Material Properties Of Cortical Bone Research Articles

Influences of human thorax variability on population rib fracture risk prediction using human body models.

Rib fractures remain a common injury for vehicle occupants in crashes. The risk of a human sustaining rib fractures from thorax loading is highly variable, potentially due to a variability in individual factors such as material properties and geometry of the ribs and ribcage. Human body models (HBMs) with a detailed ribcage can be used as occupant substitutes to aid in the prediction of rib injury risk at the tissue level in crash analysis. To improve this capability, model parametrization can be used to represent human variability in simulation studies. The aim of this study was to identify the variations in the physical properties of the human thorax that have the most influence on rib fracture risk for the population of vehicle occupants. A total of 15 different geometrical and material factors, sourced from published literature, were varied in a parametrized SAFER HBM. Parametric sensitivity analyses were conducted for two crash configurations, frontal and near-side impacts. The results show that variability in rib cortical bone thickness, rib cortical bone material properties, and rib cross-sectional width had the greatest influence on the risk for an occupant to sustain two or more fractured ribs in both impacts. Therefore, it is recommended that these three parameters be included in rib fracture risk analysis with HBMs for the population of vehicle occupants.

Validation of rib structural responses under dynamic loadings using different material properties: A finite element analysis

In this paper, human rib finite element models were created and validated based on finite element simulations. Validation tests were conducted through replicating experimental configurations of ribs under dynamic anterior-posterior bending, and by comparing numerical rib structural responses and fracture locations against experimental data. Human rib cortical bone material properties from different loading modes (tension and compression), strain rates (0.5 strain/s and 0.005 strain/s) and ages as well as porcine rib material properties were applied. Comparison of rib structural responses with various material properties was investigated. Numerical force-displacement relationship, cortical strain, rotation and fracture location correspond well with published experimental data, which demonstrates the robustness of the finite element rib models. Numerical analysis reveals that numerical strain and rotation time histories with human rib cortical compressive material properties have a better correlation with experimental data compared to those with human rib cortical tensile material properties. Also, numerical rib structural responses were found to be sensitive to material properties from different loading modes, strain rates and ages. Therefore, it is necessary to consider the effect of material properties from different loading modes, strain rates and ages when establishing rib FE models. Meanwhile, it is also indicated that porcine rib material properties can obtain similar and reasonable results compared to human rib material properties. This was the first numerical study to apply human rib compressive material properties in investigating rib dynamic structural responses and compare the results with those from tensile material properties. The present study helps better understand human rib fractures in a high velocity impact (HVI) context in a numerical way.

Are Bone Metabolism and Bone Material Strength Evaluations Worthwhile?: Commentary on an article by Tamara D. Rozental, MD, et al.: "Longitudinal Changes in Serum Markers of Bone Metabolism and Bone Material Strength in Premenopausal Women with Distal Radial Fracture".

