Elise F. Morgan

Comparison of the elastic and yield properties of human femoral trabecular and cortical bone tissue.

The ability to determine trabecular bone tissue elastic and failure properties has biological and clinical importance. To date, trabecular tissue yield strains remain unknown due to experimental difficulties, and elastic moduli studies have reported controversial results. We hypothesized that the elastic and tensile and compressive yield properties of trabecular tissue are similar to those of cortical tissue. Effective tissue modulus and yield strains were calibrated for cadaveric human femoral neck specimens taken from 11 donors, using a combination of apparent-level mechanical testing and specimen-specific, high-resolution, nonlinear finite element modeling. The trabecular tissue properties were then compared to measured elastic modulus and tensile yield strain of human femoral diaphyseal cortical bone specimens obtained from a similar cohort of 34 donors. Cortical tissue properties were obtained by statistically eliminating the effects of vascular porosity. Results indicated that mean elastic modulus was 10% lower (p<0.05) for the trabecular tissue (18.0+/-2.8 GPa) than for the cortical tissue (19.9+/-1.8 GPa), and the 0.2% offset tensile yield strain was 15% lower for the trabecular tissue (0.62+/-0.04% vs. 0.73+/-0.05%, p<0.001). The tensile-compressive yield strength asymmetry for the trabecular tissue, 0.62 on average, was similar to values reported in the literature for cortical bone. We conclude that while the elastic modulus and yield strains for trabecular tissue are just slightly lower than those of cortical tissue, because of the cumulative effect of these differences, tissue strength is about 25% greater for cortical bone.

Trabecular bone modulus–density relationships depend on anatomic site

One outstanding issue regarding the relationship between elastic modulus and density for trabecular bone is whether the relationship depends on anatomic site. To address this, on-axis elastic moduli and apparent densities were measured for 142 specimens of human trabecular bone from the vertebra (n=61), proximal tibia (n=31), femoral greater trochanter (n=23), and femoral neck (n=27). Specimens were obtained from 61 cadavers (mean+/-SD age=67+/-15 years). Experimental protocols were used that minimized end-artifact errors and controlled for specimen orientation. Tissue moduli were computed for a subset of 18 specimens using high-resolution linear finite element analyses and also using two previously developed theoretical relationships (Bone 25 (1999) 481; J. Elasticity 53 (1999) 125). Resultant power law regressions between modulus and density did depend on anatomic site, as determined via an analysis of covariance. The inter-site differences were among the leading coefficients (p<0.02), but not the exponents (p>0.08), which ranged 1.49-2.18. At a given density, specimens from the tibia had higher moduli than those from the vertebra (p=0.01) and femoral neck (p=0.002); those from the trochanter had higher moduli than the vertebra (p=0.02). These differences could be as large as almost 50%, and errors in predicted values of modulus increased by up to 65% when site-dependence was ignored. These results indicate that there is no universal modulus-density relationship for on-axis loading. Tissue moduli computed using methods that account for inter-site architectural variations did not differ across site (p>0.15), suggesting that the site-specificity in apparent modulus-density relationships may be attributed to differences in architecture.

Dependence of yield strain of human trabecular bone on anatomic site.

Understanding the dependence of human trabecular bone strength behavior on anatomic site provides insight into structure-function relationships and is essential to the increased success of site-specific finite element models of whole bones. To investigate the hypothesis that the yield strains of human trabecular bone depend on anatomic site, the uniaxial tensile and compressive yield properties were compared for cylindrical specimens from the vertebra (n=61), proximal tibia (n=31), femoral greater trochanter (n=23), and femoral neck (n=27) taken from 61 donors (67+/-15years). Test protocols were used that minimized end artifacts and loaded specimens along the main trabecular orientation. Yield strains by site (mean+/-S.D.) ranged from 0.70+/-0.05% for the trochanter to 0.85+/-0.10% for the femoral neck in compression, from 0.61+/-0.05% for the trochanter to 0.70+/-0.05% for the vertebra in tension, and were always higher in compression than tension (p<0.001). The compressive yield strain was higher for the femoral neck than for all other sites (p<0.001), as was the tensile yield strain for the vertebra (p<0.007). Analysis of covariance, with apparent density as the covariate, indicated that inter-site differences existed in yield stress even after adjusting statistically for density (p<0.035). Coefficients of variation in yield strain within each site ranged from only 5-12%, consistent with the strong linear correlations (r(2)=0.94-0.98) found between yield stress and modulus. These results establish that the yield strains of human trabecular bone can differ across sites, but that yield strain may be considered uniform within a given site despite substantial variation in elastic modulus and yield stress.

