Prediction of adjacent vertebral fracture risk associated with vertebroplasty : a computer-based simulation study

Vertebrplasty involved injecting cement into a fractured vertebra to provide stabilisation. There is clinical evidence to suggest however that vertebroplasty may be assocated with a higher risk of adjacent vertebral fracture; which may be due to the change in material properties of the post-procedure vertebra modifying the transmission of mechanical stresses to adjacent vertebrae.

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

An experimental and finite element investigation of the biomechanics of vertebral compression fractures

Osteoporosis is a disease characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporosis affects over 200 million people worldwide, with an estimated 1.5 million fractures annually in the United States alone, and with attendant costs exceeding $10 billion dollars per annum. Osteoporosis reduces bone density through a series of structural changes to the honeycomb-like trabecular bone structure (micro-structure). The reduced bone density, coupled with the microstructural changes, results in significant loss of bone strength and increased fracture risk. Vertebral compression fractures are the most common type of osteoporotic fracture and are associated with pain, increased thoracic curvature, reduced mobility, and difficulty with self care. Surgical interventions, such as kyphoplasty or vertebroplasty, are used to treat osteoporotic vertebral fractures by restoring vertebral stability and alleviating pain. These minimally invasive procedures involve injecting bone cement into the fractured vertebrae. The techniques are still relatively new and while initial results are promising, with the procedures relieving pain in 70-95% of cases, medium-term investigations are now indicating an increased risk of adjacent level fracture following the procedure. With the aging population, understanding and treatment of osteoporosis is an increasingly important public health issue in developed Western countries. The aim of this study was to investigate the biomechanics of spinal osteoporosis and osteoporotic vertebral compression fractures by developing multi-scale computational, Finite Element (FE) models of both healthy and osteoporotic vertebral bodies. The multi-scale approach included the overall vertebral body anatomy, as well as a detailed representation of the internal trabecular microstructure. This novel, multi-scale approach overcame limitations of previous investigations by allowing simultaneous investigation of the mechanics of the trabecular micro-structure as well as overall vertebral body mechanics. The models were used to simulate the progression of osteoporosis, the effect of different loading conditions on vertebral strength and stiffness, and the effects of vertebroplasty on vertebral and trabecular mechanics. The model development process began with the development of an individual trabecular strut model using 3D beam elements, which was used as the building block for lattice-type, structural trabecular bone models, which were in turn incorporated into the vertebral body models. At each stage of model development, model predictions were compared to analytical solutions and in-vitro data from existing literature. The incremental process provided confidence in the predictions of each model before incorporation into the overall vertebral body model. The trabecular bone model, vertebral body model and vertebroplasty models were validated against in-vitro data from a series of compression tests performed using human cadaveric vertebral bodies. Firstly, trabecular bone samples were acquired and morphological parameters for each sample were measured using high resolution micro-computed tomography (CT). Apparent mechanical properties for each sample were then determined using uni-axial compression tests. Bone tissue properties were inversely determined using voxel-based FE models based on the micro-CT data. Specimen specific trabecular bone models were developed and the predicted apparent stiffness and strength were compared to the experimentally measured apparent stiffness and strength of the corresponding specimen. Following the trabecular specimen tests, a series of 12 whole cadaveric vertebrae were then divided into treated and non-treated groups and vertebroplasty performed on the specimens of the treated group. The vertebrae in both groups underwent clinical-CT scanning and destructive uniaxial compression testing. Specimen specific FE vertebral body models were developed and the predicted mechanical response compared to the experimentally measured responses. The validation process demonstrated that the multi-scale FE models comprising a lattice network of beam elements were able to accurately capture the failure mechanics of trabecular bone; and a trabecular core represented with beam elements enclosed in a layer of shell elements to represent the cortical shell was able to adequately represent the failure mechanics of intact vertebral bodies with varying degrees of osteoporosis. Following model development and validation, the models were used to investigate the effects of progressive osteoporosis on vertebral body mechanics and trabecular bone mechanics. These simulations showed that overall failure of the osteoporotic vertebral body is initiated by failure of the trabecular core, and the failure mechanism of the trabeculae varies with the progression of osteoporosis; from tissue yield in healthy trabecular bone, to failure due to instability (buckling) in osteoporotic bone with its thinner trabecular struts. The mechanical response of the vertebral body under load is highly dependent on the ability of the endplates to deform to transmit the load to the underlying trabecular bone. The ability of the endplate to evenly transfer the load through the core diminishes with osteoporosis. Investigation into the effect of different loading conditions on the vertebral body found that, because the trabecular bone structural changes which occur in osteoporosis result in a structure that is highly aligned with the loading direction, the vertebral body is consequently less able to withstand non-uniform loading states such as occurs in forward flexion. Changes in vertebral body loading due to disc degeneration were simulated, but proved to have little effect on osteoporotic vertebra mechanics. Conversely, differences in vertebral body loading between simulated invivo (uniform endplate pressure) and in-vitro conditions (where the vertebral endplates are rigidly cemented) had a dramatic effect on the predicted vertebral mechanics. This investigation suggested that in-vitro loading using bone cement potting of both endplates has major limitations in its ability to represent vertebral body mechanics in-vivo. And lastly, FE investigation into the biomechanical effect of vertebroplasty was performed. The results of this investigation demonstrated that the effect of vertebroplasty on overall vertebra mechanics is strongly governed by the cement distribution achieved within the trabecular core. In agreement with a recent study, the models predicted that vertebroplasty cement distributions which do not form one continuous mass which contacts both endplates have little effect on vertebral body stiffness or strength. In summary, this work presents the development of a novel, multi-scale Finite Element model of the osteoporotic vertebral body, which provides a powerful new tool for investigating the mechanics of osteoporotic vertebral compression fractures at the trabecular bone micro-structural level, and at the vertebral body level.

