Beyond BMD: Disclosures Bone Quality and Consultant / advisor: Bone Strength Amgen, Eli Lilly, Merck Mary L. Bouxsein, PhD Research funding: Amgen, Merck Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA mbouxsei@bidmc.harvard.edu UCSF Osteoporosis Course June 2013 Outline Structural failure of the skeleton • Determinants of Bone Strength • Limitations of BMD • Beyond BMD • Biomechanics of Fractures: Comparing applied loads to strength 1
Design of a Structure Determinants of Whole Bone Strength Morphology size ( mass ) shape ( distribution of mass ) porosity microarchitecture • Consider what loads it must sustain Properties of Bone Matrix • Design options mineralization collagen – Overall geometry microdamage – Building materials …others… – Architectural details Bouxsein, Osteop Int, 2003 Hierarchical Structure of Bone Assessing Bone Structural Cell nanometer Biomechanical Properties Properties 100’s nanometer Matrix micron Lamellar LOAD Osteonal Material micron to 100’s micron Properties µ -architecture millimeter and DISPLACEMENT beyond Whole Bone 2
Mechanical Behavior of Common Materials Biomechanical Testing Key Properties Glass (brittle) Strength Load LOAD Stiffness (Stress) Plastic Energy absorbed (toughness) (ductile) DISPLACEMENT Deformation (Strain) Outline Mechanical Behavior of Bone and Its Constituents • Osteoporosis & Bone Strength Mineral • Limitations of BMD Bone Stress Collagen Strain 3
Clinical Assessment of Bone Strength Age and BMD Are Independent Risk Factors for Hip Fracture Areal BMD by DXA 10 Year Fracture Probability (%) • Bone mineral / projected area (g/cm 2 ) Age (yrs) • Reflects (indirectly) 20 80 – Bone size > 5- 5- fold old increase ncrease in 70 – Mineralization fr fractu cture p probability ility from a fr age 50 to to 80 10 • Moderate to strong correlation with 60 whole bone strength (r 2 = 50 - 90%) 50 • Strong predictor of fracture risk in Bouxsein et al, 1999 untreated women (Marshall et al, 1996) 0 -3 -2 -1 0 1 Hip BMD T-score (SD) Kanis et al, 2004 Fracture risk prediction: History of Previous Fracture is a Risk Factor for Future Fracture, Independent of BMD Less than half of patients who fracture have osteoporosis by BMD testing (ie t-scores > -2.5*) 5.8 Vert Frx 3.4 • Only 34% of women and 21% of men suffering a non-vertebral frx had BMD in osteoporotic range (Schuit et al, 2004; 2006) 2.3 BMD Tertiles • Only half of elderly women with incident hip frx had BMD in Low 1.7 osteoporotic range at baseline (Wainwright et al , JCEM 2005) Middle No Vert Frx 1.0 High 0.2 0 1 2 3 4 5 6 Risk of Vertebral Fractures (% / yr) * Based on WHO guidelines for Osteoporosis Diagnosis Ross et al, Ann Int Med, 1991 4
Bone Strength Outline • Osteoporosis & Bone Strength MORPHOLOGY MATRIX PROPERTIES size & shape mineralization • Limitations of BMD microarchitecture collagen traits etc… • Beyond BMD BONE REMODELING formation / resorption OSTEOPOROSIS DRUGS Bouxsein, Best Practice in Clin Rheum, 2005 Distribution of Mass Affects Mechanical Bone Strength Behavior MATRIX PROPERTIES MORPHLOGY tissue composition size & shape matrix properties microarchitecture d Moment of Inertia BONE REMODELING proportional to d 4 formation / resorption 5
Effect of cross-sectional geometry on Bone Strength long bone strength MATRIX PROPERITES SIZNE & SHAPE tissue composition macroarchitecture matrix properties microarchitecture aBMD (by DXA) = = = Compressive Strength = ↑ ↑ BONE REMODELING Bending Strength formation / resorption = ↑↑ ↑↑ ↑↑↑ ↑↑↑ Excessive Bone Resorption Weakens Trabecular Age-Related Changes in Trabecular Microarchitecture Architecture Decline in bone mass L . Mosekilde , 1998 and deterioration of trabecular bone structure both Stress concentration contribute to decreased (focal weakness) bone strength. Perforation 6