Quantitative computed tomography estimates of the mechanical properties of human vertebral trabecular bone

The objective of this study was to report our quantitative computed tomography (QCT) density‐mechanical property regressions for trabecular bone for use in biomechanical modelling of the human spine. Cylindrical specimens of human vertebral trabecular bone (from T10 to L4) were cored from 32 cadavers (mean ± SD age = 70.1 ± 16.8; 13 females, 19 males) and scanned using QCT. Mechanical tests were conducted using a protocol that minimized end‐artifacts over the apparent density range tested (0.09–0.38 g/ cm3). To account for the presence of multiple specimens per donor in this data set, donor was treated as a random effect in the regression model. Mean modulus (319 ± 189 MPa) was higher and mean yield strain (0.78 ± 0.06%) was lower than typical values reported previously due to minimization of the end‐artifact errors. QCT density showed a strong positive correlation with modulus (n = 76) and yield stress (r2 = 0.90–0.95, n = 53, p < 0.001). There was a weak positive linear correlation with yield strain (r2 = 0.58, n = 53, p = 0.07). Prediction errors, incurred when estimating modulus or strength for specimens from a new donor, were 30–36% of the mean values of these properties. Direct QCT density‐mechanical property regressions gave more precise predictions of mechanical properties than if physically measured wet apparent density was used as an intermediate variable to predict mechanical properties from QCT density. Use of these QCT density‐mechanical property regressions should improve the fidelity of QCT‐based biomechanical models of the human spine for whole bone and bone‐implant analyses.

Micro-computed tomography assessment of fracture healing: Relationships among callus structure, composition, and mechanical function

Non-invasive characterization of fracture callus structure and composition may facilitate development of surrogate measures of the regain of mechanical function. As such, quantitative computed tomography- (CT-) based analyses of fracture calluses could enable more reliable clinical assessments of bone healing. Although previous studies have used CT to quantify and predict fracture healing, it is unclear which of the many CT-derived metrics of callus structure and composition are the most predictive of callus mechanical properties. The goal of this study was to identify the changes in fracture callus structure and composition that occur over time and that are most closely related to the regain of mechanical function. Micro-computed tomography (microCT) imaging and torsion testing were performed on murine fracture calluses (n=188) at multiple post-fracture timepoints and under different experimental conditions that alter fracture healing. Total callus volume (TV), mineralized callus volume (BV), callus mineralized volume fraction (BV/TV), bone mineral content (BMC), tissue mineral density (TMD), standard deviation of mineral density (sigma(TMD)), effective polar moment of inertia (J(eff)), torsional strength, and torsional rigidity were quantified. Multivariate statistical analyses, including multivariate analysis of variance, principal components analysis, and stepwise regression were used to identify differences in callus structure and composition among experimental groups and to determine which of the microCT outcome measures were the strongest predictors of mechanical properties. Although calluses varied greatly in the absolute and relative amounts of mineralized tissue (BV, BMC, and BV/TV), differences among timepoints were most strongly associated with changes in tissue mineral density. Torsional strength and rigidity were dependent on mineral density as well as the amount of mineralized tissue: TMD, BV, and sigma(TMD) explained 62% of the variation in torsional strength (p<0.001); and TMD, BMC, BV/TV, and sigma(TMD) explained 70% of the variation in torsional rigidity (p<0.001). These results indicate that fracture callus mechanical properties can be predicted by several microCT-derived measures of callus structure and composition. These findings form the basis for developing non-invasive assessments of fracture healing and for identifying biological and biomechanical mechanisms that lead to impaired or enhanced healing.

Enhanced Chondrogenesis and Wnt Signaling in PTH-Treated Fractures†

Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt‐signaling in PTH‐treated bones at multiple time‐points across the time‐course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling.

Diminished Bone Formation During Diabetic Fracture Healing is Related to the Premature Resorption of Cartilage Associated With Increased Osteoclast Activity

Histological and molecular analysis of fracture healing in normal and diabetic animals showed significantly enhanced removal of cartilage in diabetic animals. Increased cartilage turnover was associated with elevated osteoclast numbers, a higher expression of genes that promote osteoclastogenesis, and diminished primary bone formation.