Commentary The article by Dr. Tamara D. Rozental and colleagues introduces us to 2 innovative methods to improve our understanding of bone strength and fracture-healing biochemistry that maybe relevant to clinical practice. Bone mineral density (BMD) is the standard for determining bone quality and fracture risk but does not define the structural and mechanical properties of bone1. Impact microindentation provides information on the material properties of cortical bone that we as orthopaedic surgeons need in order to improve our choice of fixation strategy2. Markers of bone metabolism (MBM) have been used to assess the results of osteoporotic treatment but have not been applied to the non-osteoporotic patient to assess fracture healing or to predict potential osteoporosis3,4. Impact microindentation is a minimally invasive technique that measures the ability of the tibial cortex to resist a standardized impact force. This measures the bone’s material quality, which is the interaction of the bone’s mineral and organic elements to resist failure. This technique might allow for a better determination of the ability of bone to hold implants that are used for fracture fixation (for example, the ability to achieve screw purchase). A greater understanding of such variables would facilitate fixation decisions, including the potential need to augment fixation with use of locking screws or bone substitutes. In this study, the microindentation technique did not prove valuable in assessing bone quality, but the investigators demonstrated that the test was possible to administer in a clinical setting. MBM have demonstrated promise as markers of the healing response following the treatment of a fracture5. Sclerostin (a glycoprotein produced by osteocytes) and Dickkopf 1 (DKK1) both decrease bone formation were initially increased but then both dropped to low levels allowing the healing response to occur. Tartrate-resistant acid phosphatase (TRAP) and C-terminal telopeptide (both of which are indicators of osteoclastic activity) peaked early, indicating the need for bone removal secondary to fracture site necrosis. Bone-formation markers such as N-terminal extension propeptide of type-I collagen (P1NP) and bone-specific alkaline phosphatase (BSAP) increased throughout the healing phase. These longitudinal results are evidence that, in premenopausal women, the biochemistry of fracture healing can be evaluated. This study provides the impetus to evaluate whether MBM can determine problems in fracture healing earlier than radiographic evidence and also whether MBM can serve as an indication of early osteopenia and osteoporosis in premenopausal women6. This article had a number of strengths. Patient selection was appropriate (although it was limited to a specific group of premenopausal women with a distal radial fracture). The fractures were classified with use of an acceptable system that can be used to determine severity on the basis of the mechanism of injury (i.e., high or low energy). Finally, the study included both operatively and nonoperatively managed patients, with the former demonstrating an elevated BSAP. This article also had also several areas of concern. MBM vary depending on patient activity and the time of day when the samples are taken. The authors acknowledge this limitation, but it is important for the reader to understand that the controls were only sampled once, so any assumption regarding longitudinal MBM levels may not hold. Another issue is that there is no consensus on what constitutes a meaningful clinical difference in these results. As this study is the first to measure MBM during fracture healing, one is unsure of what these results mean. It is obvious that the results appear to coincide with our understanding of fracture healing, but this relationship has not been proven. Although this study has limitations, including a small sample size in a very specific patient population, it opens the door to a better understanding of fracture healing. Orthopaedic surgeons, particularly those specializing in fracture care, should consider this study as an impetus to further investigate the physiology and biochemistry of fracture healing.

A comparison of rib cortical bone compressive and tensile material properties: Trends with age, sex, and loading rate

The objectives of this study were to develop novel methods for quantifying human rib cortical bone material properties in compression and to compare the compressive material property data to existing tensile data for matched subjects. Cylindrical coupons were obtained from the rib cortical bone of 30 subjects (M = 19, F = 11) ranging from 18 to 95 years of age (Avg. = 48.5 ± 24.3). Two coupons were obtained from each subject. One coupon was tested in compression at 0.005 strain/s, while the other coupon was tested in compression at 0.5 strain/s. Load and displacement data were recorded so that the elastic modulus, yield stress, yield strain, ultimate stress, ultimate strain, elastic strain energy density (SED), plastic SED, and total SED could be calculated. All compressive material properties were significantly different between the two loading rates. An ANOVA revealed that sex alone had no significant effect on the compressive material properties. The interaction between sex and age was significant for some material properties, but this may have been a consequence of the lack of older females in the subject pool. None of the compressive material properties were significantly correlated with age, but were more correlated with sample density. This finding differed for the tensile material properties, which showed stronger correlations with age. When comparing between tension and compression, significant differences were observed for all material properties except for the total SED, once the effects of loading rate and age had been accounted for. This was the first study to quantify the material properties of human rib cortical bone in compression. The results of this study demonstrated that rib and thorax finite element models should consider the effects of loading rate, loading mode, and age when incorporating material properties published in the literature.

Amelioration of bone fragility by pulsed electromagnetic fields in type 2 diabetic KK-Ay mice involving Wnt/β-catenin signaling.

