Elsevier

Acta Astronautica

Volume 132, March 2017, Pages 67-77
Acta Astronautica

In vivo bone remodeling rates determination and compressive stiffness variations before, during 60 days bed rest and two years follow up: A micro-FE-analysis from HR-pQCT measurements of the berlin Bed Rest Study-2

https://doi.org/10.1016/j.actaastro.2016.12.002Get rights and content

Highlights

  • For the first time bone micro-FEA of in vivo HR-pQCT data after bed rest were done.

  • in vivo HR-pQCT measurements can monitor bone adaption even in short times.

  • µ-finite element analysis are required to estimate subject specific real fracture risk.

  • Vibration resistive exercises maintain bone biomechanical integrity during bed rest.

Abstract

Bed rest studies are used for simulation and study of physiological changes as observed in unloading/non-gravity environments. Amongst others, bone mass reduction, similar as occurring due to aging osteoporosis, combined with bio-fluids redistribution and muscle atrophy have been observed and analyzed. Advanced radiological methods of high resolution such as HR-pQCT (XtremeCT) allow 3D-visualizing in vivo bone remodeling processes occurring during absence/reduction of mechanical stimuli (0 to <1 g) as simulated by bed rest. Induced bone micro-structure (e.g. trabecular number, cortical thickness, porosity) and density variations can be quantified. However, these parameters are average values of each sample and important information regarding bone mass distribution and within bone mechanical behaviour is lost. Finite element models with hexa-elements of identical size as the HR-pQCT measurements (0.082 mm×0.082 mm×0.082 mm, ca. 7E6 elements/sample) can be used for subject-specific in vivo stiffness calculation. This technique also allows quantifying if bone microstructural changes represent a risk of mechanical bone collapse (fracture).

Materials and methods

In the Berlin Bed Rest Study-2, 23 male subjects (20–50 YO) were maintained 60 days under restricted bed rest (6° HDT) aiming to test a - for this study specifically designed - vibration resistive exercise regime for maintenance of bone mass and muscle functionality at normal levels (base line measurements). For comparison a resistive exercise without vibration and a control group were included. Base line HR-pQCT measurements (3 days before bed rest: base line), as well as during 30 days bed rest (BR30 and BR59, 3 days of recovery (R3), R15, R30, R90, R180, R360, and R720 were performed. CT-scan voxels were converted into finite elements (hexa-82 µm edge length) for calculating in vivo compressive stiffness during the experiment duration. Histograms of stresses and strains distributions as well as anatomical regions susceptible for mechanical failure were identified and compared.

Results:

Resistive vibration exercises (RVE) were able to maintain in the majority of the subjects compressive bone strength as determined after modelling a compressive test using finite element models. Compressive bone stiffness using FEA was monitored through analysis of the internal deformation on the trabecular structures and cortical bone, reaction forces, and minimum principal strains on the in vivo CT measured bone regions during the experiment duration. Stress distributions (main stresses) and von Mises stress distribution remained comparable with those determined in the base line measurements for the RVE-group. However, no major differences were found in the group with resistive exercise training alone. Without mechanical stimuli an increment of bone regions with high stress concentration was observed and a reduction of up to 10% of bone compressive stiffness was quantified by using subject-specific finite-element analysis. Anatomically von Mises stress concentrations, thus bone regions susceptible to fail mechanically, were observed at the center of the cancellous bone and at the antero- posterior region of the cortical bone.

Conclusions:

Finite element simulations from bed rest studies are an invaluable tool to determine subject-specific in vivo compressive stiffness and anatomical mechanically compromised regions under controlled mechanical conditions (unloading) which - until now - are not possible to be determined with any other method. Vibration exercise combined with a resistive compressive force was able to maintain bone structure and density even during 60 days of bed rest.

