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

Transcription

1 Understanding osteoporosis in rheumatic diseases beyond bone density - bone quality and strength 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 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 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 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 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, Incidence of fractures related to the dose and duration of glucocorticoid exposure Van Staa, T.P. et al. J. Bone Miner. Res. 15, Fragility fracture is common occurs as a result of a fall from standing height or less.

8 Increased fracture risk in RA Study Study cohort Follow-up duration Britain (GPRD) 1 30,262 (male and female) Median 7.6 years Relative risk (RR) All osteoporotic #: 1.5 ( ) Men: 1.4 ( ) Female: 1.5 ( ) US (Mayo 388 (female) 25 years Pelvic#: 2.56 ( ) clinic) 2 Proximal femur #: 1.51 ( ) Distal forearm #: 1.39 ( ) Most marked increase Hip and spine Pelvis and proximal femur US (HIRD) 3 Finland 4 47,034 (male and female) 517 (male and female) 1.63 years Hip #: 1.62 ( ) Pelvis #: 2.02 ( ) Wrist #: 1.15 ( ) Humerus #: 1.51 ( ) - Hip #: 3.26 ( ) - Pelvis and hip 1 van Staa TP et al Arthritis Rheum 2006, 54: ; 2 Hooyman JR et al Arthritis Rheum 1984, 27: ; 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%) Li EK, Tam LS, et al. J Rheumatol 2009;36: Mok CC et al. Lupus. 2005;14(2): Bultink IE, et al. Arthritis Rheum 2005;52: Borba VZ, et al. Lupus 2005;14: Naganathan V, et al. Arch Intern Med 2000;160: Almed K, et al. Arthritis Res Ther. 2010;12(4):R153. Li EK, Tam LS et al. Br J Rheumatol Apr;37(4):405-10

10 Assessment of fracture risk- DXA A normal BMD T-score cannot exclude the possibility of osteoporosis - 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 fracture 2 in15% SLE with T-score > Schuit SC. Bone 34: ; Li EK et al. J Rheum 36: ;

11 Assessment of fracture risk Limitations of DXA: - Does not measure true volumetric BMD - Cannot distinguish between cortical and trabecular bone compartments - Does not have an adequate resolution to measure cortical and trabecular architecture Sornay-Rendu E et al Journal of bone and mineral research 22:

12 Bone strength Bone density Mineralization Bone strength Material properties Crystallinity Organic phase of bone Remodeling Structural design Cortical and trabecular microstructure Microdamage

13 Bone architecture normal Perfect continuous trabecular network osteoporotic thinning of the horizontal trabeculae and some loss of continuity Dempster 2000

14 Risk of fracture normal Osteoporotic

15 Assessment of bone microarchitecture Histomorphometric assessment of bone biopsies High resolution micro-computed tomography (μct) MRI High resolution peripheral quantitative computed tomography (HR-pQCT)

16 High-resolution peripheral quantitative computed tomography (HR-pQCT) Xtreme CT, Scanco Medical AG Images courtesy of Qin L

17 High-resolution peripheral quantitative computed tomography (HR-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) Low radiation (3-4 μsv) and short scan time (3 minutes) 1.Burghardt AJ et al Clin Orthop Relat Res Epub 23 Feb 2011; 2.Rubin CD. Current medical Research and Opinion 21:

18 Parameters measured by HR-pQCT and FEA Geometry Total area Cortical area Trabecular area Cross-sectional area (CSA) Volumetric BMD (vbmd) Average density (D100) Cortical density (Dcomp) Trabecular density (Dtrab) Meta trabecular density (Dmeta) Inner trabecular density (Dinn) 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) Stress Biomechanical Properties Stiffness Failure load Apparent modulus

19 Distal radius Distal tibia 9.02mm, 110 slices Krug, R et al. Radio Clin N Am 48:

20 High-resolution peripheral quantitative computed tomography (HR-pQCT) Distal radius Distal tibia Distal-most Proximal-most 3D reconstruction Krug, R et al Radio Clin N Am 48:

21 High-resolution peripheral quantitative computed tomography (HR-pQCT) Medullary/inner trabecular bone - marrow environment Cortex Peripheral/meta trabecular bone endocortical resorptive activity Image courtesy of Qin L

22 Alterations of bone architecture are associated with fractures in postmenopausal women, partially independent of decreased BMD by DXA Distal radius abmd: Ultradistal radius: 0.309g/cm 2 Total hip: 0.782g/cm 2 Distal tibia abmd: Ultradistal radius: 0.316g/cm 2 Total hip: 0.820g/cm 2 Trabecular densities: radius: 77mg/cm 3 tibia: 81mg/cm 3 Trabecular densities: radius: 139mg/cm 3 tibia: 131mg/cm 3 Sornay-Rendu E, et al, Journal of Bone and Mineral Research 22:

23 To assess alterations of cortical and trabecular microarchitecture in SLE patients with and without vertebral fractures on chronic corticosteroid therapy using HR-pQCT Li EK et al. J Rheum :

24 Fracture and bone microarchitecture in SLE

25 Non-Fracture case Fracture case

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. Tang XL, et al. Osteoporos Int 2013;24(6):

27 Bone microarchitecture, bone strength in SLE on long-term GC compared with healthy controls SLE Control Proximalmost Distal-most 3D Cortex (pores) Tang XL, et al. Osteoporos Int 2013;24(6):

28 Risk factor for deterioration in vbmd, bone microarchitecture in SLE on long-term GC J Rheumatol 2012;39;

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30 SLE disease per se contributes to deterioration in bone mineral density, microstructure and bone strength Tang XL et al. Lupus 2013 July 24

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. SLE disease per se contributes to the deterioration in bone density, cortical microstructure and bone strength.