Type 2 diabetes mellitus (T2DM) results in compromised bone microstructure and quality, and subsequently increased risks of fractures. However, it still lacks safe and effective approaches resisting T2DM bone fragility. Pulsed electromagnetic fields (PEMFs) exposure has proven to be effective in accelerating fracture healing and attenuating osteopenia/osteoporosis induced by estrogen deficiency. Nevertheless, whether and how PEMFs resist T2DM-associated bone deterioration remain not fully identified. The KK-Ay mouse was used as the T2DM model. We found that PEMF stimulation with 2 h/day for 8 wk remarkably improved trabecular bone microarchitecture, decreased cortical bone porosity, and promoted trabecular and cortical bone material properties in KK-Ay mice. PEMF stimulated bone formation in KK-Ay mice, as evidenced by increased serum levels of bone formation (osteocalcin and P1NP), enhanced bone formation rate, and increased osteoblast number. PEMF significantly suppressed osteocytic apoptosis and sclerostin expression in KK-Ay mice. PEMF exerted beneficial effects on osteoblast- and osteocyte-related gene expression in the skeleton of KK-Ay mice. Nevertheless, PEMF exerted no effect on serum biomarkers of bone resorption (TRAcP5b and CTX-1), osteoclast number, or osteoclast-specific gene expression (TRAP and cathepsin K). PEMF upregulated gene expression of canonical Wnt ligands (including Wnt1, Wnt3a, and Wnt10b), but not noncanonical Wnt5a. PEMF also upregulated skeletal protein expression of downstream p-GSK-3β and β-catenin in KK-Ay mice. Moreover, PEMF-induced improvement in bone microstructure, mechanical strength, and bone formation in KK-Ay mice was abolished after intragastric administration with the Wnt antagonist ETC-159. Together, our results suggest that PEMF can improve bone microarchitecture and quality by enhancing the biological activities of osteoblasts and osteocytes, which are associated with the activation of the Wnt/β-catenin signaling pathway. PEMF might become an effective countermeasure against T2DM-induced bone deterioration.NEW & NOTEWORTHY PEMF improved trabecular bone microarchitecture and suppressed cortical bone porosity in T2DM KK-Ay mice. It attenuated T2DM-induced detrimental consequence on trabecular and cortical bone material properties. PEMF resisted bone deterioration in KK-Ay mice by enhancing osteoblast-mediated bone formation. PEMF also significantly suppressed osteocytic apoptosis and sclerostin expression in KK-Ay mice. The therapeutic potential of PEMF on T2DM-induced bone deterioration was associated with the activation of Wnt/ß-catenin signaling.

Effect of geometrical structure variations on the viscoelastic and anisotropic behaviour of cortical bone using multi-scale finite element modelling

Multi-scale finite element analysis is performed to ascertain the effect of geometrical changes at multiple structural scales on the mechanical properties of cortical bone. Finite element models are developed, with reference to experimental data from existing literature, to account for bone's viscoelastic behaviour and anisotropic structure from the most fundamental level of bone consisting of mineralised collagen fibrils, up to the macroscopic level consisting of osteons and the Haversian canals. A statistical approach is incorporated to perform sensitivity analyses on the effects of different geometrical parameters on the effective material properties of cortical bone at each length scale. Numerical results indicate that there is an exponential correlation between the mineral volume fraction and the effective stiffness constants at each length scale. This contributes to the exponential behaviour of the instantaneous moduli describing cortical bone's two-phase stress relaxation process: a fast and slow response relaxation behaviour. Results indicate that the fast response relaxation time is independent of bone's structural anisotropy, whilst being dependent on variations in the global mineral volume fraction between length scales. However, the slow response relaxation time is independent of the changes in mineral volume fraction. It is also observed that the slow response relaxation time varies with bone's anisotropic structure, and therefore, contributes to the anisotropic properties of bone.

Impact microindentation measurements correlate with cortical bone material properties measured by Fourier transform infrared imaging in humans.

Bone Material Strength index (BMSi) measured by Impact Microindentation is generally lower in subjects with fragility fractures independently of BMD values. We recently reported that in humans, BMSi values are strongly associated with material properties of subperiosteal mineralized bone surface (local mineral content, nanoporosity, pyridinoline content). In the present study we investigated the relationship of BMSi with material properties of the whole bone cortex, by analyzing thin sections of iliac crest biopsies (N=12) from patients with different skeletal disorders and a wide range of BMD with or without fractures, by Fourier transform infrared imaging (FTIRI). The calculated parameters were: i) mineral and organic matrix content and their ratio (MM), ii) mineral maturity/crystallinity (MMC) and iii) the ratio of pyridinoline (Pyd) and divalent collagen cross-links (XLR). Results were expressed as images, which were converted to histogram distributions. For each histogram the characteristics recorded were: mean value, mode (most often occurring value), skewness, and kurtosis and their association with BMSi values was examined by correlation analysis. BMSi values were significantly correlated only with MM mean and mode values (r=0.736, p=0.0063, and r=0.855, p=0.0004, respectively), and with XLR mode values (r=-0.632, p=0.0274). The results of the present study demonstrate that BMSi values are strongly associated with MM, a metric that corrects the mineral content for the organic matrix content, and may also depend on organic matrix quality. These and our previous observations strongly suggest that BMSi assesses material properties of cortical bone.

