Professor Department of Medicine & Therapeutics The Chinese University of Hong Kong

(1)

Understanding osteoporosis in Understanding osteoporosis in rheumatic diseases beyond bone rheumatic diseases beyond bone

density

density -- bone quality and bone quality and strength

strength

Lai-Shan Tam, MD Lai-Shan Tam, MD Professor

Department of Medicine & Therapeutics The Chinese University of Hong Kong

(2)

Objective

To introduce bone microarchitecture

assessment as a predictor of spinal fracture and its utility in monitoring treatment effect

(3)

Aims

Burden of osteoporosis in SLE and RA Bone microarchitecture assessment by

high-resolution peripheral quantitative high-resolution peripheral quantitative computed tomography (HR-pQCT)

Utility of bone mircoarchitecture

assessment in predicting fracture risk and monitoring of treatment effect for GIOP in SLE and RA

(4)

What is osteoporosis?

Low bone mass (BMD) Microarchitectural disruption disruption Skeletal fragility ↓bone strength ↑ risk of fracture

(5)

Bone mineral density definition

T-score — SD between a patient's BMD

and that of a young-adult reference population

Osteoporosis : T score ≤ -2.5 Osteoporosis : T score ≤ -2.5 Osteopenia: T score <-1 to -2.5

(6)

Risk Factors of Low BMD

female sex

Increased age

estrogen deficiency (early menopause or premature

ovarian failure)

low body weight (<127lbs) or body mass index

low body weight (<127lbs) or body mass index family history of osteoporosis

smoking

excessive alcohol consumption

poor dietary intake of Ca and vitamin D glucocorticoid

NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis and Therapy. JAMA 2001;285:785-95

(7)

GIO and Fractures

Fractures occur in up to 30% of patients

on chronic steroid therapy

Shaker J.L. et al. Endocrinol. Metab. Clin. North Am. 34,341–356

Incidence of fractures related to the dose

and duration of glucocorticoid exposure

Van Staa, T.P. et al. J. Bone Miner. Res. 15, 993–1000 Van Staa, T.P. et al. J. Bone Miner. Res. 15, 993–1000

Fragility fracture is common

(8)

Increased fracture risk in RA

Study Study cohort Follow-up duration

Relative risk (RR) Most marked increase Britain (GPRD)1 30,262 (male and female) Median 7.6 years All osteoporotic #: 1.5 (1.4-1.6) Men: 1.4 (1.2-1.7) Female: 1.5 (1.4-1.6)

Hip and spine

US (Mayo clinic)2

388 (female) 25 years Pelvic#: 2.56 (1.32-4.47)

Proximal femur #: 1.51 (1.01-2.17) Distal forearm #: 1.39 (0.88-2.09)

Pelvis and proximal femur Distal forearm #: 1.39 (0.88-2.09)

US (HIRD)3 47,034 (male and female)

1.63 years Hip #: 1.62 (1.43-1.84) Pelvis #: 2.02 (1.77-2.30) Wrist #: 1.15 (1.00-1.32) Humerus #: 1.51 (1.27-1.84)

Pelvis and hip

Finland4 517 (male and female)

- Hip #: 3.26 (2.26-4.70)

-1 van Staa TP et al Arthritis Rheum 2006, 54:3-104--12; 2 Hooyman JR et al Arthritis Rheum 1984, 27:1353-61; 3 Kim SY et al Arthritis Res Ther 2010, 12:R154; 4 Huusko TM Ann Rheum Dis 2001, 60:521-2

(9)

Systemic lupus erythematosus (SLE)

Increased prevalence of bone loss and

osteoporosis (4 – 23%)

Increased prevalence of fracture

(9-29%) 29%)

Li EK, Tam LS, et al. J Rheumatol 2009;36:1646-52. Mok CC et al. Lupus. 2005;14(2):106-12

Bultink IE, et al. Arthritis Rheum 2005;52:2044-50. Borba VZ, et al. Lupus 2005;14:529-33.

Naganathan V, et al. Arch Intern Med 2000;160:2917-22. Almed K, et al. Arthritis Res Ther. 2010;12(4):R153.