Development of a multi-scale finite element model of the osteoporotic lumbar vertebral body for the investigation of apparent level vertebra mechanics and micro-level trabecular mechanics.

Osteoporotic spinal fractures are a major concern in ageing Western societies. This study develops a multi-scale finite element (FE) model of the osteoporotic lumbar vertebral body to study the mechanics of vertebral compression fracture at both the apparent (whole vertebral body) and micro-structural (internal trabecular bone core)levels. Model predictions were verified against experimental data, and found to provide a reasonably good representation of the mechanics of the osteoporotic vertebral body. This novel modelling methodology will allow detailed investigation of how trabecular bone loss in osteoporosis affects vertebral stiffness and strength in the lumbar spine.

The anatomical and biomechanical consequences of anterior vertebral stapling for the fusionless correction of scoliosis

Fusionless scoliosis surgery is an emerging treatment for idiopathic scoliosis as it offers theoretical advantages over current forms of treatment. Anterior vertebral stapling using a nitinol staple is one such treatment. Despite increasing interest in this technique, little is known about the effects on the spine following insertion, or the mechanism of action of the staple. The aims of this study were threefold; (1) to measure changes in the bending stiffness of a single motion segment following staple insertion, (2) to describe the forces that occur within the staple during spinal movement, and (3) to describe the anatomical changes that occur following staple insertion. Results suggest that staple insertion consistently decreased stiffness in all directions of motion. An explanation for the finding may be found in the outcomes of the strain gauge testing and micro-CT scan. The strain gauge testing showed that once inserted, the staple tips applied a baseline compressive force to the surrounding trabecular bone and vertebral end-plate. This finding would be consistent with the current belief that the clinical effect of the staples is via unilateral compression of the physis. Interestingly however, as each specimen progressed through the five cycles of each test, the baseline load on the staple tips gradually decreased, implying that the force at the staple tip-bone interface was decreasing. We believe that this was likely occurring as a result of structural damage to the trabecular bone and vertebral end-plate by the staple effectively causing ‘loosening’ of the staple. This hypothesis is further supported by the findings of the micro-CT scan. The pictures depict significant trabecular bone and physeal injury around the staple blades. These results suggest that the current hypothesis that stapling modulates growth through physeal compression may be incorrect, but rather the effect occurs through mechanical disruption of the vertebral growth plate.

Computed tomography evaluation of axial vertebral derotation in endoscopic anterior instrumentation for adolescent idiopathic scoliosis

Thoracoscopic instrumented anterior spinal fusion for adolescent idiopathic scoliosis (AIS) has clinical benefits that include reduced pulmonary morbidity, postoperative pain, and improved cosmesis. However, quantitative data on radiological improvement of vertebral rotation using this method is lacking. This study’s objectives were to measure preoperative and postoperative axial vertebral rotational deformity at the curve apex in endoscopically-treated anterior-instrumented scoliosis patients using CT, and assess the relevance of these findings to clinically measured chest wall rib hump deformity correction. This is the first quantitative CT study to confirm that endoscopic anterior instrumented fusion for AIS substantially improves axial vertebral body rotational deformity at the apex of the curve. The margin of correction of 43% compares favourably with historically published figures of 24% for patients with posterior all-hook-rod constructs. CT measurements correlated significantly to the clinical outcome of rib hump deformity correction.

