Estrogen Regulates the Satellite Cell Compartment in Females

Skeletal muscle mass, strength, and regenerative capacity decline with age, with many measures showing a greater deterioration in females around the time estrogen levels decrease at menopause. Here, we show that estrogen deficiency severely compromises the maintenance of muscle stem cells (i.e., satellite cells) as well as impairs self-renewal and differentiation into muscle fibers. Mechanistically, by hormone replacement, use of a selective estrogen-receptor modulator (bazedoxifene), and conditional estrogen receptor knockout, we implicate 17β-estradiol and satellite cell expression of estrogen receptor α and show that estrogen signaling through this receptor is necessary to prevent apoptosis of satellite cells. Early data from a biopsy study of women who transitioned from peri- to post-menopause are consistent with the loss of satellite cells coincident with the decline in estradiol in humans. Together, these results demonstrate an important role for estrogen in satellite cell maintenance and muscle regeneration in females

Mapping anisotropy improves QCT-based finite element estimation of hip strength in pooled stance and side-fall load configurations

Hip fractures are one of the most severe consequences of osteoporosis. Compared to the clinical standard of DXA-based aBMD at the femoral neck, QCT-based FEA delivers a better surrogate of femoral strength and gains acceptance for the calculation of hip fracture risk when a CT reconstruction is available. Isotropic, homogenised voxel-based, finite element (hvFE) models are widely used to estimate femoral strength in cross-sectional and longitudinal clinical studies. However, fabric anisotropy is a classical feature of the architecture of the proximal femur and the second determinant of the homogenised mechanical properties of trabecular bone. Due to the limited resolution, fabric anisotropy cannot be derived from clinical CT reconstructions. Alternatively, fabric anisotropy can be extracted from HR-pQCT images of cadaveric femora. In this study, fabric anisotropy from HR-pQCT images was mapped onto QCT-based hvFE models of 71 human proximal femora for which both HR-pQCT and QCT images were available. Stiffness and ultimate load computed from anisotropic hvFE models were compared with previous biomechanical tests in both stance and side-fall configurations. The influence of using the femur-specific versus a mean fabric distribution on the hvFE predictions was assessed. Femur-specific and mean fabric enhance the prediction of experimental ultimate force for the pooled, i.e. stance and side-fall, (isotropic: r2=0.81, femur-specific fabric: r2=0.88, mean fabric: r2=0.86,p<0.001) but not for the individual configurations. Fabric anisotropy significantly improves bone strength prediction for the pooled configurations, and mapped fabric provides a comparable prediction to true fabric. The mapping of fabric anisotropy is therefore expected to help generate more accurate QCT-based hvFE models of the proximal femur for personalised or multiple load configurations

A novel contact interaction formulation for voxel-based micro-finite-element models of bone

Voxel-based micro-finite-element (μFE) models are used extensively in bone mechanics research. A major disadvantage of voxel-based μFE models is that voxel surface jaggedness causes distortion of contact-induced stresses. Past efforts in resolving this problem have only been partially successful, ie, mesh smoothing failed to preserve uniformity of the stiffness matrix, resulting in (excessively) larger solution times, whereas reducing contact to a bonded interface introduced spurious tensile stresses at the contact surface. This paper introduces a novel "smooth" contact formulation that defines gap distances based on an artificial smooth surface representation while using the conventional penalty contact framework. Detailed analyses of a sphere under compression demonstrated that the smooth formulation predicts contact-induced stresses more accurately than the bonded contact formulation. When applied to a realistic bone contact problem, errors in the smooth contact result were under 2%, whereas errors in the bonded contact result were up to 42.2%. We conclude that the novel smooth contact formulation presents a memory-efficient method for contact problems in voxel-based μFE models. It presents the first method that allows modeling finite slip in large-scale voxel meshes common to high-resolution image-based models of bone while keeping the benefits of a fast and efficient voxel-based solution scheme

Dementia-friendly interventions to improve the care of people living with dementia admitted to hospitals: a realist review

