0
20
40
60
Age (years)
Brockstedt et al. Bone 1993; 14:681-91
80

22. 22
Age-related changes in femoral neck cortex and
association with hip fracture
Mayhew et al,
Lancet 2005
20-year-old
80-year-old
Those with hip fractures have:
• Preferential thinning of the inferior anterior cortex
• Increased cortical porosity
Bell et al. Osteoporos Int 1999; 10:248-57
Jordan et al. Bone, 2000; 6:305-13

23. 23
Age-related changes in bone properties
associated with fracture risk
• Decreased bone mass and BMD
• Altered geometry
• Altered architecture
young
– Cortical thinning
– Cortical porosity
– Trabecular deterioration
elderly
Images from L. Mosekilde, Technology and
Health Care. 1998

24. 24
Outline
• Determinants of bone strength
• Age-related changes that contribute to femoral fragility
• Interaction between skeletal loading and bone strength

25. Etiology of age-related fractures
Loads applied
to the bone
FRACTURE?
Bone strength
25

26. 26
The factor of risk concept
Φ=
Applied load
Bone strength
Φ > 1, Frx
Φ < 1, no Frx
•
Identify activities associated with fracture
•
Use biomechanical models to determine loads applied to bone for
those activities
•
Estimate bone failure load for those activities
Hayes et al. Radiol Clin N Amer. 1991; 29:85-96
Bouxsein et al. J Bone Miner Res. 2006; 21:1475-82

27. 27
Falls and hip fracture
• Over 90% of hip fx’s associated with a fall
• Less than 2% of falls result in hip fracture
• Fall is necessary but not sufficient condition
• Sideways falls are most dangerous
• What factors dominate fracture risk?

28. 28
Independent risk factors for hip fracture
Factor
Adjusted Odds Ratio
Fall to side
5.7
(2.3 - 14)
Femoral BMD
2.7
(1.6 - 4.6)*
Fall energy
2.8
(1.5 - 5.2)**
Body mass index
2.2
(1.2 - 3.8)*
* calculated for a decrease of 1 SD
** calculated for an increase of 1 SD
Greenspan et al, JAMA, 1994; 271(2):128-33

29. Estimating loads applied to the hip during a
sideways fall
Human cadavers
Human volunteers
Crash dummy
Mathematical models and
simulations
Peak impact forces applied to greater trochanter:
270 - 730 kg (2400 - 6400 N)
(for 5th to 95th percentile woman)
Robinovitch et al. 1991; Biomech Eng. 1991;
113:366-74
Robinovitch et al.1997; Ann Biomed Eng. 1997;
25:499-508
van den Kroonenberg et al J Biomechanic
Engl.1995; 117:309-18
van den Kroonenberg et al J Biomech.
1996; 29:807-11
29

30. 30
Failure load (kN)
Femur is strongest in habitual loading
conditions
9
8
7
6
5
4
3
2
1
0
P < 0.001
7978 ± 700 N
2318 ± 300 N
Stance Sideways fall
Keyak et al. J Biomech. 1998; 31:125-33

31. 31
Failure load (kN)
Femur is strongest in habitual loading
conditions
9
8
7
6
5
4
3
2
1
0
Applied load
Φ=
Failure load
Fall load
P < 0.001
7978 ± 700 N
2318 ± 300 N
Stance Sideways fall
Keyak et al. J Biomech. 1998; 31:125-33
van den Kroonenberg et al. J Biomech. 1996; 29:807-11
Thus, Φ > 1 for sideways
fall in elderly persons

32. 32
Vertebral fractures
• Difficult to study
– Definition is controversial
– Many do not come to clinical attention
– Slow vs. acute onset
– The event that causes the fracture is often
unknown
• Poor understanding of the relationship
between spinal loading and vertebral
fragility

33. 33
Estimating loads on the lumbar spine
Schultz et al.1991; Spine. 1991; 16:1211-6
Wilson et al.1994; Radiology. 1994 ; 193:419-22
Bouxsein et al. J Bone Miner Res. 2006; 21:1475-82

34. 34
Factor of risk for vertebral fracture (L2)
Bending forwards 90o with 10 kg weight in hands
1.8
Men
1.8
1.6
11.9%
1.4
1.6
1.4
1.2
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.0
+28% over life**
10 20 30 40 50 60 70 80 90 100
Age
** P<0.005 for age-regressions
†
30.1%
1.2
1.0
Women
p<0.01 for comparison of age-related change in M and W
Bouxsein et al. J Bone Miner Res. 2006; 21:1475-82
0.2
+92% over life** †
0.0
10 20 30 40 50 60 70 80 90 100
Age

