Beyond BMD: Bone Quality and Bone Strength

Beyond BMD: Bone Quality and Bone Strength Consultant / advisor: Amgen, Eli Lilly, Merck Disclosures Mary L. Bouxsein, PhD Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA mbouxsei@bidmc.harvard.edu Research funding: Amgen, Merck UCSF Osteoporosis Course July 26-27, 212 1

Structural failure of the skeleton Outline Determinants of Bone Strength Limitations of BMD Beyond BMD Biomechanics of Fractures: Comparing applied loads to strength Design of a Structure Consider what loads it must sustain Design options Overall geometry Building materials Architectural details Evolving View of Osteoporosis Skeletal disorder characterized by decreased bone mass and architectural deterioration leading to an increased risk of fracture. NIH Consensus Conference, 1993 Skeletal disorder characterized by compromised bone strength leading to an increased risk of fracture. NIH Consensus Conference, 2 2

Determinants of Whole Bone Strength Morphology size (mass) shape (distribution of mass) porosity microarchitecture Cell Matrix Hierarchical Structure of Bone nanometer 1 s nanometer Bouxsein, Osteop Int, 23 Properties of Bone Matrix mineralization collagen microdamage others Lamellar Osteonal µ-architecture Whole Bone micron micron to 1 s micron millimeter and beyond Assessing Bone Biomechanical Properties Structural Properties Biomechanical Testing Key Properties Strength LOAD Material Properties LOAD Stiffness Energy absorbed (toughness) DISPLACEMENT DISPLACEMENT 3

Mechanical Behavior of Common Materials Mechanical Behavior of Bone and Its Constituents Load (Stress) Glass (brittle) Deformation (Strain) Plastic (ductile) Stress Mineral Strain Bone Collagen Outline Osteoporosis & Bone Strength Limitations of BMD Clinical Assessment of Bone Strength Areal BMD by DXA Bone mineral / projected area (g/cm 2 ) Reflects (indirectly) Bone size Mineralization Moderate to strong correlation with whole bone strength (r 2 = 5-9%) Strong predictor of fracture risk in untreated women (Marshall et al, 1996) Bouxsein et al, 1999 4

Age and BMD Are Independent Risk Factors for Hip Fracture History of Previous Fracture is a Risk Factor for Future Fracture, Independent of BMD 2 1 Kanis et al, 24 Age (yrs) 8 7 6 5 > 5-fold increase in fracture probability from age 5 to 8-3 -2-1 1 Hip BMD T-score (SD) Vert Frx No Vert Frx.2 Ross et al, Ann Int Med, 1991 1. 1.7 2.3 3.4 5.8 BMD Tertiles Low 1 2 3 4 5 6 Risk of Vertebral Fractures (% / yr) Middle High Fracture risk prediction: Less than half of patients who fracture have osteoporosis by BMD testing (ie t-scores > -2.5*) Only 34% of women and 21% of men suffering a nonvertebral frx had BMD in osteoporotic range (Schuit et al, 24; 26) Only half of elderly women with incident hip frx had BMD in osteoporotic range at baseline (Wainwright et al, JCEM 25) Treatment monitoring Changes in BMD underestimate reduction in fracture risk Changes in BMD explain a small proportion of reduction in fracture risk * Based on WHO guidelines for Osteoporosis Diagnosis More later. Dr. Bauer, Friday afternoon 5

Outline Bone Strength Osteoporosis & Bone Strength Limitations of BMD MORPHOLOGY size & shape microarchitecture MATRIX PROPERTIES mineralization collagen traits etc Beyond BMD BONE REMODELING formation / resorption OSTEOPOROSIS DRUGS Bouxsein, Best Practice in Clin Rheum, 25 Bone Strength Distribution of Mass Affects Mechanical Behavior MORPHLOGY size & shape microarchitecture MATRIX PROPERTIES tissue composition matrix properties BONE REMODELING formation / resorption d Moment of Inertia proportional to d 4 6