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Objectives: To identify features of programmes and approaches to make healthcare delivery in secondary healthcare settings more dementia friendly, providing a context-relevant understanding of how interventions achieve outcomes for people living with dementia. Design: A realist review conducted in three phases (1) stakeholder interviews and scoping of the literature to develop an initial programme theory for providing effective dementia care; (2) structured retrieval and extraction of evidence; (3) analysis and synthesis to build and refine the programme theory. Data sources: PubMed, CINAHL, Cochrane Library, NHS Evidence, Scopus, grey literature. Eligibility criteria: Studies reporting interventions and approaches to make hospital environments more dementia friendly. Studies not reporting patient outcomes or contributing to the programme theory were excluded. Results: Phase 1 combined findings from 15 stakeholder interviews and 22 publications to develop candidate programme theories. Phases 2 and 3 identified and synthesised evidence from 28 publications. Prominent context-mechanism-outcome configurations were identified to explain what supported dementia-friendly healthcare in acute settings. Staff capacity to understand the behaviours of people living with dementia as communication of an unmet need, combined with a recognition and valuing of their role in their care prompted changes to care practices. Endorsement from senior management gave staff confidence and permission to adapt working practices to provide good dementia care. Key contextual factors were the availability of staff and an alignment of ward priorities to value person-centred care approaches. Preoccupation with risk generated responses that were likely to restrict patient choice and increase their distress. Conclusions: This review suggests strategies such as dementia awareness training alone will not improve dementia care or outcomes for patients with dementia. Instead, how staff are supported to implement learning and resources by senior team members with dementia expertise is a key component for improving care practices and patient outcomes. PROSPERO Trial Registration Number: CRD42015017562Peer reviewedFinal Published versio

Mapping Anisotropy of the Proximal Femur for Improved Image-Based Finite Element Analysis

Finite element (FE) models of bone derived from clinical quantitative computed tomography (QCT) rely on realistic material properties to accurately predict patient-specific bone strength in vivo. QCT cannot resolve microarchitecture, therefore QCT-based FE models lack the directionality apparent within trabecular bone. Maps of anisotropy were constructed from high-resolution peripheral QCT (HR-pQCT) images of seven femur specimens using a „direct mechanics‟ method to measure local anisotropy. The resulting directionality reflected all the major structural patterns visible within the microarchitecture of the proximal femur. Principal stiffness directions were interpolated into QCT-based femur models, and whole bone stiffness was calculated for orthotropic and isotropic models in a sideways fall configuration. Comparing model stiffness to experimental data revealed no difference in correlation (R2ORTH = 0.780, R2ISO = 0.788). These results suggest that the variability in stiffness explained by anisotropy at the microarchitecture level does not scale to whole bone models for this specific loading configuration

