11

Pathogenesis of Fragility Fractures:

A Biomechanical View

A.Arputha Selvaraj-APMP – IIM C

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

Design of a structure

• Consider what loads it must sustain

• Design options to achieve desired function

– Overall geometry

– Building materials

– Architectural details

4

Determinants of whole bone strength

• Geometry

– Gross morphology (size & shape)

– Microarchitecture

• Properties of Bone Material / Bone Matrix

– Mineralization

– Collagen characteristics

– Microdamage

5

Hierarchical nature of bone structure

Seeman & Delmas N Engl J Med 2006; 354:2250-61

Macrostructure

Microstructure

Matrix Properties

Cellular Composition and Activity

6

FRACTURE?

Loads applied to the bone

Bone strength

Hayes et al. Radiol Clin N Amer. 1991; 29:85-96

Bouxsein et al. J Bone Miner Res. 2006; 21:1475-82

Applied load

Bone strength> 1 fracture

Factor ofrisk

Bone MassGeometry

Material properties

Fall traitsProtective responses

Bending, lifting

Biomechanical approach to fractures

7

Pathogenesis of fragility fractures

Age-related changes that contribute to fragility fractures:

1) Decreased bone strength

2) Increased propensity to fall

8

Assessing bone biomechanical properties

Deformation

Force

StructuralProperties

MaterialProperties

Biomechanical testing

Key properties

Displacement

Force

Failure load

Energy absorbed

Stiffness

10Review of the relevant material & geometric properties vs loading mode

compression

bending

Cross-sect area, A r2

Axial rigidity, E•A

Moment of inertia, I r4

Section modulus, Z r3

Bending rigidity, E•I

Material: Elastic modulus E (density)a Ultimate strength S (density)b

11

Effect of cross-sectional geometry on long bone strength

aBMD (by DXA) = =

Compressive strength

Bending strength

=

=

Bouxsein, Osteoporos Int, 2001

12

Bone strength

SIZE & SHAPE macroarchitecturemicroarchitecture

MATERIAL tissue compositionmatrix properties

BONE REMODELINGformation / resorption

OSTEOPOROSIS DRUGS

Bouxsein. Best Practice Res Clin Rheumatol, 2005; 19:897-911

13

Outline

• Determinants of bone strength

• Age-related changes that contribute to skeletal fragility

14

Age-related changes in mechanical properties of bone tissue

Cortical bone % loss 30-80 yrs

-8%

-11%

-34%

Elastic modulus, E

Ultimate strength, S

Toughness

Cancellous bone % loss 30-80 yrs

-64%

-68%

-70%

Bouxsein & Jepsen, Atlas of Osteoporosis, 2003

15

Whole bone strength declines dramatically with age

0

2000

4000

6000

8000

10000 Femoral neck(sideways fall)

young

old

Courtney et al. J Bone Joint Surg Am. 1995; 77:387-95 Mosekilde. Technology and Health Care 1998; 6:287-97

Lumbar vertebrae(compression)

Wh

ole

bo

ne

str

en

gth

(N

ewto

ns

)

0

2000

4000

6000

8000

10000

youngold

16

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

17

Age-related changes in femoral neck vBMD, geometry, and strength indices

Trabecular vBMDCortical vBMD

Total areaMOIap

Axial rigidityBending rigidity

WomenF vs M

(P-value)Men% Change, ages 20-90 yrs

For age regressions: *P<0.05, **P<0.005

- 56** - 24**

13** - 1 - 39** - 25**

- 45** - 13**

7* - 21** - 31**- 24**

<0.001<0.001

ns ns ns ns

Riggs et al. J Bone Miner Res. 2004; 19:1945-54Riggs et al. J Bone Miner Res. 2006; 21(2):315-23

368 women, 320 men, aged 20-97

18

Age-related changes in trabecular microarchitecture

• Decreased bone volume, trabecular thickness and number

• Decreased connectivity

• Decreased mechanical strength

Image courtesy of David Dempster

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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

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Theoretical effect of cross-struts on buckling strength

# Horizontal Effective Buckling Trabeculae Length Strength

0 L S

1 1/2 L 4 x S

Bouxsein. Best Practice Res Clin Rheumatol, 2005; 19:897-911

21

Cortical porosity increases with age(41 iliac biopsies, age 19-90)

Age (years)

0

3

6

9

12

15

0 20 40 60 80

r = 0.78 P < 0.001

(%)

Brockstedt et al. Bone 1993; 14:681-91

4-fold increase incortical porosity from

age 20 to 80

Increased heterogeneity with age

22

20-year-old 80-year-old

Age-related changes in femoral neck cortex and association with hip fracture

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

Mayhew et al, Lancet 2005

23

Age-related changes in bone properties associated with fracture risk

• Decreased bone mass and BMD

• Altered geometry

• Altered architecture

– Cortical thinning

– Cortical porosity

– Trabecular deterioration

Images from L. Mosekilde, Technology and Health Care. 1998

young

elderly

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

FRACTURE?

