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Research
Biomechanical Epidemiology — Biomechanics of Vertebral Fractures
Biomechanical Epidemiology — Biomechanics of Vertebral Fractures
More specifically, we are using 3D quantitative computed tomography scans from the population-based Framingham Heart Study to determine the effects of age, sex, and spinal location on vertebral body strength and its determinates, as well as on trunk muscle morphology in the lumbar and thoracic spine. We are also using the high-resolution imaging data to build subject-specific biomechanical models of the spine and estimate vertebral loading during various activities of daily life. The model currently incorporates subject-specific muscle morphology, and we are working to incorporate subject-specific spinal curvatures as well as subject-specific muscle quality parameters. We are also assessing muscle quality by measuring CT attenuation of trunk muscles, and plan to incorporate this information into our models.
The findings from this project will provide a better understanding of the interaction between spinal loading and the determinants of vertebral strength. This may improve diagnostic sensitivity and specificity, and lead to therapeutic interventions for prevention and treatment of vertebral fractures that are targeted to specific biomechanical deficiencies. Ultimately such an approach will contribute to cost effective use of therapy. Altogether, the findings will have important implications for clinical management of individual patients at risk for osteoporosis and for public health policy. This work is funded by NIH R01AR053986, R01AR/AG041398, R44AR052234, T32 AG023480, and the National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study (NIH/NHLBI Contract N01-HC-25195). Recent Publications: Kim YM, Demissie S, Eisenberg R, Samelson EJ, Kiel DP, Bouxsein ML. Intra-and inter-reader reliability of semi-automated quantitative morphometry measurements and vertebral fracture assessment using lateral scout views from computed tomography. Osteoporos Int. 2011. PDF (in press, Jan 27, 2011) Samelson EJ, Christiansen BA, Demissie S, Broe KE, Zhou Y, Meng CA, Yu W, Cheng X, O'Donnell CJ, Hoffmann U, Genant HK, Kiel DP, Bouxsein ML. Reliability of vertebral fracture assessment using multidetector CT lateral scout views: the Framingham Osteoporosis Study. Osteoporos Int. 2011; 22(4):1123-31. PDF Iyer S, Christiansen BA, Roberts BJ, Valentine MJ, Manoharan RK, Bouxsein ML. A biomechanical model for estimating loads on thoracic and lumbar vertebrae. Clin Biomech (Bristol, Avon). 2010; 25(9):853-8. PDF Christiansen BA, Kopperdahl D, Kiel DP, Keaveny TM, Bouxsein ML. Contributions of cortical and trabecular bone to age-related declines in vertebral strength are not the same for men and women. J Bone Miner Res. 2011; 26(5):974-83. PDF Christiansen BA and Bouxsein ML Biomechanics of vertebral fractures and the vertebral fracture cascade. Curr Osteoporos Rep 2010; 8(4):198-204. PDF
Effects of partial weight bearing on musculoskeletal system and inhibition of disuse induced bone loss with novel therapeutics
Our long-term goal is to take advantage of this unique model to gain insight into the mechanisms underlying the musculoskeletal response to reduced mechanical loading, thereby identifying new targets for preventing musculoskeletal deterioration in due to age-, disease- or injury-induced reductions in mechanical loading. Thus, we propose to extensively characterize the mechanical stimuli associated with our partial weight-bearing model, and to determine the timing and magnitude of the musculoskeletal response to partial weight-bearing, as compared to both normal weight-bearing and full hindlimb unloading via tail suspension. Establishment of a model where quadrupedal gait is maintained, yet loads can be reduced by prescribed amounts will provide the opportunity to test long-held views about the minimal loading stimulus necessary to maintain bone and muscle tissue under conditions of disuse. A major advantage to developing a partial weight-bearing murine model is that it will be ideally suited for future studies designed to delineate the genetic, cellular and molecular mechanisms associated with musculoskeletal adaptation to altered loading environments. We will use our partial weight-bearing model to quantify the musculoskeletal effects of 10, 21 and 35 days exposure to 20, 40, 60 or 100% body weight loading in adult female mice, and compare the response to that of tail suspension (0% body weight). Outcome assessments will include in vivo bone mineral density, body composition, as well as ex vivo muscle weight, bone architecture by µCT, and femoral biomechanics. Serum markers of bone turnover, marrow fat assessment, histology and dynamic histomorphometry will be used to delineate mechanisms underlying the response to partial weight-bearing.