Effect of cross-sectional geometry on long bone strength Role of Geometry in the Prediction of Hip Fracture by QCT: MrOS abmd (by DXA) = = = Compressive Strength = Bending Strength = MrOS - a prospective, observational study 5995 men > 65 yrs from six US sites QCT subset, n=3358 Used QCT to measure femoral neck vbmd & geometry Followed prospectively for fracture, mean 5 ± 1 yrs 4 hip fractures in QCT cohort Analyses adjusted for age, BMI, race, and clinic Black et al, JBMR 28 Femoral neck measures and hip fracture risk: Multivariate analyses Hazard ratios per SD reduction All models adjusted for age, BMI, race, clinic site Femoral neck measures and hip fracture risk: Multivariate analyses Hazard ratios per SD reduction All models adjusted for age, BMI, race, clinic site QCT HR per SD % cortical volume 3.4 (2.3 4.9) Min FNeck 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) Min Fem Neck area 1.6 (1.3 2.1) 1.5 (1.1 2.) Trab vbmd 1.6 (1.1 2.3) 1.2 (.8 1.9) Fem Neck abmd (g/cm 2 ) 2.1 (1.1-3.9) Black et al, JBMR 28 Black et al, JBMR 28 7

Bone Strength Age-Related Changes in Trabecular Microarchitecture SIZNE & SHAPE macroarchitecture microarchitecture MATRIX PROPERITES tissue composition matrix properties Decline in bone mass and deterioration of trabecular bone structure both contribute to decreased bone strength. BONE REMODELING formation / resorption Excessive Bone Resorption Weakens Trabecular Architecture Excessive Bone Resorption Weakens Trabecular Architecture Stress concentration (focal weakness) L. Mosekilde, 1998 Stress concentration (focal weakness) Perforation Perforation 8

Effect of Increased Bone Resorption on Trabecular Architecture Effect of Resorption Cavities on Trabecular Bone Strength Perforation of Trabecular Strut Trabecular Microfracture 2% decrease in bone mass 1) trabecular thinning 3% decrease in strength 2) add resorption cavities 5% decrease in strength L. Mosekilde, Tech and Health Care, 1998 van der Linden, et al, JBMR 21 Effect of Density Reduction on Strength: Change in Trabecular Thickness vs. Number 1 Trabecular Thickness Importance of Cross-struts Residual Strength (%) 75 5 25 Trabecular Number 2% reduction in strength 65% reduction in strength Silva and Gibson, Bone, 1997 5 1 15 Density Reduction (%) 9

Microarchitectural changes that influence bone strength Theoretical effect of cross-struts on buckling strength Buckling Strength proportional to (Strut Length) 2 Force required to cause a slender column to buckle: Directly proportional to Column material Cross-sectional geometry Inversely proportional to (Length of column) 2 Force # Horizontal Effective Buckling Trabeculae Length Strength L S 1 1/2 L 4 x S L Mosekilde, Bone, 1988 High Resolution pqct (X-treme CT, Scanco Medical AG) ~ 82 µm 3 voxel size ~ 3 min scan time, < 4 µsv Distal Radius Distal Tibia Reproducibility: density:.7 to 1.5% * structure: 1.5-4.4 * Peripheral skeleton only Specialized equipment * Boutroy, et al, JCEM 25 1

Fracture vs No Fracture, % Difference HR-pQCT discriminates osteopenic women with and without history of fragility fracture (age = 69 yrs, n=35 with prev frx, n=78 without fracture) 3 25 2 15 1 5-5 -1-15 Spine -.3 BMD.4 Femoral Neck Boutroy et al, JCEM (25) 3 25 2 15 1 5-5 -1-15 BV/TV TbN TbTh -12.4 * HR-pQCT at the Radius -8.5 * -5.6 * 12.8 TbSp 25.6 TbSpSD * p <.5 vs fracture free controls * Distal Tibia Distal Radius Osteopenic by DXA BMD (7 yr old woman) Images courtesy of S. Boutroy & P. Delmas, Inserm U831, Lyon Dramatic Changes in Trabecular Architecture in Early Postmenopausal Women Anti-Resorptive Tx Preserves Trabecular Architecture in Early Postmenopausal Women (Placebo vs Risedronate, 5 mg/d, 1 yr) Baseline (52 yr old woman, 3 yrs post-menopause) 1 yr % change from baseline 15 1 5 5 1 15 3.3 * 2. * 15.2 13.5 * 6.4 13.1 * 7.2 PBO (n=12) RIS (n=14) *P<.5 vs baseline. P<.5 vs PBO. 2 Spine BMD 2.3* Trabecular bone volume Trabecular number Trabecular separation Dufresne TE et al. Calcif Tissue Int. 23;73:423-432. Dufresne TE et al. Calcif Tissue Int. 23; 73:423-432. 11

