1

Mary L. Bouxsein, PhD Center for Advanced Orthopedic Studies

Department of Orthopedic Surgery, Harvard Medical School MIT-Harvard Health Sciences and Technology Program

Boston, MA

Beyond BMD: Bone Quality and Bone Strength

Disclosures

Consultant / Advisory board: Agnovos Healthcare, Acceleron Pharma, Radius Health, Inc

Research funding: Amgen

Fractures = structural failure of the skeleton

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Engineering approach to design a structure

•  Consider what loads it must sustain

•  Design options –  Overall geometry –  Building materials –  Architectural details

Determinants of whole bone strength

Quantity size and mass (BMD)

Distribution shape or geometry cortical : trabecular mass microstructure

Properties of Bone Matrix mineralization proteins microdamage …others?

Basic bone biomechanics

Displacement (mm)

Forc

e (N

)

Maximum Load

Energy

Stiffness (slope)

Strain

Stre

ss

Ultimate Stress

Toughness

Elastic modulus

Structural Properties (extrinsic)

Material Properties (intrinsic)

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Mechanical behavior of bone tissue and its constituents

Bone

Collagen

Mineral

Deformation (Strain)

Force (Stress)

Clinical assessment of bone (strength) today

Areal BMD by DXA •  Bone mass / area (g/cm2) •  Reflects (indirectly)

–  Bone size –  Mineralization of matrix

•  Strong predictor of fracture risk in untreated women (Marshall et al, 1996)

•  Misses many who fracture

•  Neglects many structural aspects of bone strength

BMD explains > 70% of whole bone strength in ex vivo human cadaver studies

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0 0.2 0.4 0.6 0.8 1 1.2 Femoral Neck BMD (g/cm2)

Fem

oral

Str

engt

h (N

)

r2 = 0.71

Bouxsein © 1999

Moro et al, CTI, 1995

Vert

ebra

l Str

engt

h (lb

s)

0 . 2 0 . 4 0 . 6 . 8 1 0

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3000

4000

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6000

. . . 0 . Spine BMD (g/cm2)

Proximal Femur (sideways fall) Vertebral body (L2)

(compression + forward flexion)

r2 = 0.79

Johannesdottir et al (in review)

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Age-related changes in bone structure

27 yr old woman

87 yr old woman

Khosla et al JBMR 2006

Changes from age 20 – 90 in women

Trabecular density -27%

Cortical density -22%

Cortical thickness -52%

Simulated bone atrophy at distal radius: Bone strength more sensitive to cortical than

trabecular bone loss

Change in bone volume

Mechanism of bone loss

Decrease in strength

-20% ↓ Trab Number -11%

-20% ↓ Trab

Thickness -9%

-20% ↓ Cortical Thickness -39%

Pistoia et al, Bone 2003

Age-related changes in bone structure

Khosla et al JBMR 2006

Changes from age 20 – 90

Trabecular density -56%

Cortical density -24%

20 yr old 80 yr old Mayhew  et  al,  2005;  Poole  et  al,  JBMR  2010  

0.0

1.0

2.0

3.0

4.0

0.0

1.0

2.0

3.0

4.0

Age  25   85  

Age  25   85  

Ct  Th  (Sup-­‐Post)  

Ct  Th  (Inf-­‐Ant)  

*

*

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Effect of resorption cavities on trabecular bone strength

van der Linden, et al, JBMR 2001

20% decrease in bone mass

1) trabecular thinning ↓

30% decrease in strength

2) add resorption cavities ↓ 50% decrease in strength

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

Force

Mosekilde, Bone, 1988

L

Effect of Resorption on Buckling Strength

Buckling strength is Inversely proportional to (Length of column)2

# Horizontal Effective Buckling Trabeculae Length Strength

0 L S

1 1/2 L 4 x S

Mosekilde, Bone, 1988

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Porosity is profound in the aging femoral neck

Bousson et al, JBMR, 2004

19 elderly female cadavers (87 ± 8 yrs)

Intracortical porosity ranged from 5% to 39%

Cortical porosity with increasing age

Zebaze et al, Lancet 2010

29 yr

67 yr

90 yr

Bone loss (mg/HA)

Cortical Trabecular

Perimeter available for remodeling

Cortical Trabecular

50-64 yrs 65-79 yrs > 80 yrs

Whole bone strength declines dramatically with age

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10000 Femoral Neck (sideways fall)

young

old

Courtney et al, J Bone Jt Surg 1995; Mosekilde L. Technology and Health Care. 1998.