(10)

Assessment of fracture risk

Assessment of fracture risk-- DXA

DXA

A normal BMD T-score cannot exclude the

possibility of osteoporosis

- 56% and 79% of non-vertebral fractures occurred in - 56% and 79% of non-vertebral fractures occurred in women and men, respectively, with a DXA femoral neck T-score >-2.5 (Rotterdam study)1

- vertebral fracture2 in15% SLE with T-score >-2.5

1. Schuit SC. Bone 34:195-202; 2. 2. Li EK et al. J Rheum 36:1646-52;

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Assessment of fracture risk

Limitations of DXA:

- Does not measure true volumetric BMD

- Cannot distinguish between

cortical and trabecular bone

- Cannot distinguish between

cortical and trabecular bone compartments

- Does not have an adequate

resolution to measure cortical and trabecular architecture

(12)

Bone strength

Bone strength Bone density Material properties Mineralization Crystallinity strength properties

Organic phase of bone

Structural design

Cortical and trabecular microstructure

Microdamage

(13)

normal osteoporotic

Bone architecture

Dempster 2000

thinning of the horizontal trabeculae and some loss of continuity

Perfect continuous trabecular network

(14)

↑

Risk of fracture

(15)

Assessment of bone

microarchitecture

Histomorphometric assessment of bone

biopsies

High resolution micro-computed tomography

(μCT) MRI

MRI

High resolution peripheral quantitative

(16)

High

High--resolution peripheral quantitative resolution peripheral quantitative computed tomography (HR

computed tomography (HR--pQCT)pQCT)

Xtreme CT, Scanco Medical AG

(17)

High

High--resolution peripheral quantitative

resolution peripheral quantitative

computed tomography (HR

computed tomography (HR--pQCT)

pQCT)

Dedicated extremity imaging system designed

for trabecular-scale imaging

Significantly higher SNR and spatial resolution

compared with multi-detector CT and MRI (nominal isotropic voxel of 82μm)

(nominal isotropic voxel of 82μm)

Low radiation (3-4 μSv) and short scan time

(3 minutes)

(18)

Parameters measured by HR-pQCT and FEA Geometry •Total area •Cortical area •Trabecular area •Cross-sectional area (CSA) Microarchitecture •Cortical thickness (Ct.Th) •Trabecular bone volume fraction (BV/TV)

•Trabecular number (Tb.N) •Trabecular thickness (Tb.Th) •Trabecular separation (Tb.Sp) •Structure model index (SMI) area (CSA)

•Average density (D100) •Cortical density (Dcomp) •Trabecular density (Dtrab)

•Meta trabecular density (Dmeta) •Inner trabecular density (Dinn)

Volumetric BMD (vBMD) Biomechanical Properties •Stress •Stiffness •Failure load •Apparent modulus

(19)

Distal radius Distal tibia

Krug, R et al. Radio Clin N Am 48: 601-621.

(20)

Distal radius

High

High--resolution peripheral quantitative resolution peripheral quantitative computed tomography (HR

computed tomography (HR--pQCT)pQCT)

Distal tibia

Krug, R et al Radio Clin N Am 48: 601-621.

(21)

High

High--resolution peripheral quantitative resolution peripheral quantitative computed tomography (HR computed tomography (HR--pQCT)pQCT) Medullary/inner trabecular bone -marrow environment

Image courtesy of Qin L environment Peripheral/meta trabecular bone – endocortical resorptive activity Cortex

(22)

Alterations of bone architecture are associated Alterations of bone architecture are associated with fractures in postmenopausal women,

with fractures in postmenopausal women,

partially independent of decreased BMD by DXA partially independent of decreased BMD by DXA

Distal radius aBMD: Ultradistal radius: 0.309g/cm2 Total hip: aBMD: Ultradistal radius: 0.316g/cm2 Total hip:

Sornay-Rendu E, et al, Journal of Bone and Mineral Research 22: 425-433

Distal tibia Total hip: 0.782g/cm2 Total hip: 0.820g/cm2 Trabecular densities: radius: 139mg/cm3 tibia: 131mg/cm3 Trabecular densities: radius: 77mg/cm3 tibia: 81mg/cm3

(23)

To assess alterations of cortical and trabecular

microarchitecture in SLE patients with and without vertebral fractures on chronic

corticosteroid therapy using HR-pQCT

(24)

Fracture and bone microarchitecture in

SLE

(25)

(26)

Bone microarchitecture, bone strength in SLE on long-term GC compared with healthy controls

A B HR-pQCT

Cortical bone density and microarchitecture were dramatically deteriorated in SLE.

