Determinants of bone damage: An ex-vivo study on porcine vertebrae

Bone\u2019s resistance to fracture depends on several factors, such as bone mass, microarchitecture, and tissue material properties. The clinical assessment of bone strength is generally performed by Dual-X Ray Photon Absorptiometry (DXA), measuring bone mineral density (BMD) and trabecular bone score (TBS). Although it is considered the major predictor of bone strength, BMD only accounts for about 70% of fragility fractures, while the remaining 30% could be described by bone \u201cquality\u201d impairment parameters, mainly related to tissue microarchitecture. The assessment of bone microarchitecture generally requires more invasive techniques, which are not applicable in routine clinical practice, or X-Ray based imaging techniques, requiring a longer post-processing. Another important aspect is the presence of local damage in the bony tissue that may also affect the prediction of bone strength and fracture risk. To provide a more comprehensive analysis of bone quality and quantity, and to assess the effect of damage, here we adopt a framework that includes clinical, morphological, and mechanical analyses, carried out by means of DXA, \u3bcCT and mechanical compressive testing, respectively. This study has been carried out on trabecular bones, taken from porcine trabecular vertebrae, for the similarity with human lumbar spine. This study confirms that no single method can provide a complete characterization of bone tissue, and the combination of complementary characterization techniques is required for an accurate and exhaustive description of bone status. BMD and TBS have shown to be complementary parameters to assess bone strength, the former assessing the bone quantity and resistance to damage, and the latter the bone quality and the presence of damage accumulation without being able to predict the risk of fracture

Mapping Trabecular Bone Fabric Tensor by in Vivo Magnetic Resonance Imaging

The mechanical competence of bone depends upon its quantity, structural arrangement, and chemical composition. Assessment of these factors is important for the evaluation of bone integrity, particularly as the skeleton remodels according to external (e.g. mechanical loading) and internal (e.g. hormonal changes) stimuli. Micro magnetic resonance imaging (µMRI) has emerged as a non-invasive and non-ionizing method well-suited for the repeated measurements necessary for monitoring changes in bone integrity. However, in vivo image-based directional dependence of trabecular bone (TB) has not been linked to mechanical competence or fracture risk despite the existence of convincing ex vivo evidence. The objective of this dissertation research was to develop a means of capturing the directional dependence of TB by assessing a fabric tensor on the basis of in vivo µMRI. To accomplish this objective, a novel approach for calculating the TB fabric tensor based on the spatial autocorrelation function was developed and evaluated in the presence of common limitations to in vivo µMRI. Comparisons were made to the standard technique of mean-intercept-length (MIL). Relative to MIL, ACF was identified as computationally faster by over an order of magnitude and more robust within the range of the resolutions and SNRs achievable in vivo. The potential for improved sensitivity afforded by isotropic resolution was also investigated in an improved µMR imaging protocol at 3T. Measures of reproducibility and reliability indicate the potential of images with isotropic resolution to provide enhanced sensitivity to orientation-dependent measures of TB, however overall reproducibility suffered from the sacrifice in SNR. Finally, the image-derived TB fabric tensor was validated through its relationship with TB mechanical competence in specimen and in vivo µMR images. The inclusion of trabecular bone fabric measures significantly improved the bone volume fraction-based prediction of elastic constants calculated by micro-finite element analysis. This research established a method for detecting TB fabric tensor in vivo and identified the directional dependence of TB as an important determinant of TB mechanical competence

3-D visualization and prediction of spine fractures under axial loading

Thesis (Ph.D.)--Boston UniversityVertebral fractures are the hallmark of osteoporosis, yet the failure mechanisms involved in these fractures are not well understood. Current approaches to predicting fracture risk rely on average measures of bone mineral density in the vertebra, which are imperfect predictors of vertebral strength and poor predictors of fracture risk. Prior research has established that substantial regional variations in density exist throughout the vertebra and has suggested several biomechanical consequences of these variations. The overall goal of this dissertation was to characterize failure mechanisms in human vertebrae, with specific emphasis on the role of intra-vertebral heterogeneity in density and microstructure and on identifying clinically feasible techniques for predicting fracture risk. Using images obtained from micro-computed tomography (μCT) and quantitative computed tomography (QCT), the intra-vertebral heterogeneity in bone density was quantified in cadaveric specimens. Quantitative measures of this heterogeneity improved predictions of vertebral strength as compared to predictions based only on mean density. Subsequently, the intra-vertebral heterogeneity in density was measured via QCT in a cohort of post-menopausal women and was found to be lower in those who had sustained a vertebral fracture vs. in age-matched individuals without fracture. The next set of studies focused on assessing the accuracy of finite element (FE) models for predicting vertebral failure. Digital volume correlation (DVC) was used to measure the deformations sustained throughout the vertebra during compression tests. These results were compared against deformation patterns predicted using FE models created from QCT images of the vertebrae. Good agreement was found between predicted and measured deformations when the boundary conditions were accurately defined, despite simplifications made in representing material properties. The outcomes from this dissertation demonstrate that the intra-vertebral heterogeneity in density contributes to bone strength and has promise as a clinically feasible indicator of fracture risk. OCT-based FE models, which by definition account for this heterogeneity, are another promising technique, yet will likely require non-invasive techniques for estimating vertebral loading to provide the requisite accuracy in failure predictions. These two engineering approaches that account for the spatial heterogeneity in density within the vertebra may lead to more sensitive and specific indicators of fracture risk

