Beyond BMD: Bone Quality and Bone Strength 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 Disclosures Consultant / Advisory board: Agnovos Healthcare, Acceleron Pharma, Radius Health, Inc Research funding: Amgen Fractures = structural failure of the skeleton 1
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 Structural Properties (extrinsic) Material Properties (intrinsic) Stiffness (slope) Maximum Load Elastic modulus Ultimate Stress Force (N) Energy Stress Toughness Displacement (mm) Strain 2
Mechanical behavior of bone tissue and its constituents Mineral Force (Stress) Bone Collagen Deformation (Strain) Clinical assessment of bone (strength) today 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 BMD explains > 70% of whole bone strength in ex vivo human cadaver studies Bouxsein 1999 Femoral Strength (N) 10000 8000 6000 4000 2000 Proximal Femur (sideways fall) r 2 = 0.71 0 0 0.2 0.4 0.6 0.8 1 1.2 Femoral Neck BMD (g/cm 2 ) Vertebral Strength (lbs) Vertebral body (L2) (compression + forward flexion) 6000 r 2 = 0.79 5000 4000 3000 2000 1000 0 0. 2 0. 4 0. 6 0. 8 1 Spine BMD (g/cm 2 ) Johannesdottir et al (in review) Moro et al, CTI, 1995 3
Age-related changes in bone structure 27 yr old woman Changes from age 20 90 in women Trabecular density -27% 87 yr old woman Cortical density -22% Cortical thickness -52% Khosla et al JBMR 2006 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 Changes from age 20 90 Trabecular density -56% Cortical density -24% Khosla et al JBMR 2006 20 yr old 80 yr old Mayhew et al, 2005; Poole et al, JBMR 2010 4.0 3.0 2.0 1.0 0.0 Ct Th (Sup- Post) * 25 85 Age 4.0 3.0 2.0 1.0 0.0 Ct Th (Inf- Ant) * 25 85 Age 4
Effect of resorption cavities on trabecular bone strength 20% decrease in bone mass 1) trabecular thinning 30% decrease in strength 2) add resorption cavities 50% decrease in strength van der Linden, et al, JBMR 2001 Microarchitectural changes that influence bone strength Force required to cause a slender column to buckle: Force Directly proportional to Column material Cross-sectional geometry Inversely proportional to (Length of column) 2 Mosekilde, Bone, 1988 Effect of Resorption on Buckling Strength Mosekilde, Bone, 1988 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 L 5
Porosity is profound in the aging femoral neck 19 elderly female cadavers (87 ± 8 yrs) Intracortical porosity ranged from 5% to 39% Bousson et al, JBMR, 2004 Cortical porosity with increasing age 29 yr Bone loss (mg/ha) Cortical Trabecular 67 yr 90 yr 50-64 yrs 65-79 yrs > 80 yrs Perimeter available for remodeling Cortical Trabecular Zebaze et al, Lancet 2010 Whole bone strength declines dramatically with age Strength (Newtons) 10000 Femoral Neck (sideways fall) 8000 young 6000 4000 old 2000 10000 8000 6000 4000 2000 Lumbar Vertebrae (compression) 0 0 young old Courtney et al, J Bone Jt Surg 1995; Mosekilde L. Technology and Health Care. 1998. 6
Bone Strength Non-Invasive Imaging SIZE & SHAPE how much? how is it arranged?? MATRIX PROPERTIES mineralization collagen traits Bone Turnover Markers BONE REMODELING formation / resorption Osteoporosis Drugs, Diet, Exercise, Diseases,. Trabecular bone score (TBS) (FDA-approved in 2012) TbN TbSp Conn D Silva et al JBMR 2014 (accepted) 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 Incident fracture (per 1000 person-yr) Hans et al JBMR 2011 7
TBS enhances 10-yr prediction of fx risk (FRAX) Leslie et al Osteop Int 2014 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 (cm 2 ) 1.6 (1.3 2.1) Trab vbmd (g/cm 3 ) 1.6 (1.1 2.3) Black, Bouxsein et al, JBMR 2008 8
