Disclosures Beyond BMD: Bone Quality & Bone Strength Mary L. Bouxsein, PhD Center for Advanced Orthopedic Studies, BIDMC Department of Orthopedic Surgery, HMS MIT-Harvard Health Sciences and Technology Program Advisory board: Merck, Eli Lilly, Radius Consultant: Agnovos, Acceleron Pharma Research funding: Merck, Amgen Fractures = structural failure of the skeleton Design of a Structure Consider what loads it must sustain Design options Overall geometry Building materials Architectural details 1
Determinants of whole bone strength Basic bone biomechanics Quantity size and mass (BMD) Distribution shape or geometry cortical : trabecular mass microstructure Properties of Bone Matrix mineralization collagen microdamage others Force (N) Stiffness (slope) Structural Properties (extrinsic) Energy Displacement (mm) Maximum Load Stress Elastic modulus Toughness Strain Material Properties (intrinsic) Ultimate Stress Mechanical behavior of bone tissue and its constituents It is not really practical to do three point bending on a patient. Mineral Force (Stress) Bone Collagen Deformation (Strain) Slide courtesy of Paul Hansma, PhD 2
Clinical assessment of bone (strength) today BMD explains > 7% of whole bone strength in ex vivo human cadaver studies Areal BMD by DXA Bone mass / area (g/cm 2 ) 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 Femoral Strength (N) 1 8 6 4 2 Proximal Femur (sideways fall) r 2 =.71.2.4.6.8 1 1.2 Femoral Neck BMD (g/cm 2 ) Roberts et al, 21 Vertebral Strength (lbs) Bouxsein 1999 Vertebral body (L2) (compression + forward flexion) 6 r 2 =.79 5 4 3 2 1.2..4..6...8 1 Spine BMD (g/cm 2 ) Moro et al, CTI, 1995 TBS associated with fractures, weakly with BMD TBS enhances 1-yr prediction of fx risk 29,47 postmenopausal women; 1668 (5.6%) had major OP frx Weak correlation to BMD: r =.26-.33 Incident fracture (per 1 person-yr) (FRAX) Hans et al JBMR 211 Leslie et al Osteop Int 214 3
Meta-analysis of TBS and Fracture >17, subjects in 14 studies (59% women) 298 hip fx and 119 major osteoporotic fx TBS changes following ALN or TPTD treatment in GIO TPTD abmd TBS associated with fracture independent of age, and FRAX (HR ~ 1.28 to 1.5) ALN abmd TPTD TBS ALN TBS McCloskey et al, JBMR 216 Saag et al, Arthritis and Rheum 216 DXA-based methods QCT HR-pQCT Finite Element Analysis Reference point indentation QCT ~3-5 µm voxel size Trabecular & cortical bone density, geometry Axial and appendicular skeleton Associated with fracture Less sensitive to soft tissue variability than DXA Novel applications Limited micro-structure Few prospective fx studies No standard analysis Lack of reference data Radiation exposure? Engelke et al, Curr OP Report 213 4
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-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 (cm 2 ) 1.6 (1.3 2.1) Trab vbmd (g/cm 3 ) 1.6 (1.1 2.3) 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 (cm 2 ) 1.6 (1.3 2.1) 1.5 (1.1 2.) Trab vbmd (g/cm 3 ) 1.6 (1.1 2.3) 1.2 (.8 1.9) Fem Neck abmd (g/cm 2 ) 2.1 (1.1-3.9) Black, Bouxsein et al, JBMR 28 Black, Bouxsein et al, JBMR 28 QCT for Monitoring Treatment Response: Changes in Spine Bone Density by DXA and QCT: the PaTH trial Cortical thickness mapping to identify local osteoporosis Mean Change (%) 4 3 2 1 abmd by DXA vbmd by QCT (Trabecular) PTH PTH/ALN ALN Black et al, NEJM, 23 Poole et al, PLoS ONE, 211 5