The effect of insertion time on the axial pullout strength of anterior vertebral body screws

Top screw pullout occurs when the screw is under too much axial force to remain secure in the vertebral body. In vitro biomechanical pullout tests are commonly done to find the maximum fixation strength of anterior vertebral body screws. Typically, pullout tests are done instantaneously where the screw is inserted and then pulled out immediately after insertion. However, bone is a viscoelastic material so it shows a time dependent stress and strain response. Because of this property, it was hypothesised that creep occurs in the vertebral trabecular bone due to the stress caused by the screw. The objective of this study was therefore to determine whether the axial pullout strength of anterior vertebral body screws used for scoliosis correction surgery changes with time after insertion. This study found that there is a possible relationship between pullout strength and time; however more testing is required as the sample numbers were quite small. The design of the screw is made with the knowledge of the strength it must obtain. This is important to prevent such occurrences as top screw pullout. If the pullout strength is indeed decreased due to creep, the design of the screw may need to be changed to withstand greater forces.

Simulation of the nutrient supply in fracture healing

The healing process for bone fractures is sensitive to mechanical stability and blood supply at the fracture site. Most currently available mechanobiological algorithms of bone healing are based solely on mechanical stimuli, while the explicit analysis of revascularization and its influences on the healing process have not been thoroughly investigated in the literature. In this paper, revascularization was described by two separate processes: angiogenesis and nutrition supply. The mathematical models for angiogenesis and nutrition supply have been proposed and integrated into an existing fuzzy algorithm of fracture healing. The computational algorithm of fracture healing, consisting of stress analysis, analyses of angiogenesis and nutrient supply, and tissue differentiation, has been tested on and compared with animal experimental results published previously. The simulation results showed that, for a small and medium-sized fracture gap, the nutrient supply is sufficient for bone healing, for a large fracture gap, non-union may be induced either by deficient nutrient supply or inadequate mechanical conditions. The comparisons with experimental results demonstrated that the improved computational algorithm is able to simulate a broad spectrum of fracture healing cases and to predict and explain delayed unions and non-union induced by large gap sizes and different mechanical conditions. The new algorithm will allow the simulation of more realistic clinical fracture healing cases with various fracture gaps and geometries and may be helpful to optimise implants and methods for fracture fixation.

Modelling the effects of bone fragment contact in fracture healing

The fracture healing process is modulated by the mechanical environment created by imposed loads and motion between the bone fragments. Contact between the fragments obviously results in a significantly different stress and strain environment to a uniform fracture gap containing only soft tissue (e.g. haematoma). The assumption of the latter in existing computational models of the healing process will hence exaggerate the inter-fragmentary strain in many clinically-relevant cases. To address this issue, we introduce the concept of a contact zone that represents a variable degree of contact between cortices by the relative proportions of bone and soft tissue present. This is introduced as an initial condition in a two-dimensional iterative finite element model of a healing tibial fracture, in which material properties are defined by the volume fractions of each tissue present. The algorithm governing the formation of cartilage and bone in the fracture callus uses fuzzy logic rules based on strain energy density resulting from axial compression. The model predicts that increasing the degree of initial bone contact reduces the amount of callus formed (periosteal callus thickness 3.1mm without contact, down to 0.5mm with 10% bone in contact zone). This is consistent with the greater effective stiffness in the contact zone and hence, a smaller inter-fragmentary strain. These results demonstrate that the contact zone strategy reasonably simulates the differences in the healing sequence resulting from the closeness of reduction.

