Susan Broy MD FACP FACR CCDProfessor of Clinical MedicineRosalind Franklin School of Medicine, Chicago Medical School

No disclosures to report

Introduction – what is bone strength? Bone density Bone quality

Measuring bone “quality” Invasive Imaging

▪ CT and MRI, including finite element analysis (FEA)▪ DXA

▪ Hip structural analysis (HSA)▪ Trabecular bone score (TBS)

4

Healthy bone

“A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.”

“Bone strength is a composite of bone density and bone quality”

NIH Consensus Development Panel JAMA 2001;285:785

Bone “quality” Matrix properties

▪ Damage accumulation▪ Collagen quality▪ Mineralization (eg. crystal size)

Macroarchitecture ▪ Bone size ▪ Bone shape

Microarchitecture

Bone density Explains 60-80% of bone strength in

cadaveric studies1,2

1Cheng XG et al. J Bone Miner Res 1997;12:1721-82Bousson V et al. Osteoporos Int 2006;17:855-64

Invasive Mechanical studies of cadaveric bone =

direct measurement of bone strength Bone biopsy – tetracycline labeled

▪ Bone metabolism and structure

Important in research but not clinically useful

Invasive Imaging by CT/MRI

HR-pQCT, µMRI: microarchitecture QCT:

▪ 3-D geometry▪ Finite element analysis (FEA)

Imaging by DXA HSA – hip structural analysis

▪ Measures size and shape of femur i.e. macroarchitecture

TBS – trabecular bone score▪ Evaluates microarchitecture of vertebrae

Research

Dr Engelke

Cylinder B has less bone but the same strength as cylinder A

A larger bone (e.g. in a man) is a stronger bone than a smaller bone with the samevolumetric density1

1Bruno AG et al. J Bone Miner Res 2014;29(3):562-569

HSA Measurements Women

0.4

0.6

0.8

1

1.2

20 30 40 50 60 70 80 90

Age

N BMD

N CSA

N Width

Source: NHANES III courtesy Dr. Anne Looker, National Center for Health Statistics, CDCImages courtesy of Tom Beck

HSA Measurements Men

0.4

0.6

0.8

1

1.2

20 30 40 50 60 70 80 90

Age

N BMD

N CSA

N Width

CSA does not decrease as much as BMD because of an increase in femoral neck width

20 40 60 80 100Age

Density

Section modulusInner and Outer Bone Diameters expand with age

Slide courtesy of Dr Thomas Beck

BendingBending

Axial Axial CompressionCompression

Uniform across bone surface, proportional to cross-surface area (CSA)

Non-uniform across bone surface. Maximal at outer surfaces. Quantified by section modulus (SM)

Axial Compression

Bending

-40%

-30%

-20%

-10%

0%

10%

20%BMD

Section modulus

-40%

-30%

-20%

-10%

0%

10%

20%

BMD

Section Modulus

Males Females

Aging leads to decreased BMD but periosteal expansion helps preserve section modulus, especially in males

Beck TJ et al, J Bone Miner Res 2000;15:2297

CSA: cross-sectional areaCSMI: cross-sectional moment of inertiaSM: section modulusBR: buckling ratioOD: outer diameter

HAL: hip axis lengthNSA: neck-shaft angle

Software programs HSA™ (Hologic) AHA™ (GE)

Line of pixels defines a cut plane through the bone

Mass projected in cut plane describes bone cross-section

-20

0

20

40

60

80

100

120

Outer diameter

CSA

CSMI, Sm

BR = Sm/length

Profile and Cross-section have equal:

OD

• Mineral profiles are extracted from DXA images by software and used to estimate geometric properties.

• BMD, outer diameter, CSA and CSMI measured from profiles

• Sm and BR calculated

• Requires assumptions about bone shape and distribution of cortical and trabecular bone at each site.

Shaft

Intertrochanteric

Narrow Neck

Image courtesy of Thomas J. Beck, ScD..

OD: Subperiosteal width CSA: cross-sectional areaCSMI: cross-sectional moment of inertiaZ = section modulusCT: cortical thickness BR: buckling ratioHAL : Hip axis length greater trochanter to inner pelvic rimNSA: neck-shaft angle (NSA)

Neck-shaft angle

Outer diameter

d1, d2: measurements of femoral neck lengthd3 = outer diametery: measurement of radius at minimum CSMIalpha: angle femoral shaft to verticaltheta: neck-shaft angle

Yoshikawa T et al J Bone Miner Res 1994; 9:1053-64Faulkner KG et al Osteoporos Int 2006;17:593-9

Strength index (SI) =estimated strength/expected stress

Multiple studies have shown that hip geometry parameters are associated with risk of hip fracture Hip geometry parameters (especially Sm, BR, HAL and

NSA) are associated with hip fracture in postmenopausal women1,2

NSA is associated with hip fracture in men and women3

Measurements change with condition or treatment Aging4

Exercise5

Pharmacologic therapy: estrogen, raloxifene, alendronate, denosumab, teriparatide

1Kaptoge S et al. J Bone Miner Res 2008;23:1892 4Beck TJ et al J Bone Miner Res 2000;15;:297 2Leslie WD et al. Osteoporos Int 2009;20:1767 5Hind K et al. Bone 2007;40:14-27 3Faulkner KG et al. Osteoporos Int 2006;17:593

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-8

-6

-4

-2

0

2

4

6

8

10

Buckling Ratio

BMD CSA CorticalThickness

Section Modulus

Mea

n C

hang

e Fr

om B

asel

ine,

%

ALN RIS

ALN RIS

ALN RIS ALN RIS ALN RIS

* P<0.05.† P<0.005.