Monitoring of Teriparatide Treatment with HRCT EUROFORS study, Forsteo 2 µg/d, n=62 4 3 2 % Change from Baseline (1 year) Age-related changes in femoral neck cortex and association with hip fracture 1 abmd L1-4 vbmd T12 App. BV/TV T12 Mayhew et al, Lancet 25 2 yr old 8 yr old Those with hip fractures have: Preferential thinning of the inferior anterior cortex Increased cortical porosity Graeff et al, JBMR 27 months 6 months 12 months Bell et al. Osteop Int, 1999; Jordan et al. Bone, 2 Porosity is profound in the aging femoral neck Cortical porosity and trabecularization of the endocortical surface with age Bone loss (mg/ha) 29 yr Cortical Trabecular 19 elderly female cadavers (87 ± 8 yrs) Intracortical porosity ranged from 5% to 39% Bousson et al, JBMR, 24 67 yr 9 yr Zebaze et al, Lancet 21 5-64 65-79 > 8 yrs Cortical bone loss increases with age. Prior studies have likely underestimated cortical bone loss 12

Bone Strength Mechanisms that may lead to increased BMD GEOMETRY macroarchitecture microarchitecture MATERIAL tissue composition matrix properties Increase Trabecular Thickness Increase Trabecular Number Bone Mass Bone Mass BONE REMODELING formation / resorption Increase Mineralization How is mineralization density influenced by rate of bone turnover? Increased bone turnover with estrogen deficiency decreases mineralization density Slow process of 2 o mineralization Degree of Mineralization (%) 1- Decreased bone turnover allows mineralization to proceed 5 - - Primary mineralization (3 months) Secondary mineralization (years) Time Meunier and Boivin, Bone, 1997 13

Relationship between mineralization and biomechanical properties What do these changes in mineralization mean in terms of the bone strength? Load High (osteopetrosis) Displacement Normal Low (osteomalacia) Mineralization Stiffness Strength Toughness -Independent of the quantity of bone - Strength of bone material is related to mineralization in a non-linear fashion Anti-resorptive therapies mineralization by 3-11% (Roschger et al, 21; Boivin et al 23, Borah et al 26) strength of trabecular bone by 13-2% Bone remodeling & microdamage What is damage? Repetitive loading No repair process Mechanical properties Microdamage in Bone Associated with decreased mechanical properties in vitro Observed in human cortical and trabecular bone, increases with age Signal for remodeling & repair No direct relationship to fracture risk Human femoral neck Fazzalari et al, Bone, 1998 Schaffler, 1995; Wenzel et al, 1996; Mashiba et al, 21; Burr et al 1997, 22 Crack Density (#/mm 2 ) 6 5 4 3 2 1 Women Men 1 2 3 4 5 6 7 8 Age (yrs) 14

Microdamage in Bone Associated with decreased cortical bone strength Microcracks seen in human femur & vertebra, increase with age Age-related changes in bone properties that lead to decreased bone strength Decreased bone mass and BMD Altered geometry Signal for remodeling & repair in animals, microdamage increases when remodeling is suppressed No demonstrated relationship with fracture risk Human femoral neck Altered architecture Cortical thinning Cortical porosity Trabecular deterioration young Fazzalari et al, Bone, 1998 Altered matrix properties elderly Images from L. Mosekilde, Technology and Health Care. 1998 Schaffler, 1995; Wenzel et al, 1996; Mashiba et al, 21; Burr et al 1997, 22; Arlot et al 28 Whole bone strength declines dramatically with age Outline Whole Bone Strength (Newtons) 1 Femoral Neck (sideways fall) 8 young 6 4 old 2 1 8 6 4 2 Lumbar Vertebrae (compression) Determinants of Bone Strength Limitations of BMD Beyond BMD Biomechanics of Fractures: Comparing applied loads to strength young old Courtney et al, J Bone Jt Surg 1995; Mosekilde L. Technology and Health Care. 1998. 15