Altogether, this work will provide novel information about musculoskeletal adaptation across a continuum of reduced mechanical loading, and insights into the fundamental relationship between mechanical loading and musculoskeletal adaptation. Moreover, the studies will provide experimental data that can be used to test existing quantitative theories about skeletal adaptation to altered mechanical loading. Finally, development of this model will establish a basis for future studies designed to delineate the cellular and molecular mechanisms underlying skeletal response to reduced loading, and will enhance the development of interventions to prevent muscle and bone atrophy during a variety of clinical conditions of reduced musculoskeletal loading due to disease, injury or inactivity. This work is funded by NIH-NIAMS R21 AR057522, NASA NNX10AE39G, and a research grant from Amgen. Recent publications: Wagner EB, Granzella NP, Saito H, Newman DJ, Young LR, Bouxsein ML. Partial weight suspension: a novel murine model for investigating adaptation to reduced musculoskeletal loading. J Appl Physiol 2010; 109(2):350-7. PDF
Effects of diet on skeletal acquisition and maintenance Our overall goal is to understand the effect of diet on skeletal acquisition, in particular whether perinatal diet initiates developmental programming of the skeleton that alters postnatal acquisition of bone mass, microarchitecture and strength. Perinatal diet is of particular interest because maternal caloric restriction (CR) and high fat (HF) diet have each been shown to trigger developmental programming that increases the risk of metabolic disease, including obesity and type II diabetes, but skeletal effects are unknown. We hypothesize that the skeleton undergoes perinatal developmental programming, induced by early life diet, that alters postnatal skeletal acquisition and therefore adult bone mass and strength.  To test this hypothesis and establish the contribution of developmental programming to skeletal acquisition, pregnant mice are fed either a normal, HF or CR diet during gestation and/or lactation, and pups are weaned onto the same diet as their mothers were fed, or onto the opposite diet (e.g., prenatal CR weaned to postnatal HF). Mice are sacrificed at weaning (3 wks of age), adolescence (6 wks of age), young adulthood (12 wks of age) or older adulthood (20 wks of age). Bone mineral density and body composition are measured in vivo using peripheral dual-energy X-ray absorptiometry; cortical and trabecular bone microarchitecture by microCT; bone strength by biomechanical testing; serum adipokines, IGF-1 and markers of bone turnover by ELISA; and static and dynamic indices of bone formation/resorption, marrow adiposity and cellularity by histomorphometry. To date, our findings suggest that postnatal calorie restriction is highly detrimental to bone acquisition during growth, and furthermore, that calorie restriction leads paradoxically to increased bone marrow adiposity — a phenomenon also seen in young women with anorexia nervosa. This work is funded by NIH-NIAMS RC1-AR058389. Recent publications: Devlin MJ, Cloutier AM, Thomas NA, Panus DA, Lotinun S, Pinz I, Baron R, Rosen CJ, Bouxsein ML. Caloric restriction leads to high marrow adiposity and low bone mass in growing mice. J Bone Miner Res 2010; 25(9):2078-88. PDF
Bone biomechanics and skeletal fragility For several decades we have been investigating the biomechanical mechanisms underlying skeletal fragility in osteoporosis and other bone disorders, and how various interventions improve bone strength and reduce fracture risk. Our work has included studies in animal models, human cadaveric specimens and clinical studies. Our overall goals are to better understand the origins and causes of skeletal fragility, to better identify those at risk for fracture and to enhance the monitoring of treatment efficacy. Predicting Femoral Strength: Human cadaveric femora will be selected to represent the target population of individuals likely to suffer a hip fracture (ie, age > 65, BMD T-score < -1.5). Non-invasive imaging modalities will include image analysis of radiographs, DXA, multi-angle DXA, hip structural analysis, QCT, and QCT-based finite element analysis. Femurs will be divided into two groups, providing a “training set” for establishment of statistical models for prediction of bone strength (n=60 femurs) and a “test set” used to validate the model predictions (n=20 femurs). Several aspects of this study will be novel, as it will be the first to evaluate a wide variety of imaging modalities in the same experiment, to enroll specimens from individuals with low BMD only, and to use the training/test set approach to evaluate the fidelity of strength predictions for femurs tested in a sideways fall configuration. Results will provide strong evidence for qualification of surrogate markers for hip fracture risk. We are also collaborating with Professor Tony Keaveny at UC Berkeley to examine micro-finite element models of the proximal femur to better understand how the femur fails in a sideways fall configuration, and what are the contributions of trabecular and cortical morphology to this failure. Determinants of vertebral strength: This work was done in collaboration with Julien Wergyzn and Jean-Paul from Professor Pierre Delmas' and Roland Chapurlat's group in Lyon, France. We used human lumbar vertebrae to determine the contribution of trabecular bone heterogeneity and cortical shell thickness to whole vertebral strength. In addition, we investigated the factors the influence the mechanical behavior of lumbar vertebra after simulating a mild vertebral fracture (ie, 25% deformation). We are also interested in the relative contribution of bone volume, collagen cross-links, mineralization and microdamage to mechanical behavior of human vertebral trabecular bone.