Stochastic Assessment of Bone Fragility in Human Lumbar Spine

Osteoporotic fractures are a vital public health concern and create a great economic burden for our society. It is estimated that more than 2 million fractures occur in the United States at a cost of $17 billion each year. Deterioration of microarchitecture of trabecular bone is considered as a major contributor to bone fragility. Current clinical imaging modalities such as Dual-energy X-ray absorptiometry (DXA) are not able to describe bone microarchitecture due to their low resolution. The main objective of this study was to obtain the relationship between stochastic parameters calculated from bone mineral density (BMD) maps of DXA scans and the microarchitecture parameters measured from three dimensional (3D) images of human lumbar vertebrae acquired using a Micro-Computed Tomography (Micro-CT) scanner. Eighteen human lumbar vertebrae with intact posterior elements were scanned in the posterior-anterior projection using a DXA scanner. Stochastic parameters such as correlation length (L), sill variance (C) and nugget variance ( ) were calculated by fitting a theoretical model onto the experimental variogram of the BMD map of the human vertebrae. In addition, microarchitecture parameters such as bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), trabecular number (Tb.N), connectivity density (Conn.Dn), and bone surface-to-volume ratio (BS/BV) were measured from 3D images of the same human lumbar vertebrae. Significant correlations were observed between stochastic predictors and microarchitecture parameters of trabecular bone. Specifically, the sill variance was positively correlated with the bone volume fraction, trabecular thickness, trabecular number, connectivity density and negatively correlated with the bone surface to volume ratio and trabecular separation. This study demonstrates that stochastic assessment of the inhomogeneity of bone mineral density from routine clinical DXA scans of human lumbar vertebrae may have the potential to serve as a valuable clinical tool in enhancing the prediction of risks for osteoporotic fractures in the spine. The main advantage of using DXA scans is that it would be cost effective, since most hospitals already have DXA machines and there would be no need for purchasing new equipment

Role of Trabecular Microarchitecture and Its Heterogeneity Parameters in the Mechanical Behavior of Ex Vivo Human L3 Vertebrae

Low bone mineral density (BMD) is a strong risk factor for vertebral fracture risk in osteoporosis. However, many fractures occur in people with moderately decreased or normal BMD. Our aim was to assess the contributions of trabecular microarchitecture and its heterogeneity to the mechanical behavior of human lumbar vertebrae. Twenty-one human L3 vertebrae were analyzed for BMD by dual-energy X-ray absorptiometry (DXA) and microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) and then tested in axial compression. Microarchitecture heterogeneity was assessed using two vertically oriented virtual biopsies—one anterior (Ant) and one posterior (Post)—each divided into three zones (superior, middle, and inferior) and using the whole vertebral trabecular volume for the intraindividual distribution of trabecular separation (Tb.Sp*SD). Heterogeneity parameters were defined as (1) ratios of anterior to posterior microarchitectural parameters and (2) the coefficient of variation of microarchitectural parameters from the superior, middle, and inferior zones. BMD alone explained up to 44% of the variability in vertebral mechanical behavior, bone volume fraction (BV/TV) up to 53%, and trabecular architecture up to 66%. Importantly, bone mass (BMD or BV/TV) in combination with microarchitecture and its heterogeneity improved the prediction of vertebral mechanical behavior, together explaining up to 86% of the variability in vertebral failure load. In conclusion, our data indicate that regional variation of microarchitecture assessment expressed by heterogeneity parameters may enhance prediction of vertebral fracture risk. © 2010 American Society for Bone and Mineral Research

Development of Functional Interactions Among Cortical and Trabecular Traits During Growth of the Lumbar Vertebral Body

Variation in bone traits that contribute to increased fracture risk in the elderly is mainly established in adulthood. Previous studies have shown that in adults, cortical and trabecular traits are functionally related. How variations in traits develop to establish mechanical function in adult bone is not well understood. In this study, we examined temporal changes in the development of cortical and trabecular traits during growth in mouse lumbar vertebral body structures that have a wide range of genetic variants. We determined a sequence of events among traits that would suggest how functional bone structures developed. Examining bones in A/J, C57/BL6 and C3H/HeJ inbred mouse strains during postnatal growth, we identified inter-strain variation in trabecular architectural traits as seen in adult strains were established by 1 week of age while inter-strain variation in cortical area largely occurred after 4 weeks of age. Across a panel of 20 AXB/BXA Recombinant Inbred mouse strains, we observed a similar sequence in trait development from 4 weeks of age to 16 weeks of age. In addition, the alignment of trabeculae was shown to be a primary variant relative to bone size at an early age. Vertebral bodies that tended to show a large increase in trabecular alignment from 4 weeks of age to 16 weeks of age tended to show a small increase in cortical area over time. However, load borne on the trabecular bone region from 4 weeks of age despite trabecular alignment was important for mechanical stiffness and strength throughout growth. The interaction of anisotropy and bone size in conjunction with the interaction between load sharing and trabecular bone volume at an early age suggested predictive patterns in how traits changed over time relative to bone size. Together these results have great clinical significance because they provide a novel way of assessing mechanical function of the skeletal system by means of coordination of traits and benefit development of predictive models of fracture risk in humans. Understanding the interaction of corticocancellous traits during growth has important implications for genetic analyses and for interpreting the response of bone to genetic and environmental perturbations