Lumbar Vertebrae (compression)

Str

engt

h (N

ewto

ns)

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young old

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Bone Strength

SIZE & SHAPE how much?

how is it arranged?

MATRIX PROPERTIES mineralization collagen traits

BONE REMODELING formation / resorption

Osteoporosis Drugs, Diet, Exercise, Diseases, ….

Non-Invasive Imaging

Bone Turnover Markers

?

Trabecular bone score (TBS) (FDA-approved in 2012)

Silva et al JBMR 2014 (accepted)

↑TbN ↓TbSp ↑Conn D

TBS associated with fractures, weakly with BMD •  29,407 postmenopausal women; 1668 (5.6%) had major OP frx •  Weak correlation to BMD: r = 0.26-0.33

Hans et al JBMR 2011

Incident fracture

(per 1000 person-yr)

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TBS enhances 10-yr prediction of fx risk

Leslie et al Osteop Int 2014

(FRAX)

Meta-analysis of TBS and Fracture

•  >17,000 subjects in 14 studies (59% women) •  298 hip fx and 1109 major osteoporotic fx

•  TBS associated with fracture independent of age, and FRAX (HR ~ 1.28 to 1.50)

McCloskey et al, JBMR 2016

QCT-based femoral neck measures and hip fracture risk Hazard ratios per SD reduction

All models adjusted for age, BMI, race, clinic site 3347 men > 65 yrs, 42 incident hip fx

QCT HR per SD

↓ % cortical volume 3.4 (2.3–4.9) ↓ Fem Neck area (cm2) 1.6 (1.3–2.1) ↓ Trab vBMD (g/cm3) 1.6 (1.1–2.3)

Black, Bouxsein et al, JBMR 2008

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QCT-based femoral neck measures and hip fracture risk Hazard ratios per SD reduction

All models adjusted for age, BMI, race, clinic site 3347 men > 65 yrs, 42 incident hip fx

QCT QCT + DXA HR per SD HR per SD

↓ % cortical volume 3.4 (2.3–4.9) 2.5 (1.6–3.9) ↓ Fem Neck area (cm2) 1.6 (1.3–2.1) 1.5 (1.1–2.0) ↓ Trab vBMD (g/cm3) 1.6 (1.1–2.3) 1.2 (0.8–1.9)

↓ Fem Neck aBMD (g/cm2) 2.1 (1.1-3.9)

Black, Bouxsein et al, JBMR 2008

QCT for Monitoring Treatment Response: Changes in Spine Bone Density by DXA and QCT: the PaTH trial

PTH PTH/ALN ALN

Black et al, NEJM, 2003

82 µm voxel size Peripheral skeleton only < 3 µSv

HR-pQCT

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HR-pQCT discriminates osteopenic women with and without history of fragility fracture

(age = 69 yrs, n=35 with prev frx, n=78 without fracture)

* p < 0.05 vs fracture free controls

Boutroy et al, JCEM (2005)

-12.4 -8.5

-5.6

12.8

25.6

-15 -10 -5 0 5

10 15 20 25 30

-0.3 0.4

-15 -10 -5 0 5

10 15 20 25 30

Frac

ture

vs

No

Frac

ture

, %

Diff

eren

ce

Femoral Neck

BV/TV TbN TbTh

TbSp TbSpSD

Spine

*

*

*

*

BMD HR-pQCT at the Radius

Race-related differences in microarchitecture

Putman,  Yu  et  al,  JBMR  2013  

Pathophysiology of fragility in Type 2 Diabetes ?