Identifying Individuals Predisposed to Hip Fracture

The incidence of hip fracture in western society is becoming an increasingly serious concern as the population ages. While the economic and social costs are on the rise, the number of patients receiving treatment for bone fragility is in decline. Addressing this treatment gap should begin by investigating the relatively weak diagnostic technology currently being utilized in standard clinical practice. With problems including low sensitivity and a high rate of over diagnosis, it is clear that better tools are required for identifying individuals predisposed to hip fracture. Finite element (FE) models of the proximal femur derived from computed tomography have been proposed as a potential alternative. These simulations have outperformed areal bone mineral density (aBMD) measurements in predicting femoral strength within cadaver experiments, however FE models have not significantly outperformed conventional density measurements when predicting hip fracture from retrospective clinical data. The objective of this thesis was to address the limitations of state-of-the-art FE simulations of hip fracture in order to develop an improved hip fracture prediction model. A hip fracture is the result of a fall onto the hip, leading to an impact force greater than the load bearing capacity of the proximal femur. The three components of hip fracture, i.e. fall risk, fall severity, and bone strength, have typically been investigated individually, and no study thus far has attempted to fully characterize risk of fracture using a holistic understanding of all three aspects. This thesis attempts to address this knowledge gap, and was divided into three aims, each designed to enhance the biofidelity of FE simulations: In the first study, the anisotropy of trabecular bone was measured within numerous sub-volumes extracted from high-resolution scans using the conventional mean intercept length measurement. These anisotropic properties were subsequently mapped to FE models of the proximal femur, loaded in a sideways fall configuration. For the first time, isotropic and anisotropic models were compared using different material mapping strategies representing the extremes of previously published modeling techniques. The resulting whole bone stiffness and surface strains were then compared to cadaver experiments tested with similar boundary conditions. The addition of anisotropy had very little effect on whole bone stiffness and only a small effect on the resulting surface strain. Differences in principal compressive strain were identified in the femoral head, neck, and greater trochanter. The study concluded that anisotropic material properties, mapped using morphological measurements of high-resolution CT scans, has little impact on macroscopic, organ-level properties, but anisotropy could still affect localized internal strains, and could therefore be relevant depending on the modeling objectives. In the second study, a novel material mapping strategy was presented for explicit FE models of the proximal femur, validated with drop tower experiments. These non-linear material properties were designed to account for large deformations that could occur during an impact load on the hip. These properties included tensile damage, compressive densification, as well as tension/compression asymmetry and strain rate dependency. For the first time, the ultimate force predicted by the dynamic FE models was correlated with the ultimate force measured in dynamic experiments. Additionally, the simulated impulse response was strongly correlated with the force-time response measured in the drop tower experiments. Thus, these results represent the current benchmark in dynamic FE modeling of the proximal femur. Compressive strain rates over 100/s were observed in elements located in the femoral head, neck, and greater trochanter, suggesting that a better understanding of the strain rate dependency of bone tissue is still required for these loading rates. The dynamic models were able to simulate fracture patterns initiating in the sub-capital region, but were not able to predict inter-trochanteric fractures, suggesting that the material mapping strategy could still be improved in this anatomical region. The third study presented a biofidelic FE modeling technique that included models of the pelvis, soft tissue, and lower extremities that were morphed based on subject-specific biometrics. This approach was tested in a large, retrospective, clinical study to determine whether hip fracture classification models based on FE simulations provided a more accurate prediction of hip fracture incidence compared to clinical standard aBMD measurements. Logistic regression models based on simulated ultimate femur force, and surface strain in the femoral neck, marginally outperformed aBMD in terms of sensitivity and specificity, however the differences were not significant until subjects that did not report falling at baseline were excluded from the analysis. This resulted in a statistically significant difference between the simulated surface strain at the femoral neck and total femur aBMD, with AUC values of 0.85 and 0.74, respectively. These results indicate that subject-specific fall risk must be accurately estimated before mechanical assessments of fracture risk can be compared. This also suggested that fall risk could be a useful parameter for pre-screening hip fracture risk in the population. Additionally, the large number of biofidelic models tested in this study provided a novel measurement of subject-specific impact force transmitted to the proximal femur. A linear regression model found that the variance in ultimate femur force could be explained as a function of soft tissue thickness, pelvis width, and femoral head radius (R$^2$ = 0.79; RMSE = 0.46 kN). This thesis has made several important contributions to the field of hip fracture biomechanics. It has demonstrated that simulating anisotropic tissue-level properties had minimal effect on organ-level mechanics, relative to changes in the material properties. A novel material mapping strategy for explicit FE models of the proximal femur was designed in the absence of model tuning, and subsequently validated against drop tower experiments. The importance of subject-specific soft tissue thickness and fall risk was demonstrated using biofidelic FE models tested in a large retrospective study, suggesting that femoral strength alone is insufficient for accurately characterizing hip fracture risk. Finally, this thesis has presented the strongest evidence, to date, that FE simulations can predict hip fracture more accurately than conventional aBMD measurements. However, this observation was statistically significant only when subjects with high risk of falling were tested. Looking forward, the retrospective study presented in this thesis could serve as the baseline for future in silico trials simulating prophylactic interventions using biofidelic FE models. This could enable a novel estimate of the potential reduction in hip fracture incidence resulting from a preventative treatment. In conclusion, FE simulations of have the potential to improve both diagnostic and treatment technology, which could lead to meaningful change in the current standard of care for individuals predisposed to hip fracture

Correction: On the internal reaction forces, energy absorption, and fracture in the hip during simulated sideways fall impact.

