Cardiopulmonary and cerebrovascular acclimatization in children and adults at 3800 m.

Maturational differences exist in cardiopulmonary and cerebrovascular function at sea-level, but the impact of maturation on acclimatization responses to high altitude is unknown. Ten children (9.8 ± 2.5 years) and 10 adults (34.7 ± 7.1 years) were assessed at sea-level (BL), 3000 m and twice over 4 days at 3800 m (B1, B4). Measurements included minute ventilation ( V ̇ E ${\dot{V}}_{\rm{E}}$ ), end-tidal partial pressures of oxygen ( P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ ) and carbon dioxide, echocardiographic assessment of pulmonary artery systolic pressure (PASP) and stroke volume (SV) and ultrasound assessment of blood flow through the internal carotid and vertebral arteries was performed to calculate global cerebral blood flow (gCBF). At 3000 m, V ̇ E ${\dot{V}}_{\rm{E}}$ was increased from BL by 19.6 ± 19.1% (P = 0.031) in children, but not in adults (P = 0.835); SV was reduced in children (-11 ± 13%, P = 0.020) but not adults (P = 0.827), which was compensated for by a larger increase in heart rate in children (+26 beats min-1 vs. +13 beats min-1 , P = 0.019). Between B1 and B4, adults increased V ̇ E ${\dot{V}}_{\rm{E}}$ by 38.5 ± 34.7% (P = 0.006), while V ̇ E ${\dot{V}}_{\rm{E}}$ did not increase further in children. The rise in PASP was not different between groups; however, ∆PASP from BL was related to ∆ P ETO 2 ${P}_{{\rm{ETO}}_{\rm{2}}}$ in adults (R2  = 0.288, P = 0.022), but not children. At BL, gCBF was 43% higher in children than adults (P = 0.017), and this difference was maintained at high altitude, with a similar pattern and magnitude of change in gCBF between groups (P = 0.845). Despite V ̇ E ${\dot{V}}_{\rm{E}}$ increasing in children but not adults at a lower altitude, the pulmonary vascular and cerebrovascular responses to prolonged hypoxia are similar between children and adults. KEY POINTS: Children have different ventilatory and metabolic requirements from adults, which may present differently in the pulmonary and cerebral vasculature upon ascent to high altitude. Children (ages 7-14) and adults (ages 23-44) were brought from sea level to high altitude (3000 to 3800 m) and changes in ventilation, pulmonary artery systolic pressure (PASP) and cerebral blood flow (CBF) were assessed over 1 week. Significant increases in ventilation and decreases in left ventricle stroke volume were observed at a lower altitude in children than adults. PASP and CBF increased by a similar relative amount between children and adults at 3800 m. These results help us better understand age-related differences in compensatory responses to prolonged hypoxia in children, despite similar changes in pulmonary artery pressure and CBF between children and adults.

Towards novel measurements of remodeling activity in cortical bone: implications for osteoporosis and related pharmaceutical treatments.

Bone remodelling is performed by basic multicellular units (BMUs) that resorb and subsequently form discrete packets of bone tissue. Normally, the resorption and formation phases of BMU activity are tightly coupled spatially and temporally to promote relatively stable bone mass and bone quality. However, dysfunctional remodelling can lead to bone loss and is the underlying cause of osteoporosis. This review surveys how BMU activity is altered in postmenopausal, disuse and glucocorticoid-induced osteoporosis as well as the impact of anabolic and anti-resorptive pharmaceutical treatments. The dysfunctional remodelling observed during disease and following medical intervention bares many testable hypotheses regarding the regulation of BMU activity and may provide novel insights that challenge existing paradigms of remodelling dynamics, particularly the poorly understood BMU coupling mechanisms. Most bone remodelling research has focused on trabecular bone and 2D analyses, as technical challenges limit the direct assessment of BMU activity in cortical bone. Recent advances in imaging technology present an opportunity to investigate cortical bone remodelling in vivo. This review discusses innovative experimental methods, such as 3D and 4D (i.e. time- lapsed) evaluation of BMU morphology and trajectory, that may be leveraged to improve the understanding of the spatio-temporal coordination of BMUs in cortical bone.

Newborn insula gray matter volume is prospectively associated with early life adiposity gain.

BACKGROUND: The importance of energy homeostasis brain circuitry in the context of obesity is well established, however, the developmental ontogeny of this circuitry in humans is currently unknown. Here, we investigate the prospective association between newborn gray matter (GM) volume in the insula, a key brain region underlying energy homeostasis, and change in percent body fat accrual over the first six months of postnatal life, an outcome that represents among the most reliable infant predictors of childhood obesity risk. METHODS: A total of 52 infants (29 male, 23 female, gestational age at birth=39(1.5) weeks) were assessed using structural MRI shortly after birth (postnatal age at MRI scan=25.9(12.2) days), and serial Dual X-Ray Absorptiometry shortly after birth (postnatal age at DXA scan 1=24.6(11.4) days) and at six months of age (postnatal age at DXA scan 2=26.7(3.3) weeks). RESULTS: Insula GM volume was inversely associated with change in percent body fat from birth to six-months postnatal age and accounted for 19% of its variance (ß=-3.6%/S.D., P=0.001). This association was driven by the central-posterior portion of the insula, a region of particular importance for gustation and interoception. The direction of this effect is in concordance with observations in adults, and the results remained statistically significant after adjusting for relevant covariates and potential confounding variables. CONCLUSIONS: Altogether, these findings suggest an underlying neural basis of childhood obesity that precedes the influence of the postnatal environment. The identification of plausible brain-related biomarkers of childhood obesity risk that predate the influence of the postnatal obesogenic environment may contribute to an improved understanding of propensity for obesity, early identification of at-risk individuals, and intervention targets for primary prevention.