HR-pQCT DXA-based methods QCT, HR-QCT HR-pQCT Finite Element Analysis Reference point indentation 82 µm voxel size Peripheral skeleton only < 3 µsv Separation of cortical and trabecular compartments HR-pQCT discriminates osteopenic women with and without history of fragility fracture (age = 69 yrs, n=35 with prev frx, n=78 without fracture) Fracture vs No Fracture, % Difference 3 25 2 15 1 5-5 -1-15 BMD Spine.4 -.3 Femoral Neck Boutroy et al, JCEM (25) 3 25 2 15 1 5-5 -1-15 HR-pQCT at the Radius 12.8 25.6 BV/TV TbN TbTh TbSp TbSpSD -5.6-8.5-12.4 * * * p <.5 vs fracture free controls * * 6
Distal Tibia Osteopenic by DXA BMD (7 yr old woman) Worse bone architecture in premenopausal women with distal radius fracture (4 premenopausal wrist fx, 8 age-matched controls) * P <.5 * P <.5 UDR adj * Wrist Frx Distal Radius Fx - Cont (%) DXA HR-pQCT * Control * * Rozental, Bouxsein et al, JBJS (213) Race-related differences in microarchitecture Pathophysiology of fragility in Type 2 Diabetes? Control Diabetes Diabetes + Frx T2DM have same or higher BMD, but markedly higher (+36 to 12%) cortical porosity vs non-diabetic controls Putman, Yu et al, JBMR 213 Burghardt et al, J Clin Endo Metab (21) 7
DXA-based methods 3D geometry QCT HR-pQCT Finite Element Analysis Ultimate Strength material properties Reference point indentation QCT Density Crawford, et al, Bone 23 Hip and spine FEA (ON Diagnostics) Approved by FDA in 212 Diagnosis of fragile bone, BMD t-score, monitoring Image courtesy of T. Keaveny Finite element analysis in clinical practice Clinical Translation Experimentally measured femoral strength vs FEA-predicted strength (sideways fall, 73 human femora, aged 55 to 98 yrs) Femoral Failure Load (N) 1 8 6 4 2 r 2 =.78 p <.1 SEE = 9 N Women Men 2 4 6 8 1 FEA-Predicted Femoral Strength (N) Bouxsein 1999 Fidler Radiology 215 8
QCT-based FEA vs femoral BMD for prediction of hip fracture CT procedures amenable to bone strength evaluation - CT colonography, CT Enterography Fem Neck BMD Hazard Ratio (95% CI)* QCT-FEA strength Older men (Mr OS) 1 4 hip fx vs 21 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 * Adjusted for age, race 3.7 (2.5-5.6) 2.7 (1.9-3.9) 3.5 (2.3-5.3) 4.2 (2.6-6.9) 1 Orwoll et al, JBMR 29; 2 Kopperdahl et al, JBMR 214 + Osteoporosis screening in IBD patients undergoing contrast-enhanced CT Enterography DXA t-score vs FEA fragile bone strength Osteoporosis R 2 =.84 Women Y Men Fragile Bone Strength Weber et al, Am J Gastroenterology, 214 Weber et al, Am J Gastroenterology, 214 9
Bone Strength DXA-based methods QCT, HR-QCT HR-pQCT Finite Element Analysis Reference point indentation SIZE & SHAPE how much? how is it arranged? BONE REMODELING formation / resorption? MATRIX PROPERTIES mineralization collagen traits Osteoporosis Drugs, Diet, Exercise, Diseases,. How do we assess bone material and tissue level mechanical properties? Assessing bone tissue level biomechanical properties with reference probe indentation Estimated elastic modulus ult. strength toughness elastic modulus ult. strength toughness elastic modulus hardness 2.5 µm Hansma et al 28, Hansma et al 29, Diez-Perez et al JBMR 21 Total Indentation Distance ( m) Age (years) Hip Fracture Control 1