SUN-LB68 Advanced Glycation Endproducts Are Associated With Worse Bone Material Strength in Older Adults With and Without Type 2 Diabetes

Patients with Type 2 Diabetes (T2D) are at increased fracture risk despite having relatively normal or even increased BMD by DXA. The critical aspect of bone quality deterioration in T2D patients could explain this clinically important discrepancy. Material composition is a component of bone quality that has emerged as a potential factor contributing to fragility fractures in T2D patients. However, there is sparse evidence regarding whether T2D patients have decreased bone material properties compared with non-diabetic controls. We hypothesized that increased production of advanced glycation endproducts (AGEs) has an important role in reducing bone material strength in patients with and without diabetes. Thus, we used the OsteoProbe®, a bone microindentation device that provides an index of cortical bone material properties (Bone Material Strength index – BMSi) in men with T2D age ≥ 50 yrs or postmenopausal women with T2D and nondiabetic controls. We also utilized a non-invasive measure of skin AGEs (AGE Reader®) to evaluate AGEs accumulation through skin autofluorescence. Linear regression models were used to assess group differences with and without adjusting for age, Body Mass Index (BMI), and sex. Relationships between variables were assessed using adjusted Pearson correlations. A total of 152 T2D patients (mean age 68.5 ±7.6 yrs.; 59.2% men; HbA1C=7.7 ±1.0%; mean diabetes duration 15.5 yrs.) and 105 non-diabetic controls (mean age 67.2±8.8 yrs.; 41.0% men; HbA1C =5.4 ±0.3%) were recruited to the study. Overall, there was no difference in BMSi between T2DM and control subjects: unadjusted (p= 0.636); adjusted (p= 0.695). However, skin AGEs were negatively correlated with BMSi (r= -0.23, p <0.001). In subgroup analyses, skin AGEs were also negatively associated with BMSi in both T2DM (r= -0.23, p=0.004) and control (r= -0.21, p=0.033) subjects. In conclusion, these findings demonstrate that a higher burden of AGEs is associated with worse bone quality. Our findings may explain the conflicting findings regarding reductions in BMSi in T2D because only T2D patients with a high level of AGEs accumulation have impaired BMSi. Moreover, the association of skin AGEs with BMSi in non-diabetic subjects emphasizes the important role of AGEs in decreasing bone quality and potentially contributing to fracture risk. Collectively, our data indicate that non-invasive skin AGEs measurement could be used as a tool to evaluate bone quality in patients with T2D as well as in the non-diabetic population.

Assessment of Fracture Toughness in Bone Tissue Engineering

The fracture mechanisms affecting bone tissue can be described as a damage accumulation process due to the initiation and propagation of microcracks. Fracture risk does not solely depend on strength but also on fracture toughness. To replace damaged bone or cartilage tissues, hydrogels are required to provide appropriate stiffness or deformation properties as well as resistance to fracture. However, failure properties, such as the resistance to fracture, must be evaluated by fracture toughness techniques. Microindentation has emerged as a novel technique for the measurement of material properties of cortical bone. The application of this test for fracture toughness determination in these tissues can become widespread because of the simplicity of the test. The aims of this article are to discuss clinical application of fracture toughness analysis and to present a well tested and more realistic approach for estimating fracture toughness in bone. POLYM. ENG. SCI., 59:2402–2405, 2019. © 2019 Society of Plastics Engineers

Bone material strength in normoglycemic and hyperglycemic black and white older adults.

Individuals with long-standing type 2 diabetes (T2D) have altered cortical bone material properties as determined by impact microindentation. This cross-sectional study was done to determine whether altered cortical bone material properties could be detected in adults with prediabetes or early-stage T2D. Men and postmenopausal women aged ≥ 50years with no diabetes (50 white, 6 black), prediabetes (75 white, 13 black), and T2D of ≤ 5years duration (24 white and 16 black) had assessments of bone material strength index (BMSi) by impact microindentation, trabecular bone score (TBS), and bone mineral density (BMD) by DXA and the advanced glycation end product, urine pentosidine. The association between glycemia category and BMSi differed by race (interaction p = 0.037). In the whites, BMSi did not differ across the glycemia categories, after adjustment for age, sex, and BMI (no diabetes 76.3 ± 1.6 (SEM), prediabetes 77.2 ± 1.3, T2D 76.2 ± 2.5, ANCOVA p = 0.887). In contrast, in the blacks, BMSi differed (ANCOVA p = 0.020) and was significantly lower in subjects with T2D than in those with prediabetes (p < 0.05) and no diabetes (p < 0.05) (mean ± SEM BMSi in no diabetes 86.0 ± 4.3, prediabetes 91.0 ± 3.2, and T2D 71.6 ± 2.9). Neither TBS nor urine pentosidine differed significantly across the glycemia categories in either whites or blacks. These findings suggest different associations of glycemia with cortical bone material properties in blacks and whites, with blacks possibly being more susceptible to impaired cortical bone properties than whites in early diabetes. A larger study is needed to verify these observations.