Micro Finite Element models of the vertebral body: Validation of local displacement predictions

The estimation of local and structural mechanical properties of bones with micro Finite Element (microFE) models based on Micro Computed Tomography images depends on the quality bone geometry is captured, reconstructed and modelled. The aim of this study was to validate microFE models predictions of local displacements for vertebral bodies and to evaluate the effect of the elastic tissue modulus on model’s predictions of axial forces. Four porcine thoracic vertebrae were axially compressed in situ, in a step-wise fashion and scanned at approximately 39μm resolution in preloaded and loaded conditions. A global digital volume correlation (DVC) approach was used to compute the full-field displacements. Homogeneous, isotropic and linear elastic microFE models were generated with boundary conditions assigned from the interpolated displacement field measured from the DVC. Measured and predicted local displacements were compared for the cortical and trabecular compartments in the middle of the specimens. Models were run with two different tissue moduli defined from microindentation data (12.0GPa) and a back-calculation procedure (4.6GPa). The predicted sum of axial reaction forces was compared to the experimental values for each specimen. MicroFE models predicted more than 87% of the variation in the displacement measurements (R2 = 0.87–0.99). However, model predictions of axial forces were largely overestimated (80–369%) for a tissue modulus of 12.0GPa, whereas differences in the range 10–80% were found for a back-calculated tissue modulus. The specimen with the lowest density showed a large number of elements strained beyond yield and the highest predictive errors. This study shows that the simplest microFE models can accurately predict quantitatively the local displacements and qualitatively the strain distribution within the vertebral body, independently from the considered bone types

Imaging techniques for the assessment of the bone osteoporosis-induced variations with particular focus on micro-ct potential

For long time, osteoporosis (OP) was exclusively associated with an overall bone mass reduction, leading to lower bone strength and to a higher fracture risk. For this reason, the measurement of bone mineral density through dual X-ray absorptiometry was considered the gold standard method for its diagnosis. However, recent findings suggest that OP causes a more complex set of bone alterations, involving both its microstructure and composition. This review aims to provide an overview of the most evident osteoporosis-induced alterations of bone quality and a résumé of the most common imaging techniques used for their assessment, at both the clinical and the laboratory scale. A particular focus is dedicated to the micro-computed tomography (micro-CT) due to its superior image resolution, allowing the execution of more accurate morphometric analyses, better highlighting the architectural alterations of the osteoporotic bone. In addition, micro-CT has the potential to perform densitometric measurements and finite element method analyses at the microscale, representing potential tools for OP diagnosis and for fracture risk prediction. Unfortunately, technological improvements are still necessary to reduce the radiation dose and the scanning duration, parameters that currently limit the application of micro-CT in clinics for OP diagnosis, despite its revolutionary potential

Structure model index does not measure rods and plates in trabecular bone

Structure model index (SMI) is widely used to measure rods and plates in trabecular bone. It exploits the change in surface curvature that occurs as a structure varies from spherical (SMI = 4), to cylindrical (SMI = 3) to planar (SMI = 0). The most important assumption underlying SMI is that the entire bone surface is convex and that the curvature differential is positive at all points on the surface. The intricate connections within the trabecular continuum suggest that a high proportion of the surface could be concave, violating the assumption of convexity and producing regions of negative differential. We implemented SMI in the BoneJ plugin and included the ability to measure the amounts of surface that increased or decreased in area after surface mesh dilation, and the ability to visualize concave and convex regions. We measured SMI and its positive (SMI+) and negative (SMI-) components, bone volume fraction (BV/TV), the fraction of the surface that is concave (CF), and mean ellipsoid factor (EF) in trabecular bone using 38 X-ray microtomography (XMT) images from a rat ovariectomy model of sex steroid rescue of bone loss, and 169 XMT images from a broad selection of 87 species' femora (mammals, birds, and a crocodile). We simulated bone resorption by eroding an image of elephant trabeculae and recording SMI and BV/TV at each erosion step. Up to 70%, and rarely less than 20%, of the trabecular surface is concave (CF 0.155 – 0.700). SMI is unavoidably influenced by aberrations from SMI-, which is strongly correlated with BV/TV and CF. The plate-to-rod transition in bone loss is an erroneous observation resulting from SMI's close and artefactual relationship with BV/TV. SMI cannot discern between the distinctive trabecular geometries typical of mammalian and avian bone, whereas EF clearly detects birds' more plate-like trabeculae. EF is free from confounding relationships with BV/TV and CF. SMI results reported in the literature should be treated with suspicion. We propose that EF should be used instead of SMI for measurements of rods and plates in trabecular bone