Good clinical endpoints with denosumab in osteoporosis and cancer

Background: Bone loss associated with low oestrogen levels in postmenopausal women, and with androgen deprivation therapy in men with hormone-sensitive prostate cancer, result in an increased incidence of fractures. Denosumab has been shown to increase bone mineral density in these two conditions. Objectives/methods: The objective of this evaluation is to review the clinical trials that have studied clinical endpoints in these conditions. Results: FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) was an International Phase III clinical trial that measured the clinical endpoints with denosumab in postmenopausal women with osteoporosis. At 36 months, new vertebral fractures had occurred in 7.2% of subjects in the placebo group and this was lowered to 2.3% of subjects treated with denosumab. HALT (Denosumab Hormone Ablation Bone Loss Trial) studied the clinical endpoints in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. The incidence of vertebral fractures was significantly lower in the denosumab group (1.5%) than in the placebo group (3.9%). The incidence of adverse effects with denosumab in both clinical trials was low. Conclusions: Denosumab reduces the incidence of fractures in postmenopausal women with osteoporosis and in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. Denosumab is well tolerated.

Anterior vertebral stapling for the fusionless correction of scoliosis

Fusionless scoliosis surgery is an emerging treatment for idiopathic scoliosis as it offers theoretical advantages over current forms of treatment. Currently the treatment options for idiopathic scoliosis are observation, bracing and fusion. While brace treatment is non-invasive, and preserves the growth, motion, and function of the spine, it does not correct deformity and is only modestly successful in preventing curve progression. In adolescents who fail brace treatment, surgical treatment with an instrumented spinal fusion usually results in better deformity correction but is associated with substantially greater risk. Furthermore in younger patients requiring surgical treatment, fusion procedures are known to adversely effect the future growth of the chest and spine. Fusionless treatments have been developed to allow effective surgical treatment of patients with idiopathic scoliosis who are too young for fusion procedures. Anterior vertebral stapling is one such fusionless treatment which aims to modulate the growth of vertebra to allow correction of scoliosis whilst maintaining normal spinal motion The Mater Misericordiae Hospital in Brisbane has begun to use anterior vertebral stapling to treat patients with idiopathic scoliosis who are too young for fusion procedures. Currently the only staple approved for clinical use is manufactured by Medtronic Sofamor Danek (Memphis, TN). This thesis explains the biomechanical and anatomical changes that occur following anterior vertebral staple insertion using in vitro experiments performed on an immature bovine model. Currently there is a paucity of published information about anterior vertebral stapling so it is hoped that this project will provide information that will aid in our understanding of the clinical effects of staple insertion. The aims of this experimental study were threefold. The first phase was designed to determine the changes in the bending stiffness of the spine following staple insertion. The second phase was designed to measure the forces experienced by the staple during spinal movements. The third and final phase of testing was designed to describe the structural changes that occur to a vertebra as a consequence of staple insertion. The first phase of testing utilised a displacement controlled testing robot to compare the change in stiffness of a single spinal motion segment following staple insertion for the three basic spinal motions of flexion-extension, lateral bending, and axial rotation. For the second phase of testing strain gauges were attached to staples and used to measure staple forces during spinal movement. In the third and final phase the staples were removed and a testing specimen underwent micro-computed tomography (CT) scanning to describe the anatomical changes that occur following staple insertion. The displacement controlled testing showed that there was a significant decrease in bending stiffness in flexion, extension, lateral bending away from the staple, and axial rotation away from the staple following staple insertion. The strain gauge measurements showed that the greatest staple forces occurred in flexion and the least in extension. In addition, a reduction in the baseline staple compressive force was seen with successive loading cycles. Micro-CT scanning demonstrated that significant damage to the vertebral body and endplate occurred as a consequence of staple insertion. The clinical implications of this study are significant. Based on the findings of this project it is likely that the clinical effect of the anterior vertebral staple evaluated in this project is a consequence of growth plate damage (also called hemiepiphysiodesis) causing a partial growth arrest of the vertebra rather than simply compression of the growth plate. The surgical creation of a unilateral growth arrest is a well established treatment used in the management of congenital scoliosis but has not previously been considered for use in idiopathic scoliosis.

Scale-dependent fracture mode in Cu-Ni laminate composites

Fracture behavior of Cu-Ni laminate composites has been investigated by tensile testing. It was found that as the individual layer thickness decreases from 100 to 20nm, the resultant fracture angle of the Cu-Ni laminate changes from 72 degrees to 50 degrees. Cross-sectional observations reveal that the fracture of the Ni layers transforms from opening to shear mode as the layer thickness decreases while that of the Cu layers keeps shear mode. Competition mechanisms were proposed to understand the variation in fracture mode of the metallic laminate composites associated with length scale.