32 1.20 % of subjects with T score <2.5 Areal BMD, g/cm * 0 Femoral neck Total hip Lumbar spine (L1-4) Distal radius Femoral neck Total hip Lumbar spine RA Control Zhu TY, et al. J Bon Miner Res 2013; 28; RA Control

33 Volumetric BMD (% difference between RA and controls, * p-value <0.05 ) % difference between RA and controls * -6.0 * Average vbmd Tb. vbmd ptb. vbmd mtb. vbmd Ct. vbmd * -3.5 * Trabecular volumetric BMD Cortical volumetric BMD

34 Control subject RA subject Distal-most Proximal-most 3D view 3D view cortex

35 slice no. 24 slice no. 59

36 Trabecular (Tb) microstructure (% difference between RA and controls, * p-value <0.05 ) % difference between RA and controls * 11.4 * 23.1 Bone volume BV/TV Tb. number Tb. thickness Tb. separation fraction Inhomogeneity * Postmenopausal osteoporosis (PMO) Loss of trabecular network (green) 11.8 Structure model index Women Men Perforation Thinning

37 Cortical (Ct) microstructure (% difference between RA and controls, * p-value <0.05 ) % difference between RA and controls Cortical area fraction 5.5 * * * Ct. thickness Ct. Pore PoV Porosity Ct. Ct. Pore Po. Dm Ct. Po. Dm. volume index (%) diameter SD Control subject RA subject

38 Cortical porosity Osteon Haversian system Bone resorptive activity Cortical pore (cortical porosity) J Clin Endocrinol Metab 2005

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 bone microarchitecture by using HR-pQCT

41 Bone microarchitecture in the monitoring therapy effect in SLE

42 Placebo Treatment Baseline 6 months 1 Year

43 Treatment 6 months 1 Year Placebo Baseline Baseline 6 months 1 Year

44 Bone microarchitecture in the monitoring therapy effect in SLE 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 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 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 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 Roche HK Limited

47 Thank you

48 , 20 th - 22 nd

49 Imaging techniques Modality Skeletal sites Voxel size Effective radiation Radiograph Lumbar spine (AP) - 700μSv Chest - 20μSv DXA Hip (Hologic) - 9μSv QCT/MDCT/fpvCT Spine (Lunar) - 13μSv Specimens (ex vivo) Forearm (in vivo) Spine femur (in vivo) μm (in plane) μm (slice thickness) μm (in plane) μm (slice thickness) 5mSv-8mSv μct Specimens biopsies (ex vivo) μm (isotropic) Beyond human tolerance μmri Specimens biopsies (ex vivo) 137μm (in plane) 350μm (slice thickness) HR-pQCT Background radiation 8-10 hour airplane flight Specimens (ex vivo); distal radius, distal tibia (in vivo) Nominal 82μm (isotropic) Burghardt AJ et al P In Vitamin D 3 rd Edition, 2011, Elsevier Inc. Best Pract Res Clin Endocrinol Metab μSv μSv/day μSv/year μSv

50 Palmar side Dorsal side slice no. 15 slice no. 23 slice no. 45 slice no. 55 slice no. 65 slice no. 100

51 Diagnosis- Dual energy x-ray absorptiometry (DXA) Bouxsein et al. 1999

52 Relative Risk of Fracture in Steroid Users in General Practice Research Database and other Fracture Studies 2002; 13: 777 Van Staa TP et al. Osteoporos Int

53 Increased vertebral fracture risk in RA Study Study cohort Diagnosis of vertebral # Prevalence or incidence Odds ratio Norway (Oslo Register) (female) >2 mild or > 1 moderate/severe deformities (Genant method) Norway 249 (female) Morphometric (Oslo Register) 2 McCloskey algorithm 21% Netherlands 3 69 (male and female) Genant method 28.60% 4 Morocco (female) Genant method, VFA 36% OSTRA (postmenopausal female) 5-years follow-up Genant method Norway 255 (female) Loss of vertebral height (Oslo Register) 6 >20% or 25% 22.10% 1.74 ( ) 3.7 per 100 patient-year >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: ; 5 Vis M et al Osteoporos Int 2011, 22:2413-9

54 GC direct effect on bone Weinstein RS et al NEJM 365:62-70

55 Chronic inflammation with excessive pro-inflammatory cytokine production Choi et al, Nat. Rev. Rheumatol. 2009,5:543-8

56 The structural design of bone Dimension of trabeculae: μm Trabecular spaces: μm Burghardt AJ et al P In Vitamin D 3 rd Edition, 2011, Elsevier Inc.