Comparison of Effects of the Bisphosphonate Alendronate Versus the RANKL Inhibitor Denosumab on Murine Fracture Healing

The role of osteoclast‐mediated resorption during fracture healing was assessed. The impact of two osteoclast inhibitors with different mechanisms of action, alendronate (ALN) and denosumab (DMAB), were examined during fracture healing. Male human RANKL knock‐in mice that express a chimeric (human/murine) form of RANKL received unilateral transverse femur fractures. Mice were treated biweekly with ALN 0.1 mg/kg, DMAB 10 mg/kg, or PBS (control) 0.1 ml until death at 21 and 42 days after fracture. Treatment efficacy assessed by serum levels of TRACP 5b showed almost a complete elimination of TRACP 5b levels in the DMAB‐treated animals but only ∼25% reduction of serum levels in the ALN‐treated mice. Mechanical testing showed that fractured femurs from both ALN and DMAB groups had significantly increased mechanical properties at day 42 compared with controls. μCT analysis showed that callus tissues from DMAB‐treated mice had significantly greater percent bone volume and BMD than did both control and ALN‐treated tissues at both 21 and 42 days, whereas ALN‐treated bones only had greater percent bone volume and BMC than control at 42 days. Qualitative histological analysis showed that the 21‐and 42‐day ALN and DMAB groups had greater amounts of unresorbed cartilage or mineralized cartilage matrix compared with the controls, whereas unresorbed cartilage could still be seen in the DMAB groups at 42 days after fracture. Although ALN and DMAB delayed the removal of cartilage and the remodeling of the fracture callus, this did not diminish the mechanical integrity of the healing fractures in mice receiving these treatments. In contrast, strength and stiffness were enhanced in these treatment groups compared with control bones.

Bone Formation During Distraction Osteogenesis Is Dependent on Both VEGFR1 and VEGFR2 Signaling

Introduction: Distraction osteogenesis (DO) is characterized by the induction of highly vascularized new bone formation through an intramembranous process largely devoid of the formation of cartilage.

Bone marrow lesions from osteoarthritis knees are characterized by sclerotic bone that is less well mineralized.

IntroductionAlthough the presence of bone marrow lesions (BMLs) on magnetic resonance images is strongly associated with osteoarthritis progression and pain, the underlying pathology is not well established. The aim of the present study was to evaluate the architecture of subchondral bone in regions with and without BMLs from the same individual using bone histomorphometry.MethodsPostmenopausal female subjects (n = 6, age 48 to 90 years) with predominantly medial compartment osteoarthritis and on a waiting list for total knee replacement were recruited. To identify the location of the BMLs, subjects had a magnetic resonance imaging scan performed on their study knee prior to total knee replacement using a GE 1.5 T scanner with a dedicated extremity coil. An axial map of the tibial plateau was made, delineating the precise location of the BML. After surgical removal of the tibial plateau, the BML was localized using the axial map from the magnetic resonance image and the lesion excised along with a comparably sized bone specimen adjacent to the BML and from the contralateral compartment without a BML. Cores were imaged via microcomputed tomography, and the bone volume fraction and tissue mineral density were calculated for each core. In addition, the thickness of the subchondral plate was measured, and the following quantitative metrics of trabecular structure were calculated for the subchondral trabecular bone in each core: trabecular number, thickness, and spacing, structure model index, connectivity density, and degree of anisotropy. We computed the mean and standard deviation for each parameter, and the unaffected bone from the medial tibial plateau and the bone from the lateral tibial plateau were compared with the affected BML region in the medial tibial plateau.ResultsCores from the lesion area displayed increased bone volume fraction but reduced tissue mineral density. The samples from the subchondral trabecular lesion area exhibited increased trabecular thickness and were also markedly more plate-like than the bone in the other three locations, as evidenced by the lower value of the structural model index. Other differences in structure that were noted were increased trabecular spacing and a trend towards decreased trabecular number in the cores from the medial location as compared with the contralateral location.ConclusionsOur preliminary data localize specific changes in bone mineralization, remodeling and defects within BMLs features that are adjacent to the subchondral plate. These BMLs appear to be sclerotic compared with unaffected regions from the same individual based on the increased bone volume fraction and increased trabecular thickness. The mineral density in these lesions, however, is reduced and may render this area to be mechanically compromised, and thus susceptible to attrition.