Loads applied to the bone

Bone strength

26

Frx

no Frx

Applied load

Bone strength

The factor of risk concept

• 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

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?

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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

Independent risk factors for hip fracture

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

30

Femur is strongest in habitual loading conditions

Keyak et al. J Biomech. 1998; 31:125-33

0123456789

Stance Sideways fall

Fa

ilure

loa

d (

kN

)

P < 0.001

2318 ± 300 N7978 ± 700 N

31

Femur is strongest in habitual loading conditions

Keyak et al. J Biomech. 1998; 31:125-33 van den Kroonenberg et al. J Biomech. 1996; 29:807-11

0123456789

Stance Sideways fall

Fa

ilure

loa

d (

kN

)

P < 0.001

2318 ± 300 N7978 ± 700 N

= Applied load

Failure load

Thus, > 1 for sideways fall in elderly persons

Fall load

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

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

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Factor of risk for vertebral fracture (L2)Bending forwards 90o with 10 kg weight in hands

Age

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

10 20 30 40 50 60 70 80 90 100

Men

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

10 20 30 40 50 60 70 80 90 100Age

Women

11.9% 30.1%

+92% over life** †+28% over life**

** P<0.005 for age-regressions

† p<0.01 for comparison of age-related change in M and W

Bouxsein et al. J Bone Miner Res. 2006; 21:1475-82

35

Proportion of individuals with

> 1, per decade

0

10

20

30

40

50

60

20-29 30-39 40-49 50-59 60-69 70-79 80+

%

4%4% 11% 12%

21%11%

27%

42%

53%

Age

(Bending forwards 90o lifting 10 kg weight)

0

200

400

600

800

1000

1200

1400

40 50 60 70 8030 90

Incidence / 100,000 person-years

Bouxsein et al. J Bone Miner Res. 2006; 21:1475-82

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

Bouxsein et al, 1999

• Does not distinguish– Specific attributes of 3D geometry– Cortical vs cancellous density– Trabecular architecture– Intrinsic properties of bone matrix

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

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

QCT assessment of bone density and geometry

Images courtesy of Dr. Thomas Lang, UCSF

40

Non-Fx

62 yr

Fx

62 yr

Ito et al. J Bone Miner Res. 2005; 20:1828-36

Multi-detector computed tomography

Potential to show trabecular architecture…

Higher resolution, but higher radiation dose

41

Trabecular architecture in vivowith high resolution pQCT

~ 80 µm3 voxel size

~ 3 min scan time, < 4 µSv

Distal radius and tibia only

Reproducibility: density: 0.7 - 1.5% * µ-architecture: 1.5 - 4.4% *

Xtreme CT, Scanco

* Boutroy et al. J Clin Endocrinol Metab. 2005; 90:6508-15

42

Premenopausal

Postmenopausal Osteopaenia

Postmenopausal Osteoporosis

PostmenopausalSevere Osteoporosis

Boutroy et al. J Clin Endocrinol Metab. 2005; 90:6508-15

Tibia Radius

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)

* p < 0.05 vs fracture free controls

Boutroy et al. J Clin Endocrinol Metab. 2005; 90:6508-15

0.4%

-12%*-9%*

13%*

26%*

-0.3%

-10%

0%

10%

20%

30%

SpineBMD

Fem NeckBMD BV/TV TbN

TbSp TbSpSD

% D

iffer

en

ce

TbTh

-5%

44

MRI for architecture assessment in vivo

• Features of MRI

– Non-invasive

– No x-rays

– True 3D

– Oblique scanning plane

– Clinical scanners

– Image time: 12 - 15 minutes

~ 150 x 150 x 300 µm,

60 x 60 x 100 µm

Image courtesy of Dr. Felix Wehrli, UPenn

Image courtesy of Dr. Sharmila Majumdar, UCSF

45

                                     

Images from two women with similar BMD

www.micromri.com

MRI assessment of trabecular structure

46

Crawford et al, Bone 2003; 33: 744-750

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

Image courtesy of T. Keaveny

Faulkner et al, Radiology 1991; Keyak et al, J Biomechanics 1998; Pistoia, Bone 2002; van Rietbergen JBMR 2003; Crawford et al, Bone 2003

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