Impact microindentation (Osteoprobe) Hand-held, portable 2.5 µm at tip of test probe Single impact indentation, anterior midtibia Reproducibility = 1.65% (Farr et al, JBMR 214) In vivo reference point indentation Bone Material Strength Index (BMSi) Indentation distance into subject s bone normalized by indentation distance into reference material Bridges et al, Rev Sci Instr 212 Randall et al, J Med Devices 212 Bone material strength index (BMSi) in clinical studies Diabetes 1 ~ 1% lower BMSi in postmenopausal women with longstanding T2D Fracture prediction 2 ~ 5% lower BMSi in those with prior hx of fragility fracture, independent of BMD Glucocorticoid-induced osteoporosis 3 BMSi declines after initiation of glucocorticoids 1 Farr et al, 214; 2 Malgo et al, 215; 3 Mellibovsky et al 215 Neuromuscular function Medications Environmental hazards Time spent at risk Fall direction, height Protective responses Energy absorption Lifting activity Bone mass Bone geom + µ-arch Bone matrix prop s Peak bone mass Risk of fall Force applied to bone magnitude, direction Rate of bone loss Bone strength Fracture? 11
Independent risk factors for hip fracture in fallers Independent risk factors for hip fracture in elderly fallers 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 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 Greenspan et al, JAMA, 1994 Trochanteric soft tissue thickness and hip fracture 644 women (129 hip fx); 1183 men (237 hip fx) Trochanteric soft tissue thickness: too little in men to make a difference? Odds Ratio for Hip Fracture (per 1 SD increase or decrease) Women Men Fem Neck BMD 2.36 (1.77, 3.15) ** 3.34 (2.65, 4.21) ** Fall force 1.67 (1.25, 2.25) ** 1.23 (1., 1.51) * Trochanteric Soft Tissue Thickness 1.79 (1.35, 2.37) ** 1.1 (.84, 1.23) * p <.5; ** p <.1 Framingham Osteoporosis Study, MrOS, and Rancho Bernardo Cohorts Trochanteric soft tissue thickness (mm) 12
Biomechanics of vertebral fractures Occurrence of vertebral fractures varies along the spine Vertebral fx are 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 fx 14 12 1 8 6 4 2 T4 T6 T8 T1 T12 L2 L4 Relative fracture prevalence from 13562 European women and men over age 5 (Ismail et al, 1999) Estimating Loads on the Spine Muscle Strength & Quality Spinal Curvature Activity Loads applied to the vertebra Vertebral strength FRACTURE? Alex Bruno HST PhD candidate 13
Predicted Loads on Lumbar Spine for Activities of Daily Living Variation in vertebral loads and factor-of-risk peak 9 Compressive Load (N).18 Load: strength ratio Activity Load (% BW) Standing 51 Rise from chair 173 Stand, hold 8 kg, 23 arms extended Stand, flex trunk 3 o, 146 arms extended Lift 15 kg from floor 319 for a 162 cm, 57 kg woman Vertebral Compressive Loading (N) Vertebral Compressive Load (N) 8 7 6 5 4 3 2 1 T1 T3 T5 T7 T9 T11 L1 L3 L5 3 25 2 15 1 5 T1 T3 T5 T7 T9 T11 L1 L3 L5 Factor-of-Risk Factor-of-risk.16.14.12.1.8.6.4.2 T6 T8 T1 T12 L2 L4.7.6.5.4.3 TK =.2 TK = 26 TK = 5.1 TK = 74 T6 T8 T1 T12 L2 L4 Non-invasive assessment of bone strength: where are we today? A few techniques have recent FDA approval TBS may add to BMD predictions of fracture QCT-based FEA may expand number of individuals diagnosed Techniques are well suited for clinical research and clinical trials Pathophysiology & differentiate mechanism of action Our vision: a clinically relevant tool Bone strength estimates Improved fracture risk prediction? Patient specific loading estimates Not yet clear how to use in routine clinical practice QCT & FEA: No clear advantage over BMD for fx prediction Indentation -- early stage & many questions remain Examining non-bmd aspects of fracture risk (ie, loading) may provide important insights 14
NIH AR53986Funding Funding support: NIH R1 AR53986, R1 AR/AG41398, T32 AG2348, NHLBI Framingham Heart Study, and research grants from Amgen and Merck & Co. 15