35. 35
Proportion of individuals
with
Φ > 1, per decade
(Bending forwards 90 lifting 10 kg weight)
o
Incidence / 100,000 person-years
1400
1200
1000
800
600
400
200
0
30
40
50
60
70
60
90
53%
50
%
80
42%
40
27%
30
20
4%
10
0
20-29 30-39 40-49
Bouxsein et al. J Bone Miner Res. 2006; 21:1475-82
Age
11%
4% 11%
12%
50-59 60-69 70-79
21%
80+

36. 36
Outline
• Determinants of bone strength
• Age-related changes that contribute to femoral fragility
• Interaction between skeletal loading and bone strength
• Non-invasive assessment of bone strength

37. 37
Clinical assessment of bone strength by DXA
• Areal BMD by DXA
– Bone mineral / projected area (g/cm2)
• Reflects (indirectly)
– Geometry / Mass / Size
– Mineralization
• Moderate to strong correlation with whole
bone strength at spine, radius & femur
(r2 = 50 - 90%)
• Strong predictor of fracture risk
• Does not distinguish
–
–
–
–
Specific attributes of 3D geometry
Cortical vs cancellous density
Trabecular architecture
Intrinsic properties of bone matrix
Bouxsein et al, 1999

38. 38
Estimating hip geometry from 2D DXA
“Hip Strength Analysis”
Estimate femoral geometry and strength indices
• Use 2D image data to derive 3D geometry
•
Requires assumptions that have not been tested for all populations and
treatments
Beck et al. 1999, 2001

39. 39
QCT assessment of bone density and geometry
Images courtesy of Dr. Thomas Lang, UCSF

40. 40
Multi-detector computed tomography
Non-Fx
62 yr
Fx
62 yr
Potential to show trabecular architecture…
Higher resolution, but higher radiation dose
Ito et al. J Bone Miner Res. 2005; 20:1828-36

41. 41
Trabecular architecture in vivo
with high resolution pQCT
~ 80 µm3 voxel size
Xtreme CT, Scanco
~ 3 min scan time, < 4 µSv
Distal radius and tibia only
Reproducibility:
density:
0.7 - 1.5% *
µ-architecture: 1.5 - 4.4% *
* Boutroy et al. J Clin Endocrinol Metab. 2005; 90:6508-15

42. Tibia
42
Radius
Premenopausal
Postmenopausal
Osteopaenia
Postmenopausal
Osteoporosis
Postmenopausal
Severe Osteoporosis
Boutroy et al. J Clin Endocrinol Metab. 2005; 90:6508-15

43. Discrimination of osteopaenic women with
and without history of fracture by HR-pQCT
(age = 69 yrs, n=35 with prev frx, n=78 without fracture)
% Difference
30%
26%*
20%
10%
Spine
BMD
Fem
Neck
BMD
13%*
BV/TV
TbN
TbTh
0%
TbSp
-0.3% 0.4%
TbSpSD
-5%
-10%
-9%*
-12%*
* p < 0.05 vs fracture free controls
Boutroy et al. J Clin Endocrinol Metab. 2005; 90:6508-15
43

44. MRI for architecture assessment in vivo
• Features of MRI
– Non-invasive
– No x-rays
– True 3D
– Oblique scanning plane
Image courtesy of Dr. Felix Wehrli, UPenn
– Clinical scanners
– Image time: 12 - 15 minutes
~ 150 x 150 x 300 µm,
60 x 60 x 100 µm
Image courtesy of Dr. Sharmila Majumdar, UCSF
44

45. 45
MRI assessment of trabecular structure
Images from two women with similar BMD
www.micromri.com

46. 46
QCT-based finite element analysis
• FEA is a well-established
engineering method for analysis of
complex structures
• Integrates geometry and density
information from QCT scan to
provide measures of bone strength
• In some cases, more strongly
associated with whole bone strength
in cadavers than DXA
• Further clinical validation needed
Faulkner et al, Radiology 1991; Keyak et al, J Biomechanics 1998;
Pistoia, Bone 2002; van Rietbergen JBMR 2003; Crawford et al, Bone 2003
Image courtesy of T. Keaveny
Crawford et al, Bone 2003; 33: 744-750

47. Conclusions
• Whole bone strength is determined by bone mass, geometry,
microarchitecture and characteristics of bone material
• Hip fractures result from an increase in traumatic loading —
in particular, falls to the side — coupled with a deterioration
in bone strength with increased age
• Biomechanically based assessment of fracture risk may
improve diagnosis and understanding of treatment effects
• New tools are being developed for non-invasive assessment
of bone strength and fracture risk
47