[This corrects the article DOI: 10.1371/journal.pone.0200952.]

On the internal reaction forces, energy absorption, and fracture in the hip during simulated sideways fall impact.

The majority of hip fractures have been reported to occur as a result of a fall with impact to the greater trochanter of the femur. Recently, we developed a novel cadaveric pendulum-based hip impact model and tested two cadaveric femur-pelvis constructs, embedded in a soft tissue surrogate. The outcome was a femoral neck fracture in a male specimen while a female specimen had no fracture. The aim of the present study was, first, to develop a methodology for constructing and assessing the accuracy of explicit Finite Element Models (FEMs) for simulation of sideways falls to the hip based on the experimental model. Second, to use the FEMs for quantifying the internal reaction forces and energy absorption in the hip during impact. Third, to assess the potential of the FEMs in terms of separating a femoral fracture endpoint from a non-fracture endpoint. Using a non-linear, strain rate dependent, and heterogeneous material mapping strategy for bone tissue in these models, we found the FEM-derived results to closely match the experimental test results in terms of impact forces and displacements of pelvic video markers up to the time of peak impact force with errors below 10%. We found the internal reaction forces in the femoral neck on the impact side to be approximately 35% lower than the impact force measured between soft tissue and ground for both specimens. In addition, we found the soft tissue to be the component that absorbed the largest part of the energy of the tissue types in the hip region. Finally, we found surface strain patterns derived from FEM results to match the fracture location and extent based on post testing x-rays of the specimens. This is the first study with quantitative data on the energy absorption in the pelvic region during a sideways fall

Larger vertebral endplate concavities cause higher failure load and work at failure under high-rate impact loading of rabbit spinal explants

Vertebral fractures are among the most common of all osteoporosis related fracture types and its risk assessment is largely based on bone quality measures. Morphometric parameters are not yet considered, although endplate thickness and concavity shape were found to be important in fracture prediction in low-rate tests. We hypothesized that, under high-rate impact loading, the shape and size of the central endplate concavity are of key importance for fracture prediction. Therefore, we tested rabbit spinal segment explants in vitro under high-rate impact loading. With a combination of microCT to describe endplate morphometry, high-speed video imaging, and impact force measurement, endplate morphometry was correlated to the mechanical response. We found that endplate concavity shape and volume were important in describing the mechanical response: larger concavities caused higher failure load. We suggest a model for the fracture mechanism under high-rate impact loading, considering the morphometry of the endplates: wider and more voluminous concavities are protective whereas steeper slopes of the concavity edges and increasing bone volume fraction of the central endplate moiety are disadvantageous. Therefore, the shape and size of endplate morphometry are important in vertebral fracture prediction and should be considered included in vertebral fracture risk assessment

Femoral strength and strains in sideways fall: Validation of finite element models against bilateral strain measurements

Low impact falls to the side are the main cause of hip fractures in elderly. Finite element (FE) models of the proximal femur may help in the assessment of patients at high risk for a hip fracture. However, extensive validation is essential before these models can be used in a clinical setting. This study aims to use strain measurements from bilateral digital image correlation to validate an FE model against ex vivo experimental data of proximal femora under a sideways fall loading condition. For twelve subjects, full-field strain measurements were available on the medial and lateral side of the femoral neck. In this study, subject-specific FE models were generated based on a consolidated procedure previously validated for stance loading. The material description included strain rate dependency and separate yield and fracture strain limits in tension and compression. FE predicted fracture force and experimentally measured peak forces showed a strong correlation (R2 = 0.92). The FE simulations predicted the fracture initiation within 3 mm distance of the experimental fracture line for 8/12 subjects. The predicted and measured strains correlated well on both the medial side (R2 = 0.87) and the lateral side (R2 = 0.74). The lower correlation on the lateral side is attributed to the irregularity of the cortex and presence of vessel holes in this region. The combined validation against bilateral full-field strain measurements and peak forces has opened the door for a more elaborate qualitative and quantitative validation of FE models of femora under sideways fall loading