Fracture Etiology Bending, lifting activity Loads applied to the bone FRACTURE? Propensity to fall Fall traits Protective responses Soft-tissue padding Impact surface Spine curvature Muscle strength Disc degeneration Loads applied to the bone direction & magnitude FRACTURE? Bone Strength Φ = Applied Load Failure Load Geometry Microstructure Material Properties Bone strength Biomechanics of Hip Fracture Independent Risk Factors for Hip Fx Over 9% of hip fx s associated with a fall Less than 2% of falls result in hip fracture Fall is necessary but not sufficient 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)* What is a high risk fall? * calculated for a decrease of 1 SD ** calculated for an increase of 1 SD Greenspan et al, JAMA, 1994 16

l l Estimating Loads Applied to the Hip 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 Very high forces applied to the hip during a sideways fall Human cadavers Human volunteers Crash dummy Mathematical models and simulations Peak impact forces applied to greater trochanter: 27-73 kg (6-16 lbs) (for 5th to 95th percentile woman) Robinovitch et al, 1991; 1997; van den Kroonenberg et al 1995, 1996 Peak impact forces applied to greater trochanter: 27-73 kg (6-16 lbs) (for 5th to 95th percentile woman) Robinovitch et al, 1991; 1997; van den Kroonenberg et al 1995, 1996 Femoral strength depends on loading direction Femur is weak in atypical loading conditions Failure Load (kn) 9 8 7 6 5 4 3 2 1 7978 ± 7 N Stance 3.4-fold lower P <.1 2318 ± 3 N Sideways Fall Keyak et al, J Biomechanics, 1998 Stance Sideways Fall 17

Femur Strength (Newtons) Femoral strength in sideways fall declines markedly with age 1 8 6 4 2 Young (age = 33) Courtney et al, J Bone Jt Surg 1995 Old (age = 74) Older femurs are half as strong and absorb 1/3 as much energy as young femurs Load during } sideways fall Femur Strength (Newtons) Effect of Aging on the Load / Strength Ratio Sideways Fall Configuration 1 8 6 4 2 Young (age = 33) Courtney et al, J Bone Jt Surg 1995 Old (age = 74) Φ = Applied Load Failure Load Thus, Φ is often > 1 for sideways fall in elderly persons Range of Loads } during sideways fall Biomechanics of Vertebral Fractures Estimating Loads on the Spine Φ = Applied Load Failure Load Difficult to study 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 fragility Biomechanical model Simulate bending and lifting activities Height, weight, body position Determine compressive forces on vertebra for different activities 18

Predicted Loads on Lumbar Spine for Activities of Daily Living 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 Ratio of load to strength for L3 during activities of daily living Get up from sitting Lift 15 kg knees straight Lift 15 kg w/ deep knee bend Lift 3 kg knees straight Lift 3 kg w/ deep knee bend Open window w/ 6 kg of force Open window w/ 1 kg of force Tie shoes sitting down Adapted from Myers and Wilson, Spine, 1997-3.5-2.8-2.2-1.5 -.8 1.5 2.6 1.1.7 2.1.9 3.7 1.5 1..7 3. 1.3.8 1.1 1.4 1.4 Lateral Spine BMD t-score.6.4.3.2.2.5.4.3.6.4.3.3.6.5.6.5.4.5.3.2.2.1.6.4.3.2.2.6.4.3.2.2 1.8 1.6 1.4 Men Factor of Risk for Vertebral Fracture (L2) Bending forwards 9 o with 1 kg weight in hands 1.2 1.2 1. 1..8.8.6.6.4.4.2 +28% over life**.2 +92% over life**.. 1 2 3 4 5 6 7 8 9 1 1 2 3 4 5 6 7 8 9 1 Age Age ** P<.5 for age-regressions; p<.1 for comparison of age-related change in M and W Bouxsein et al, JBMR 26 1.8 1.6 1.4 Women 11.9% 3.1% Proportion of individuals with Φ > 1, per decade (Bending forwards 9 o lifting 1 kg weight) % 6 5 4 3 2 1 4% 11% 27% 42% 53% 4% 11% 12% 21% 2-29 3-39 4-49 5-59 6-69 7-79 8+ Age 14 12 1 Incidence / 1, person-yrs 8 6 4 2 3 4 5 6 7 8 9 Bouxsein et al, JBMR 26 19

Fracture Prevention Strategies Reduce the Loads Applied to Bone Decrease fall frequency / severity Safe-landing strategies Trochanteric padding Avoid high risk lifting / bending activities Applied Load Bone Strength Summary: Factors Affecting Bone Strength and Fracture Risk Material Micro architecture Size & Shape Loading Maintain or Increase Bone Strength Exercise, diet (Ca, Vit D), pharmacologic treatment 2