Introduction

Bed rest studies are an established method used as space flight analogue to study physiological changes as expected under unloading conditions, immobility or in non-gravitational environments [1], [2], [3]. Furthermore, countermeasures to avoid adverse effects on the normal functionality of living organisms such as physical exercises, drug treatments, diet or specially designed devices for mechanical load application in which the magnitudes and patterns of generated and applied forces are similar as measured during physiological activities on earth (e.g. running, jumping, etc.) have been tested in several bed rest studies. In the Berlin Bed Rest Study 2, a long term bed rest study (BR>30 days) with up to two years follow-up measurements, the effectiveness of a specifically designed vibration resistive exercise as training for maintaining bone mass against resistive exercise alone compared with a control group was determined. Amongst others physiological measurements, bone microstructural and density changes were monitored in vivo and compared. It was expected that without mechanical stimuli bone mass will be reduced and that the microstructure will be negatively altered. Specifically, a reduction of the trabecular number, reduction of cortical thickness, increment of cortical porosity and increment of trabecular separation were expected to occur, thus changes of bone density and bone microstructure such as observed due to aging osteoporosis. The questions are how much bone mass will be reduced during immobility/absence of mechanical stimuli? Which regions are primary biomechanically affected and if that takes place, are these changes reversible? When did these changes occur? The employment of non-invasive methods such as radiological monitoring of the bone microstructure and its density allows to quantify and to visualize three-dimensionally bone adaption processes in vivo in humans. In our study, the µCT with until now worldwide highest existing isometric resolution for in vivo measurements in humans was used for allowing 3D visualization of changes on the bone microstructure and density with and without usage of a countermeasure for avoiding, amongst others, loss of bone mass during unloading conditions. The finite element method (FEM) was employed for quantifying variations of compressive bone stiffness in vivo, which are impossible to be measured experimentally. Current technological advances in parallel computing have allowed subject specific µ-finite element analysis before, during 60 days bed rest and after bed rest for a recovery time of up to two years. The usage of numerical methods in computational mechanics like FEM has the advantage not only of allowing estimation of the effect of bone quality on compressive bone stiffness under unloading conditions (bed rest) but is also able to show the changes of strains and stress distribution in time both during load application (by using incremental load application in several steps) and for the duration of the experiment (2 years). Furthermore and more important subject-specific FE analysis permits 3D visualization of particular microstructural regions (trabeculae and cortical bone) that present high stress and strains values, thus the mechanical competence of bone microstructure and their anatomical location can be evaluated for each subject in vivo during the experiment duration. Radiological non-invasive measurements provide invaluable data about bone remodeling processes in vivo. In bed rest studies the most used radiological measurements for monitoring bone loss includes DXA, pQCT, and MRI. However, DXA is not able to provide information about bone microstructure, an important issue for estimating fracture risk, and other radiological methods do not have sufficient resolution to allow determination of quantifiable microstructural parameters. Until today only High Resolution peripheral Computed Tomography (HR-pQCT) is able to visualize, thus permitting quantification, of bone microstructure and density (trabecular network, cortical thickness, cortical porosity, cortical density and trabecular density) in vivo in humans. In only two bed rest studies in vivo high resolution peripheral computed tomography measurements (82 µm isometric resolution, voxel size: 0.082 mm×0.082 mm×0.082 mm, also slice thickness 0.082 mm) before, during and after bed rest have been done: The Woman International Space Simulation for Exploration Study (WISE, Toulouse) and the Berlin Bed Rest Study - 2 (BBR-2) [4], [5]. For the first time µ-finite element analysis from HR-pQCT measurements before, during and after 60 days bed rest have been performed and will be reported and discussed in this paper. Using the finite element method the aim of this study was to quantify the effectiveness of vibration resistive exercise as countermeasure for avoiding amongst others the detriment of bone quality caused by unloading conditions thus, reducing fracture risk. To test and to quantify the effectiveness of vibration exercise as countermeasure for avoiding loss of bone mass and muscle atrophy is important considering that newly performed studies have shown that other training exercises used as countermeasure, amongst others, to avoid loss of bone mass and muscle atrophy appear to fail [6], [7].

Section snippets

Experiment setup

To confirm the hypothesis that vibration exercise is able to preserve bone microstructure and density as required for normal functional physiological labels, even during immobility, 23 male subjects were maintained under restricted bed rest for a period of 60 days (6° HDT) in a clinical study: the “Berlin Bed Rest Study - 2″ (BBR-2). The BBR-2 was designed in conformity and using key parameters tested in a first phase (BBR-1). The BBR-1 found that resistive vibration exercise (RVE) training was

From the experimental setup

The experimental setup as well as the occurrence and management of some unplanned issues has been widely discussed and published [8], [9], [20]. Therefore, only one relevant aspect concerns to the analysis and results presented here can be mentioned: one of the subjects from the resistive vibration exercise group was not able to complete the training during the bed rest period and was switched into the control group. This subject was identified and excluded for finite element modelling and

On the HR-pQCT measurements (in vivo Remodeling rate of microstructure and density measurements

Bed rest studies are a valuable model for analysing physiological changes induced by controlled reduced mechanical stimuli. Specifically, reduction of bone mass, trabecular number and thickness were quantified.

In unloading conditions, a maximal reduction of −9.4% in trabecular number without training and a maximal gain in bone mass 1.8% can be expected by using RVE as countermeasure. RVE was able not only to maintain Tb. N as measured in normal conditions (BDC) but to increase it up to a

Acknowledgments

Our special thanks go to the BBR-2 volunteers, to the European Space Agency (ESA, grant 14431/02/NL/SH2) and the German Aerospace Agency (DLR, grant 50WB0720 (Felsenberg)) for sponsoring this study and especially to the North-German Supercomputing Alliance (HLRN) for providing HPC resources that have contributed to the research results reported in this paper.

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    However, as external morphology only allows inferences about manipulative capacity, and not necessarily actual behavior, many researchers have begun to quantify epigenetic changes to bone that result from repetitive loading (e.g., compression, tension, and shear; Frost, 1987). This phenomenon, commonly referred to as bone functional adaptation, has been experimentally observed to alter the structure in ways that improve the mechanical competence of repeatedly-loaded bone (Lanyon and Rubin, 1985; Pontzer et al., 2006; Ruff et al., 2006; Barak et al., 2011; Schulte et al., 2013; Christen et al., 2014; Cresswell et al., 2016; Christen and Muller, 2017; Ritter et al., 2017). For instance, cortical bone adjusts in thickness for improved resistance to bending forces, while trabecular bone alters the thickness, spacing, and orientation of struts adjacent to loaded regions in a way that enhances the transfer of kinetic energy away from joint surfaces (Cowin et al., 1985; Keaveny et al., 2001; Sugiyama et al., 2010; Currey, 2011; Barak et al., 2013; Reznikov et al., 2015; but see Demes et al., 1998; Ozcivici and Judex, 2014; Wallace et al., 2015a,b; Fairfield et al., 2017).

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