Recent publications: Roberts BJ, Thrall E, Muller J, Bouxsein ML. Comparison of hip fracture risk by femoral aBMD to Comparison of hip fracture risk prediction by femoral BMD and by the factor-of-risk for hip fracture derived from direct measurements of femoral strength. Bone. 2010; 46(3):742-6. PDF Roux J, Wegrzyn J, Arlot M, Guyen O, Delmas P, Chapurlat R, Bouxsein M. Contribution of trabecular and cortical components to biomechanical behavior of human vertebrae: an ex-vivo study. J Bone Miner Res. 2010; 25(2): 356-61. PDF Wegrzyn J, Roux JP, Arlot ME, Boutroy S, Vilayphiou N, Guyen O, Delmas PD, Chapurlat R, Bouxsein ML. Role of trabecular microarchitecture and its heterogeneity parameters in the mechanical behavior of ex-vivo human L3 vertebrae. J Bone Miner Res. 2010; 25(11): 2324-31. PDF Wegrzyn J, Roux JP, Arlot ME, Boutroy S, Vilayphiou N, Guyen O, Delmas PD, Chapurlat R, Bouxsein ML. Determinants of the mechanical behavior of human lumbar vertebrae after simulated mild fracture. J Bone Miner Res. 2011; 26(4):739-46. PDF Follet H, Viguet-Carrin S, Burt-Pichat B, Depalle B, Bala Y, Gineyts E, Munoz F, Arlot M, Boivin G, Chapurlat R, Delmas PD, Bouxsein ML. Effects of preexisting microdamage, collagen cross-links, degree of mineralization, age and architecture on compressive mechanical properties of elderly human vertebral trabecular bone. J Orthop Res. 2011; 29(4):481-8. PDF
Effects of low magnitude mechanical stimulation on skeletal health in elders Preliminary data in animals and humans suggest that high frequency, low magnitude mechanical stimulation (LMMS) delivered by way of a vibrating platform, can preserve BMD against systemic pressures to resorb (due to disuse and/or aging), and can stimulate new bone formation. To confirm and extend these observations, in collaboration with Douglas Kiel, MD and Marian Hannan, PhD of Hebrew Senior Life, and funded by NIH-NIAMS, we are conducting a 3-year, clinical trial of LMMS in elderly women and men (65 years of age and older), with low body mass index (< 26 kg/m2) and BMD values between 0 and 2 standard deviations below normal peak bone mass ("T-scores" of 0 to -2.0). We expect to observe an increase in BMD, achieved through an increase in bone formation, predominantly in the trabecular compartment of the weight-bearing skeleton. Outcomes include areal bone mineral density by DXA, trabecular volumetric bone density by quantitative computed tomography (QCT), serum bone turnover markers, and measures of postural stability. Dr. Bouxsein is a co-investigator on this project, serves on the steering committee, and the Bouxsein Lab is responsible for evaluation of the QCT images. This project is funded by NIH-NIA AG025489. Recent publications: Kiel DP, Hannan MT, Barton BA, Bouxsein ML, Lang TF, Brown KM, Shane E, Magaziner J, Zimmerman S, Rubin CT. Insights from the conduct of a device trial in older persons: low magnitude mechanical stimulation for musculoskeletal health. Clin Trials. 2010; 7(4):354-67. PDF |
Fractures occur when the load applied to a bone exceeds its ability to resist that load. This ratio of skeletal loading to bone strength is referred to as the factor-of-risk, and our group has shown previously that factor of risk explains much of the age- and sex-specific patterns of wrist and hip fractures. We are now working to apply the factor-of-risk concept to understand the unique pathophysiology of vertebral fractures. This project brings together expertise in epidemiology, biostatistics, biomechanics and 3D-imaging, as well as a diverse set of collaborators, including the 