(27)

Bone microarchitecture, bone strength in SLE on long-term GC compared with healthy controls

SLE Control Proximal-most Distal-most 3D Cortex (pores)

(28)

Risk factor for deterioration in vBMD, bone microarchitecture in SLE on long-term GC

(29)

(30)

SLE disease per se contributes to deterioration in bone mineral density, microstructure and bone strength

(31)

Bone microarchitecture in SLE

HR-pQCT of the distal radius seems to

be better than DXA _{examination at}

discriminating SLE patients with or without vertebral fracture.

without vertebral fracture.

SLE disease per se contributes to the

deterioration in bone density, cortical microstructure and bone strength.

(32)

1.20 10.6 7.6 7.6 6.1 0 4.5 0 2 4 6 8 10 12

Femoral neck Total hip Lumbar spine

% o f su b je ct s w it h T s co re < 2 .5 RA Control * 0.00 0.20 0.40 0.60 0.80 1.00

Femoral neck Total hip Lumbar spine (L1-4) Distal radius

A re a l B M D , g /c m 2 RA Control

(33)

-6.2 -10.7 -6.0 -3.5 -12.0 -10.0 -8.0 -6.0 -4.0 -2.0 0.0 % d if fe r e n c e b e t w e e n R A a n d c o n t r o ls

Volumetric BMD

(% difference between RA and controls, * p-value <0.05 )

* * -10.7 -17.7 -20.0 -18.0 -16.0 -14.0 -12.0 Average vBMD Tb. vBMD pTb. vBMD mTb. vBMD Ct. vBMD % d if fe r e n c e b e t w e e n R A a n d c o n t r o ls * *

Trabecular volumetric BMD Cortical

(34)

Control subject

RA subject RA subject

(35)

slice no. 24

(36)

-5.7 -5.9 11.4 23.1 11.8 -10.0 -5.0 0.0 5.0 10.0 15.0 20.0 25.0 % d if fe r e n c e b e t w e e n R A a n d c o n t r o ls * * Trabecular (Tb) microstructure Trabecular (Tb) microstructure

(% difference between RA and controls, * p

(% difference between RA and controls, * p--value <0.05 )value <0.05 )

Loss of trabecular network (green)

-10.8 -15.0

-10.0

BV/TV Tb. number Tb. thickness Tb. separation

Inhomogeneity Structure model index % d if fe r e n c e b e t w e e n R A a n d c o n t r o ls Men Women Perforation Thinning Bone volume fraction *

(37)

Cortical (Ct) microstructure

(% difference between RA and controls, * p-value <0.05 )

-0.2 5.5 128.0 93.0 8.5 17.3 0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 % d if fe r e n c e b e t w e e n R A a n d c o n t r o ls * * * -20.0 0.0 Cortical area fraction

Ct. thickness Ct. PoV Ct. Po Ct. Po. Dm Ct. Po. Dm. SD % d if fe r e n c e b e t w e e n R A a n d c o n t r o ls

Control subject RA subject

Pore volume Porosity index (%) Pore diameter

(38)

Cortical porosity

• Osteon

• Haversian system

• Bone resorptive activity

• Cortical pore (cortical

porosity)

(39)

Bone microarchitecture in RA

• Substantially lower volumetric BMD,

inferior microstructure, despite minimal differences in areal BMD

• Inflammation-associated increased bone • Inflammation-associated increased bone

resorptive activity produces greater deficits in cortical than trabecular bone

(40)

To assess the effects of oral ibandronate on

(41)

Bone microarchitecture in the

monitoring therapy effect in SLE

(42)

P la c e b o T re a tm e n t P la c e b o T re a tm e n t

(43)

P la c e b o T re a tm e n t

Baseline 6 months 1 Year

P la c e b o T re a tm e n t

Baseline 6 months 1 Year

(44)

Oral ibandronate is effective in preserving

bone architecture using HR-pQCT

HR-pQCT appears to be a useful tool for

the assessment of therapeutic efficacy for

Bone microarchitecture in the

monitoring therapy effect in SLE

the assessment of therapeutic efficacy for treatment in GIOP in future prospective studies

(45)

Conclusions

High-resolution microCT can measure noninvasively

three-dimensional evaluation of bone microarchitecture.