Effect of Resorption Cavities on Trabecular Bone Effect of Density Reduction on Strength: Strength Change in Trabecular Thickness vs. Number Trabecular 20% decrease in bone mass 100 Thickness 1) trabecular thinning 20% reduction ↓ 75 in strength 30% decrease in strength Residual Strength 50 (%) 2) add resorption cavities Trabecular 65% reduction ↓ 25 Number in strength 50% decrease in strength 0 0 5 10 15 Density Reduction (%) van der Linden, et al, JBMR 2001 Silva and Gibson, Bone, 1997 Microarchitectural changes that Theoretical effect of cross-struts on buckling influence bone strength strength Buckling Strength proportional to (Strut Length) 2 Force required to cause a Force slender column to buckle: # Horizontal Effective Buckling Trabeculae Length Strength • Directly proportional to – Column material 0 L S – Cross-sectional geometry L 1 1/2 L 4 x S • Inversely proportional to – (Length of column) 2 Mosekilde , Bone , 1988 7
Anti-Resorptive Tx Preserves Trabecular Architecture in Early Dramatic Changes in Trabecular Architecture in Early Postmenopausal Women Postmenopausal Women (Placebo vs Risedronate, 5 mg/d, 1 yr) 15.2 (52 yr old woman, 3 yrs post-menopause) PBO (n=12) 15 13.1 * % change from baseline † RIS (n=14) Baseline 1 yr 10 6.4 * P <0.05 vs baseline. 5 2.0 * † † P < 0.05 vs PBO. † 0 –3.3 * 5 † –7.2 10 15 –13.5 * 20 –20.3* Spine Trabecular Trabecular Trabecular BMD bone volume number separation Dufresne TE et al. Calcif Tissue Int. 2003;73:423-432. Dufresne TE et al. Calcif Tissue Int. 2003; 73:423-432. Age-related changes in femoral neck cortex and Porosity is profound in association with hip fracture the aging femoral neck Mayhew et al, 20 yr old 80 yr old Lancet 2005 19 elderly female Those with hip fractures have: cadavers (87 ± 8 yrs) Intracortical porosity • Preferential thinning of the inferior anterior cortex ranged from 5% to 39% • Increased cortical porosity Bousson et al, JBMR, 2004 Bell et al. Osteop Int, 1999; Jordan et al. Bone, 2000 8
Cortical porosity and trabecularization of the Bone Strength endocortical surface with age Bone loss (mg/HA) Cortical Trabecular MATERIAL GEOMETRY 29 yr tissue composition macroarchitecture matrix properties microarchitecture 67 yr 50-64 65-79 > 80 yrs 90 yr Cortical bone loss BONE REMODELING increases with age. formation / resorption Prior studies have likely underestimated cortical Zebaze et al, Lancet 2010 bone loss Increased bone turnover with estrogen deficiency How is mineralization density influenced by rate of decreases mineralization density bone turnover? Degree of • Slow process of 2 o Mineralization (%) mineralization 100- Secondary mineralization • Decreased bone 50 - (years) turnover allows mineralization to Primary proceed mineralization (3 months) 0 - Time Meunier and Boivin, Bone, 1997 9
Relationship between mineralization and Bone remodeling & microdamage biomechanical properties What is “damage” ? High Mineralization (osteopetrosis) Stiffness – Repetitive loading Normal Strength – No repair process Load Toughness – ↓ Mechanical properties Low (osteomalacia) Displacement Age-related changes in bone properties that lead to decreased bone strength Microdamage in Bone • Decreased bone mass and BMD • Altered geometry • Associated with decreased cortical bone strength • Microcracks seen in human femur & vertebra, • Altered architecture young increase with age Human femoral neck – Cortical thinning • Signal for remodeling & repair – in animals, microdamage increases when – Cortical porosity remodeling is suppressed – Trabecular deterioration • No demonstrated relationship with fracture risk • Altered matrix properties elderly Fazzalari et al, Bone, 1998 Images from L. Mosekilde, Technology and Health Care. 1998 Schaffler, 1995; Wenzel et al, 1996; Mashiba et al, 2001; Burr et al 1997, 2002; Arlot et al 2008 10
Whole bone strength declines Outline dramatically with age • Determinants of Bone Strength Whole Bone Strength (Newtons) 10000 Femoral Neck 10000 Lumbar Vertebrae (sideways fall) (compression) • Limitations of BMD 8000 8000 young 6000 6000 • Beyond BMD 4000 4000 old • Biomechanics of Fractures: 2000 2000 Comparing applied loads to strength young old 0 0 Courtney et al, J Bone Jt Surg 1995; Mosekilde L. Technology and Health Care. 1998. Bending, lifting activity Fracture Etiology Spine curvature Muscle strength Propensity to fall Loads applied Disc degeneration to the bone Fall traits Protective responses Loads applied FRACTURE? Soft-tissue padding to the bone Impact surface direction & magnitude FRACTURE? Bone Strength Geometry Φ = Applied Load Microstructure Bone strength Material Properties Failure Load 11
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