Macroscopic anisotropic bone material properties in children with severe osteogenesis imperfecta

Children with severe osteogenesis imperfecta (OI) typically experience numerous fractures and progressive skeletal deformities over their lifetime. Recent studies proposed finite element models to assess fracture risk and guide clinicians in determining appropriate intervention in children with OI, but lack of appropriate material property inputs remains a challenge. This study aimed to characterize macroscopic anisotropic cortical bone material properties and investigate relationships with bone density measures in children with severe OI. Specimens were obtained from tibial or femoral shafts of nine children with severe OI and five controls. The specimens were cut into beams, characterized in bending, and imaged by synchrotron radiation X-ray micro-computed tomography. Longitudinal modulus of elasticity, yield strength, and bending strength were 32–65% lower in the OI group (p<0.001). Yield strain did not differ between groups (p≥0.197). In both groups, modulus and strength were lower in the transverse direction (p≤0.009), but anisotropy was less pronounced in the OI group. Intracortical vascular porosity was almost six times higher in the OI group (p<0.001), but no differences were observed in osteocyte lacunar porosity between the groups (p=0.086). Volumetric bone mineral density was lower in the OI group (p<0.001), but volumetric tissue mineral density was not (p=0.770). Longitudinal OI bone modulus and strength were correlated with volumetric bone mineral density (p≤0.024) but not volumetric tissue mineral density (p≥0.099). Results indicate that cortical bone in children with severe OI yields at the same strain as normal bone, and that their decreased bone material strength is associated with reduced volumetric bone mineral density. These results will enable the advancement of fracture risk assessment capability in children with severe OI.

High resolution bone material property assignment yields robust subject specific finite element models of complex thin bone structures

Accurate finite element (FE) modeling of complex skeletal anatomy requires high resolution in both meshing and the heterogeneous mapping of material properties onto the generated mesh. This study introduces Node-based elastic Modulus Assignment with Partial-volume correction (NMAP) as a new approach for FE material property assignment to thin bone structures. The NMAP approach incorporates point spread function based deblurring of CT images, partial-volume correction of CT image voxel intensities and anisotropic interpolation and mapping of CT intensity assignment to FE mesh nodes. The NMAP procedure combined with a derived craniomaxillo-facial skeleton (CMFS) specific density-isotropic elastic modulus relationship was applied to produce specimen-specific FE models of 6 cadaveric heads. The NMAP procedure successfully generated models of the complex thin bone structures with surface elastic moduli reflective of cortical bone material properties. The specimen-specific CMFS FE models were able to accurately predict experimental strains measured under in vitro temporalis and masseter muscle loading (r=0.93, slope=1.01, n=5). The strength of this correlation represents a robust validation for CMFS FE modeling that can be used to better understand load transfer in this complex musculoskeletal system. The developed methodology offers a systematic process-flow able to address the complexity of the CMFS that can be further applied to create high-fidelity models of any musculoskeletal anatomy.

Effect of Concurrent Use of Whole-Body Vibration and Parathyroid Hormone on Bone Structure and Material Properties of Ovariectomized Mice.