Substantially lower volumetric BMD, inferior

microstructure, despite minimal differences in areal BMD

Inflammation-associated increased bone resorptive

activity produces greater deficits in cortical than activity produces greater deficits in cortical than trabecular bone

Preliminary studies suggest that alterations in

microarchitecture as detected by these techniques are associated with fracture.

HR-pQCT appears to be a useful tool for the

assessment of therapeutic efficacy for treatment in GIOP in future prospective studies

(46)

Imaging and Interventional Radiology

Prof. James Griffith

Orthopaedics and Traumatology

Prof. Ling Qin Ms. Vivian Hung Ms. Elaine Fong

The Jockey Club Centre for Osteoporosis Care and Control

Prof. Ping-Chung Leung Mr. Anthony Kwok

Ms. Betty Au Ms. Betty Au

Rheumatology, Medicine and Therapeutics

Prof. Edmund Li Dr Tracy Zhu Ms Xiaolin Tang Ms Lorraine Tseung Ms Tena Li

Dr. Arthur LS Lui, Providence Foundation Ltd Hong Kong Research Grant Council

(47)

Thank you

(48)

, 20th

(49)

Imaging techniques

Modality Skeletal sites Voxel size Effective radiation

Radiograph Lumbar spine (AP) - 700μSv

Chest - 20μSv

DXA Hip (Hologic) - 9μSv

Spine (Lunar) - 13μSv

QCT/MDCT/fp-vCT

Specimens (ex vivo) 156-300μm (in plane) 300-500μm (slice thickness)

5mSv-8mSv

Forearm (in vivo) 250-500μm (in plane)

Burghardt AJ et al P891- 925 In Vitamin D 3rd_{Edition, 2011, Elsevier Inc.}

Best Pract Res Clin Endocrinol Metab 2008

Forearm (in vivo) Spine femur (in vivo)

250-500μm (in plane) 300-700μm (slice thickness)

μCT Specimens biopsies (ex vivo) 0.3-100μm (isotropic) Beyond human tolerance μMRI Specimens biopsies (ex vivo) 137μm (in plane)

350μm (slice thickness)

0

HR-pQCT Specimens (ex vivo); distal radius, distal tibia (in vivo)

Nominal 82μm (isotropic) 3-4μSv Background radiation - - 7-10μSv/day 2400-3000μSv/year 8-10 hour airplane flight - - 60μSv

(50)

slice no. 15 _{slice no. 23} _{slice no. 45}

Palmar side

Dorsal side

slice no. 23 slice no. 45

(51)

Diagnosis- Dual energy x-ray

absorptiometry (DXA)

(52)

Relative Risk of Fracture in Steroid Users in General Practice Research Database and

other Fracture Studies

Van Staa TP et al. Osteoporos Int 2002; 13: 777

(53)

Study Study cohort Diagnosis of vertebral # Prevalence or incidence Odds ratio Norway (Oslo Register)1 229 (female) >2 mild or > 1 moderate/severe deformities (Genant method) 21% Norway (Oslo Register)2 249 (female) Morphometric McCloskey algorithm 22.10% 1.74 (1.02-3.04) Netherlands3 69 (male and female) Genant method 28.60%

4

Increased vertebral fracture risk in RA

Morocco4 172 (female) Genant method, VFA 36% OSTRA5 102

(postmenopausal female) 5-years follow-up

Genant method 3.7 per 100 patient-year

Norway (Oslo Register)6

255 (female) Loss of vertebral height >20% or 25%

>20%: 6.7 per 100 patient-years >25%: 2.9 per 100 patient-years

1 Orstavik RE et al Arthritis Rheum 2003, 49:355-60; 2. Orstavik RE et al Arch Intern Med 2004, 164:420-5; 3 Ursum J et al Ann Rheum Dis 2009, 68:1512-3; 4 Maghraoui AE et al Rheumatology 2010, 49:1303-10; 5 Vis M et al Osteoporos Int 2011, 22:2413-9

(54)

GC direct effect on bone

(55)

Chronic inflammation with excessive pro-inflammatory cytokine production

(56)

The structural design of bone

Burghardt AJ et al P891- 925 In Vitamin D 3rd_{Edition, 2011, Elsevier Inc.}

Dimension of trabeculae: 100-300μm Trabecular spaces: 200-2000μm