Mechanical loading is necessary for proper development and maintenance of the musculoskeletal system. Yet, despite the profound effects of reduced mechanical loading on muscle atrophy and skeletal fragility, there has been little investigation into the physiological effects of clinically relevant partial weight-bearing environments, such as bed rest, immobilization, stroke, cerebral palsy, muscular dystrophy, spinal cord injury or age-related reductions in physical activity. 
The major obstacle to such research has been the lack of a suitable animal model. We have developed a novel model of titrated weight-bearing that offers a unique capability for exploring the chronic effects of reduced quadrupedal loading in mice. The system allows studies with controlled exposure to 10-80% weight-bearing compared to normally loaded controls in an identical environment 
We are also testing whether new therapeutic interventions can inhibit bone loss during disuse. In particular, we are testing whether a new anti-resorptive therapy, antibody to RANKL (denosumab) and whether a new anabolic therapy, sclerostin antibody, inhibits skeletal deterioration across the spectrum of partial weight bearing environments. Denosumab, a fully human monoclonal antibody to the receptor activator of nuclear factor-B ligand (RANKL), inhibits development and activity of osteoclasts, and thereby markedly decreases bone resorption. Semi-annual subcutaneous injections of denosumab significantly reduce vertebral and non-vertebral fracture risk in postmenopausal women with osteoporosis. The secreted protein sclerostin is a key negative regulator of bone formation. Humans with genetic mutations leading to sclerostin deficiency have increased bone mass, and in rodents, inhibition of sclerostin via pharmacologic antibody treatment or genetic manipulation leads to anabolic skeletal effects. Moreover, mice deficient in sclerostin are resistant to disuse-induced bone loss. Our preliminary studies demonstrate that treatment with sclerostin antibody leads to bone formation even is a disuse model. Images at the right show 3D rendering of representative microCT images of the mouse distal femur, with the unloaded, vehicle treated animal on the top and the unloaded, sclerostin-treated animal on the bottom.
Measurement of BMD by DXA is the current gold standard for diagnosis of osteoporosis. However, several studies have identified limitations in BMD measurements with regard to assessing fracture risk and monitoring efficacy of osteoporosis therapies. New imaging methods, combined with state-of-the art biomechanical analyses, may improve prediction of hip fracture risk. This main goal of this study is to evaluate the ability of different imaging modalities to predict the strength of human proximal femur in a sideways fall configuration. Secondary goals are to determine the relative contribution of BMD, femoral geometry, and cortical and trabecular bone microarchitecture to femoral strength.
Structural mechanics dictates that whole-bone mechanical behavior depends on bone size (or mass), geometry, and the intrinsic material properties of bone tissue. The effect of geometry on whole-bone strength is well documented, but the role of tissue material properties is less well understood. Indentation measurements offer an opportunity to study the material properties of bone tissue independent of geometrical and bone mass contributions. A novel microindentation instrument, termed reference probe indentation (RPI), uses cyclic loading to assess the ability of bone to resist crack generation and propagation. The insights gained from RPI may be useful for identifying mechanisms underlying different forms of skeletal fragility. We are examining a number of mouse models — either exposing the excised bones to conditions that alter the bone matrix or using genetically modified mice with alterations to the bone matrix. Images of bone indentation in mouse bone are shown in SEM images.
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