This study was designed to determine the effectiveness of whole-body vibration (WBV) and intermittent parathyroid hormone (iPTH) in combination against estrogen deficiency-induced osteoporosis. Female C57BL/6J mice were bilaterally ovariectomized (OVX, n=40) or sham-operated (sham-OVX, n=8) at 9weeks of age. Two weeks later, the OVX mice were randomly divided into four groups (n=10 each): the control group (c-OVX) and groups treated with iPTH (p-OVX), WBV (w-OVX) and both (pw-OVX). The p-OVX and pw-OVX groups were given human PTH (1-34) at a dose of 30µg/kg/day. The w-OVX and pw-OVX groups were exposed to WBV at an acceleration of 0.3g and 45Hz for 20min/day. All mice were euthanized after the 18-day treatment, and the left tibiae were harvested. The proximal metaphyseal region was µCT-scanned, and its cortical bone cross-section was analyzed by Fourier transform infrared microspectroscopy and nanoindentation testing. A single application of iPTH or WBV to OVX mice had no effect on bone structure or material properties of cortical bone, which were compromised in comparison to those in sham-OVX mice. The combination of iPTH and WBV improved trabecular bone volume, thickness, and connectivity in OVX mice. Although the combined treatment failed to improve cortical bone structure, its mineral maturity and hardness were restored to the levels observed in sham-OVX mice. There was no evidence of interaction between the two treatments, and the combined effects seemed to be additive. These results suggest combining WBV with iPTH has great potential for treating postmenopausal osteoporosis.

The Role of Water Compartments in the Material Properties of Cortical Bone.

Comprising ~20% of the volume, water is a key determinant of the mechanical behavior of cortical bone. It essentially exists in two general compartments: within pores and bound to the matrix. The amount of pore water-residing in the vascular-lacunar-canalicular space-primarily reflects intracortical porosity (i.e., open spaces within the matrix largely due to Haversian canals and resorption sites) and as such is inversely proportional to most mechanical properties of bone. Movement of water according to pressure gradients generated during dynamic loading likely confers hydraulic stiffening to the bone as well. Nonetheless, bound water is a primary contributor to the mechanical behavior of bone in that it is responsible for giving collagen the ability to confer ductility or plasticity to bone (i.e., allows deformation to continue once permanent damage begins to form in the matrix) and decreases with age along with fracture resistance. Thus, dehydration by air-drying or by solvents with less hydrogen bonding capacity causes bone to become brittle, but interestingly, it also increases stiffness and strength across the hierarchical levels of organization. Despite the importance of matrix hydration to fracture resistance, little is known about why bound water decreases with age in hydrated human bone. Using (1)H nuclear magnetic resonance (NMR), both bound and pore water concentrations in bone can be measured ex vivo because the proton relaxation times differ between the two water compartments, giving rise to two distinct signals. There are also emerging techniques to measure bound and pore water in vivo with magnetic resonance imaging (MRI). The NMR/MRI-derived bound water concentration is positively correlated with both the strength and toughness of hydrated bone and may become a useful clinical marker of fracture risk.

Modeling of transient wave propagation in a heterogeneous solid layer coupled with fluid: application to long bones.

The aim of this work is to evaluate the effects of the heterogeneity and anisotropy of material properties of cortical bone on its ultrasonic response obtained by using axial transmission method. The heterogeneity and anisotropy of material properties are introduced by using a parametric probabilistic model. The geometrical configuration of the tested sample is described by a tri-layer medium composed of a heterogeneous and anisotropic solid layer sandwiched between two acoustic fluid layers of which one of these layers is excited by an acoustic linear source. The numerical results focus on studying of an interest quantity, called velocity of the first arriving signal, showing that it strongly depends on the dispersion induced by statistical fluctuations of stochastic elasticity field.

Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs

Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in the cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than the bone's material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of the cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1ml/kg/day) or alendronate (ALN) at a clinical dose (0.2mg/kg/day). Treatment duration ranged from 3months to 3years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of the femoral cortical bone in humans.

Cortical Bone Mechanical Properties Are Altered in an Animal Model of Progressive Chronic Kidney Disease

Chronic kidney disease (CKD), which leads tocortical bone loss and increasedporosity,increases therisk of fracture. Animal models have confirmed that these changes compromise whole bone mechanical properties. Estimates from whole bone testing suggest that material properties are negatively affected, though tissue-level assessmentshavenot been conducted. Therefore, the goal of the present study was to examine changes in cortical bone at different length scales using a rat model with theprogressive development of CKD. At 30 weeks of age (∼75% reduction in kidney function), skeletally mature male Cy/+ rats were compared to their normal littermates. Cortical bone material propertieswere assessed with reference point indentation (RPI), atomic force microscopy (AFM), Raman spectroscopy,and high performance liquid chromatography (HPLC). Bones from animals with CKD had higher (+18%) indentation distance increase and first cycle energy dissipation (+8%) as measured by RPI.AFM indentation revealed a broader distribution of elastic modulus values in CKD animals witha greater proportion of both higher and lower modulus values compared to normal controls. Yet, tissue composition, collagen morphology, and collagen cross-linking fail to account for these differences. Though the specific skeletal tissue alterations responsible for these mechanical differences remain unclear, these results indicate that cortical bone material properties are altered in these animals and may contribute to the increased fracture risk associated with CKD.