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 (cm 2 ) 1.6 (1.3 2.1) 1.5 (1.1 2.0) Trab vbmd (g/cm 3 ) 1.6 (1.1 2.3) 1.2 (0.8 1.9) Fem Neck abmd (g/cm 2 ) 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 HR-pQCT 82 µm voxel size Peripheral skeleton only < 3 µsv 9
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 30 25 20 15 10 5 0-5 -10-15 Spine -0.3 BMD 0.4 Femoral Neck Boutroy et al, JCEM (2005) 30 25 20 15 10 5 0-5 -10-15 HR-pQCT at the Radius 12.8 25.6 BV/TV TbN TbTh TbSp TbSpSD -5.6-8.5-12.4 * * * p < 0.05 vs fracture free controls * * Race-related differences in microarchitecture Putman, Yu et al, JBMR 2013 Pathophysiology of fragility in Type 2 Diabetes? Control Diabetes Diabetes + Frx T2DM have same or higher BMD, but markedly higher (+36 to 120%) cortical porosity vs non-diabetic controls Burghardt et al, J Clin Endo Metab (2010) 10
Finite element analysis in clinical practice Clinical Translation Fidler Radiology 2015 Experimentally measured femoral strength vs FEA-predicted strength (sideways fall, 73 human femora, aged 55 to 98 yrs) Bouxsein 1999 Femoral Failure Load (N) 10000 8000 6000 4000 2000 r 2 = 0.78 p < 0.001 SEE = 900 N Women Men 0 0 2000 4000 6000 8000 10000 FEA-Predicted Femoral Strength (N) QCT-based FEA vs femoral BMD for prediction of hip fracture Fem Neck BMD Hazard Ratio (95% CI)* 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) * Adjusted for age, race 1 Orwoll et al, JBMR 2009; 2 Kopperdahl et al, JBMR 2014 11
CT procedures amenable to bone strength evaluation - CT colonography, CT Enterography + Osteoporosis screening in IBD patients undergoing contrast-enhanced CT Enterography R 2 = 0.84! Women Y Men Weber et al, Am J Gastroenterology, 2014 Loading conditions Bone strength Fracture? 12
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 Greenspan et al, JAMA, 1994 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 Peak impact forces applied to greater trochanter: 270-730 kg (600-1600 lbs) (for 5th to 95th percentile woman) Robinovitch et al, 1991; 1997; van den Kroonenberg et al 1995, 1996 Trochanteric soft tissue thickness and hip fracture 644 women (129 hip fx); 1183 men (237 hip fx) 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 * p < 0.05; ** p < 0.001 1.8 (1.4, 2.4) ** 1.01 (0.8, 1.2) Framingham Osteoporosis Study, MrOS, and Rancho Bernardo Cohorts 13
Trochanteric soft tissue thickness: too little in men to make a difference? --- Male control --- Male hip fx --- Female control --- Female hip Fx Trochanteric sod Essue thickness (mm) Circumstances surrounding vertebral fracture are unclear Reported Activity % of fractures Falls 44.0 Other severe trauma 7.1 No or minimal trauma 11.3 "Spontaneous" or Unknown 37.5 ~50% occurred under unknown circumstances, or without specific trauma Cooper, et al., JBMR, 1992 Freitas, et al., OI, 2008 Spinal Curvature Muscle Morphology Activity Loads applied to the vertebra Vertebral strength Factor- of- risk = Applied Load / Strength 14
Predicted Loads on Lumbar Spine for Activities of Daily Living Activity Load (% BW) Standing 51 Rise from chair 173 Stand, hold 8 kg, 230 arms extended Stand, flex trunk 30 o, 146 arms extended Lift 15 kg from floor 319 for a 162 cm, 57 kg woman Load to strength ratio for L3 Lateral Spine BMD t-score -3.5-2.8-2.2-1.5-0.8 0 Get up from sitting 1.5 0.6 0.4 0.3 0.2 0.2 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 2.6 1.1 0.7 0.5 0.4 0.3 2.1 0.9 0.6 0.4 0.3 0.3 3.7 1.5 1.0 0.7 0.6 0.5 3.0 1.3 0.8 0.6 0.5 0.4 1.1 1.4 1.4 0.5 0.6 0.6 0.3 0.4 0.4 0.2 0.3 0.3 0.2 0.2 0.2 0.1 0.2 0.2 Adapted from Myers and Wilson, Spine, 1997 Factors Affecting Bone Strength and Fracture Risk Material Micro architecture Size & Shape Loading 15