ALN = alendronate.RIS = risedronate.CSA = cross-sectional area.

†

*

†

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†

†

†

†

†

†

†

†

†

††

†

†

†

†

†

†

†

†

†

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Reproduced from Bonnick SI et al. Poster presented at the 28th Annual Meeting of the American Society for Bone and Mineral Research; September 16, 2006; Philadelphia, PA. Poster SA345.

Alendronate 70 mg once weekly for 2 years

Risedronate 35 mg once weekly for 2 years

–

–

–

–

Pros FDA-approved software

▪ HSA™ ▪ AHA ™

Can do at same time as DXA

Evidence correlates with fracture risk in women

Cons Variable precision –

depends on image quality, positioning

Except for HAL, not clear if fracture risk is independent of BMD

Need universally accepted standards for use▪ Need cut-off points▪ Can geometric

measurements be incorporated into FRAX calculations?ISCD Position Development Conference

addressing these issues

Bone “quality” Matrix properties

▪ Damage accumulation▪ Collagen quality▪ Mineralization (eg. crystal size)

Macroarchitecture ▪ Bone size ▪ Bone shape

Microarchitecture

Bone density Explains 60-80% of bone strength in

cadaveric studies*

*Cheng XG et al. J Bone Miner Res 1997;12:1721-8Bousson V et al. Osteoporos Int 2006;17:855-64

Normal Loss of Loss ofQuantity and Quantity Architecture Architecture

Loss BMD No change in BMD

Normal

Dempster 2000

Microarchitectural Changes in Osteoporosis

Osteoporotic

Horizontal Disconnections

Bone biopsyHR-pQCTMicro-MRI

TBS

Research

Textural index: DXA software that extracts bone texture information from a regular AP spine DXA scan image

Gray-level variations in the image provide an indirect assessment of microarchitecture

Has been shown to be related to bone microarchitecture and fracture risk

Provides information independent of BMD

Well-structured trabecular

bone

Degradedtrabecular bone

Pothuaud et al. Bone 2008;42:775-87 Hans et al. JCD 2011;14:302-12

Winzenrieth et al. JCD 2013; 16:287-96

Experimental variogram of

pixel gray-levelsDXA image

TBS = 1.459

TBS = 1.243

BMD=0.972

BMD=0.969

Silva BC at al. J Bone Miner Res 2014;29(3):518-30

Low variability, high amplitude

Large variability, small amplitude

Normative database for USA: Simonelli C et al. J Clin Densitom 2014

Many studies 61 entries for TBS in PubMed (November 2014) 1 ASBMR abstract in 2011, 19 in 2012, 33 in

2013, 22 in 2014 Correlates with mechanical behavior of

cadaveric vertebrae1

Correlates with microarchitectural parameters Cadaveric vertebrae 1,2

In vivo µCT3

Predicts fracture31Roux JP et al. Osteoporos Int 2013;24(9):2455-602 Hans D et al. J Clin Densitom 2011;14(3):302-12

3Silva BC at al. J Bone Miner Res 2014;29(3):518-30

Pothaud ‘09Winzenreith ‘10Rabier ‘10Krueger’13Lamy’12

Del Rio ‘13

Pothaud ‘09Krueger ‘13Lamy ‘12

Cross-sectional studies Prospective studies*

Manitoba ’11 JPOS ‘13OPUS ’13

Manitoba ‘11

Manitoba ‘11OFELY ’13OPUS

Silva BC at al. J Bone Miner Res 2014;29(3):518-30* F/U 4.7 – 8years

Hans D et al. J Bone Miner Res 2011;26:2762-9

•Manitoba, Canada•N=29,407 women >50•Mean F/U 4.7 years•1668 major osteoporotic fractures (MOF)*

*MOF = spine, hip, humerus or radius

Control Diabetic with fracture

Link TM Skeletal Radiol 2010;39:943-55

HR-pQCT Distal Tibia Postmenopausal Women

Leslie WD et al. J Clin Endocrinol Metab 2013;98:602-9

Odds ratios (95% CI bars) for BMD or TBS measurement in the lowest vs highest tertile according to presence of diabetes. TBS predicted fracture in those with diabetes as well as those without diabetes.

OR 0.66

OR 2.61

OR 0.68OR 0.80

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

L14 BMD Fem Neck BMD Total Hip BMD L14 TBS

Ad

jus

ted

OR

Pros FDA-approved in 2012 Can do at same time as DXA EvidenceTBS correlates with

▪ Mechanical strength▪ Microarchitectural parameters ▪ Fracture risk (cross-sectional

and prospective studies)

Provides information independent of BMD

Might be helpful in cases of secondary osteoporosis▪ Type 2 diabetes1

Cons No reimbursement Need universally accepted

standards for use▪ Need cut-off points▪ Can TBS be incorporated

into FRAX calculations?2

▪ German osteoplogy society (DVO) 2014 guidelines include a TBS offset for FRAX calculations

1Leslie WD et al. J Clin Endocrinol Metab 2013;98:602-92Johannson H et al. IOF meeting 2013 Hong Kong

ISCD PDC addressing these issues

Bone strength includes bone density and bone “quality”

Bone “quality” can be assessed by Invasive: mechanical studies of cadaveric bone, bone

biopsy Research: HR-pQCT, µMRI (microarchitecture), 3-D QCT

(macroarchitecture) Possible clinical use:

▪ FEA ▪ HSA (geometry i.e. macroarchitexture)▪ TBS (microarchitecture)

ISCD Position Development ConferenceWill review the evidence and develop official positions on the

clinical utility of non DXA BMD measures of fracture risk