Control Diabetes Diabetes + Frx

Burghardt et al, J Clin Endo Metab (2010)

T2DM have same or higher BMD, but markedly higher (+36 to 120%) cortical porosity

vs non-diabetic controls

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Fidler  Radiology  2015  

Clinical Translation

Finite element analysis in clinical practice

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Fem

oral

Fai

lure

Loa

d (N

)

0 2000 4000 6000 8000 10000 FEA-Predicted Femoral Strength (N)

r2 = 0.78p < 0.001SEE = 900 N

Experimentally measured femoral strength vs FEA-predicted strength

(sideways fall, 73 human femora, aged 55 to 98 yrs) Bouxsein © 1999

Men Women

QCT-based FEA vs femoral BMD for prediction of hip fracture

Fem Neck BMD

QCT-FEA strength

Older men (Mr OS)1 40 hip fx vs 210 controls

4.4 (2.4-9.1) 6.5 (2.3-18.3)

Older men (AGES)2 Older women (AGES) 171 hip fx vs 877 control

3.7 (2.5-5.6) 2.7 (1.9-3.9)

3.5 (2.3-5.3) 4.2 (2.6-6.9)

1Orwoll et al, JBMR 2009; 2Kopperdahl et al, JBMR 2014

* Adjusted for age, race

Hazard Ratio (95% CI)*

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CT procedures amenable to bone strength evaluation - CT colonography, CT Enterography

+

Osteoporosis screening in IBD patients undergoing contrast-enhanced CT Enterography

R2 = 0.84! WomenY Men

Weber et al, Am J Gastroenterology, 2014

Loading conditions

Bone “strength”

Fracture?

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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

Independent risk factors for hip fracture in elderly fallers

Sideways Falls

●  In young volunteers, only 2/6 were able to break the fall

●  85% of impact force delivered directly to femur

●  Force ↑ by ↑ body wt ●  Force ↓ by ↑ thickness of

trochanteric soft tissue

Robinovitch et al, 1991; 1997; van den Kroonenberg et al 1995, 1996

Peak impact forces applied to greater trochanter: 270 - 730 kg (600 - 1600 lbs)

(for 5th to 95th percentile woman)

Trochanteric soft tissue thickness and hip fracture

Odds Ratio for Hip Fracture (per 1 SD increase or decrease)

Women Men

↓ Fem Neck BMD 2.4 (1.8, 3.2) ** 3.3 (2.7, 4.2) **

↑ Fall force 1.7 (1.3, 2.3) ** 1.2 (1.0, 1.5) *

↓ Trochanteric Soft Tissue Thickness

1.8 (1.4, 2.4) ** 1.01 (0.8, 1.2)

644 women (129 hip fx); 1183 men (237 hip fx)

* p < 0.05; ** p < 0.001 Framingham Osteoporosis Study,

MrOS, and Rancho Bernardo Cohorts

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Trochanteric soft tissue thickness: too little in men to make a difference?

Trochanteric  soD  Essue  thickness  (mm)  

--- Male control --- Male hip fx --- Female control --- Female hip Fx

Circumstances surrounding vertebral fracture are unclear

Cooper,  et  al.,  JBMR,  1992  

Freitas,  et  al.,  OI,  2008  

Reported Activity % of fractures

Falls 44.0Other severe trauma 7.1No or minimal trauma 11.3"Spontaneous" or Unknown 37.5

~50%  occurred  under  unknown  circumstances,  or  without  specific  trauma  

Vertebral strength Loads applied to the vertebra

Activity

Factor-­‐of-­‐risk  =  Applied  Load  /  Strength  

Muscle Morphology Spinal Curvature

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Standing 51

Rise from chair 173

Stand, hold 8 kg, 230 arms extended

Stand, flex trunk 30o, 146 arms extended

Lift 15 kg from floor 319 for a 162 cm, 57 kg woman

Activity Load (% BW)

Predicted Loads on Lumbar Spine for Activities of Daily Living

Load to strength ratio for L3

Adapted from Myers and Wilson, Spine, 1997

1.5

2.6 1.1 0.7

2.1 0.9

3.7 1.5 1.0 0.7

3.0 1.3 0.8

1.1

1.4

1.4

0.6 0.4 0.3 0.2 0.2

0.5 0.4 0.3

0.6 0.4 0.3 0.3

0.6 0.5

0.6 0.5 0.4

0.5 0.3 0.2 0.2 0.1

0.6 0.4 0.3 0.2 0.2

0.6 0.4 0.3 0.2 0.2

Get up from sitting

Lift 15 kg knees straight Lift 15 kg w/ deep knee bend Lift 30 kg knees straight Lift 30 kg w/ deep knee bend Open window w/ 6 kg of force Open window w/ 10 kg of force Tie shoes sitting down

-3.5 -2.8 -2.2 -1.5 -0.8 0

Lateral Spine BMD t-score

Factors Affecting Bone Strength and Fracture Risk

Micro architecture

Size & Shape Loading Material