Application of an effective medium theory for modeling ultrasound wave propagation in healing long bones

Quantitative ultrasound has recently drawn significant interest in the monitoring of the bone healing process. Several research groups have studied ultrasound propagation in healing bones numerically, assuming callus to be a homogeneous and isotropic medium, thus neglecting the multiple scattering phenomena that occur due to the porous nature of callus. In this study, we model ultrasound wave propagation in healing long bones using an iterative effective medium approximation (IEMA), which has been shown to be significantly accurate for highly concentrated elastic mixtures. First, the effectiveness of IEMA in bone characterization is examined: (a) by comparing the theoretical phase velocities with experimental measurements in cancellous bone mimicking phantoms, and (b) by simulating wave propagation in complex healing bone geometries by using IEMA. The original material properties of cortical bone and callus were derived using serial scanning acoustic microscopy (SAM) images from previous animal studies. Guided wave analysis is performed for different healing stages and the results clearly indicate that IEMA predictions could provide supplementary information for bone assessment during the healing process. This methodology could potentially be applied in numerical studies dealing with wave propagation in composite media such as healing or osteoporotic bones in order to reduce the simulation time and simplify the study of complicated geometries with a significant porous nature.

Overexpression of DMP1 accelerates mineralization and alters cortical bone biomechanical properties in vivo

Dentin matrix protein-1 (DMP1) is a key regulator of biomineralization. Here, we examine changes in structural, geometric, and material properties of cortical bone in a transgenic mouse model overexpressing DMP1. Micro-computed tomography and three-point bending were performed on 90 femora of wild type and transgenic mice at 1, 2, 4, and 6 months. Fourier transform infrared imaging was performed at 2 months. We found that the transgenic femurs were longer ( p < 0.01 ), more robust in cross-section ( p < 0.05 ), stronger ( p < 0.05 ), but had less post-yield strain and displacement ( p < 0.01 ), and higher tissue mineral density ( p < 0.01 ) than the wild type femurs at 1 and 2 months. At 2 months, the transgenic femurs also had a higher mineral-to-matrix ratio ( p < 0.05 ) and lower carbonate substitution ( p < 0.05 ) compared to wild type femurs. These findings indicate that increased mineralization caused by overexpressing DMP1 led to increased structural cortical bone properties associated with decreased ductility during the early post-natal period.

Assessment of Trabecular Bone Architecture and Intrinsic Properties of Cortical bone Tissue in a Mouse Model of Chronic Kidney Disease

Chronic kidney disease (CKD) is often associated with increased fracture risk; however, the CKD-effects on bone microstructure and intrinsic material properties have not been fully elucidated. This study was undertaken to evaluate the time course of trabecular architectural changes and material properties of cortical bone in the tibia of a mouse model of high-turnover CKD. Male mice subjected to 5/6 nephrectomy (Nx, n=8) and those sham-operated (Sham, n=8) were used. Starting at 8 weeks of age (2 weeks after surgery), Nx mice were fed with high phosphate diet. The tibial metaphysis was scanned by in vivo micro-computed tomography (μCT) for trabecular architecture analysis from 10 to 26 weeks of age with 4-week interval. Then, the animal was blood-sampled before sacrifice, and the scanned tibia was harvested. The midlayer of a cortical cross-section was evaluated for mineral-to-matrix ratio, mineral maturity, and collagen maturity by Fourier transform infrared microspectroscopy and for stiffness and hardness by the nanoindentation test. Serum chemicals showed the successful induction of high-turnover CKD in Nx. The age-related regression of trabecular network was observed in both groups but to the higher degree in Nx. In vivo μCT revealed significant interactions between age and CKD in trabecular number, thickness, and separation. On the other hand, the chemical and mechanical properties of cortical bone did not differ significantly between Nx and Sham. Thus, the compromised trabecular architecture will be contributory to bone fragility in high-turnover CKD.