Role of endocortical contouring methods on precision of HR-pQCT-derived cortical micro-architecture in postmenopausal women and young adults.

UNLABELLED: Precision errors of cortical bone micro-architecture from high-resolution peripheral quantitative computed tomography (pQCT) ranged from 1 to 16 % and did not differ between automatic or manually modified endocortical contour methods in postmenopausal women or young adults. In postmenopausal women, manually modified contours led to generally higher cortical bone properties when compared to the automated method. INTRODUCTION: First, the objective of the study was to define in vivo precision errors (coefficient of variation root mean square (CV%RMS)) and least significant change (LSC) for cortical bone micro-architecture using two endocortical contouring methods: automatic (AUTO) and manually modified (MOD) in two groups (postmenopausal women and young adults) from high-resolution pQCT (HR-pQCT) scans. Second, it was to compare precision errors and bone outcomes obtained with both methods within and between groups. METHODS: Using HR-pQCT, we scanned twice the distal radius and tibia of 34 postmenopausal women (mean age ± SD 74 ± 7 years) and 30 young adults (27 ± 9 years). Cortical micro-architecture was determined using AUTO and MOD contour methods. CV%RMS and LSC were calculated. Repeated measures and multivariate ANOVA were used to compare mean CV% and bone outcomes between the methods within and between the groups. Significance was accepted at P < 0.05. RESULTS: CV%RMS ranged from 0.9 to 16.3 %. Within-group precision did not differ between evaluation methods. Compared to young adults, postmenopausal women had better precision for radial cortical porosity (precision difference 9.3 %) and pore volume (7.5 %) with MOD. Young adults had better precision for cortical thickness (0.8 %, MOD) and tibial cortical density (0.2 %, AUTO). In postmenopausal women, MOD resulted in 0.2-54 % higher values for most cortical outcomes, as well as 6-8 % lower radial and tibial cortical BMD and 2 % lower tibial cortical thickness. CONCLUSIONS: Results suggest that AUTO and MOD endocortical contour methods provide comparable repeatability. In postmenopausal women, manual modification of endocortical contours led to generally higher cortical bone properties when compared to the automated method, while no between-method differences were observed in young adults.

Cortical Bone Porosity: What Is It, Why Is It Important, and How Can We Detect It?

There is growing recognition of the role of micro-architecture in osteoporotic bone loss and fragility. This trend has been driven by advances in imaging technology, which have enabled a transition from measures of mass to micro-architecture. Imaging trabecular bone has been a key research focus, but advances in resolution have also enabled the detection of cortical bone micro-architecture, particularly the network of vascular canals, commonly referred to as 'cortical porosity.' This review aims to provide an overview of what this level of porosity is, why it is important, and how it can be characterized by imaging. Moving beyond a 'trabeculocentric' view of bone loss holds the potential to improve diagnosis and monitoring of interventions. Furthermore, cortical porosity is intimately linked to the remodeling process, which underpins bone loss, and thus a larger potential exists to improve our fundamental understanding of bone health through imaging of both humans and animal models.

Structural Characterization of Sm(III)(EDTMP).

Samarium-153 ethylenediamine-N,N,N',N'-tetrakis(methylenephosphonic acid) ((153)Sm-EDTMP, or samarium lexidronam), also known by its registered trademark name Quadramet, is an approved therapeutic radiopharmaceutical used in the palliative treatment of painful bone metastases. Typically, patients with prostate, breast, or lung cancer are most likely to go on to require bone pain palliation treatment due to bone metastases. Sm(EDTMP) is a bone-seeking drug which accumulates on rapidly growing bone, thereby delivering a highly region-specific dose of radiation, chiefly through ß particle emission. Even with its widespread clinical use, the structure of Sm(EDTMP) has not yet been characterized at atomic resolution, despite attempts to crystallize the complex. Herein, we prepared a 1:1 complex of the cold (stable isotope) of Sm(EDTMP) under alkaline conditions and then isolated and characterized the complex using conventional spectroscopic techniques, as well as with extended X-ray absorption fine structure (EXAFS) spectroscopy and density functional structure calculations, using natural abundance Sm. We present the atomic resolution structure of [Sm(III)(EDTMP)-8H](5-) for the first time, supported by the EXAFS data and complementary spectroscopic techniques, which demonstrate that the samarium coordination environment in solution is in agreement with the structure that has long been conjectured.

Molybdenum distributions and variability in drinking water from England and Wales.

An investigation has been carried out of molybdenum in drinking water from a selection of public supply sources and domestic taps across England and Wales. This was to assess concentrations in relation to the World Health Organization (WHO) health-based value for Mo in drinking water of 70 µg/l and the decision to remove the element from the list of formal guideline values. Samples of treated drinking water from 12 water supply works were monitored up to four times over an 18-month period, and 24 domestic taps were sampled from three of their supply areas. Significant (p < 0.05) differences were apparent in Mo concentration between sources. Highest concentrations were derived from groundwater from a sulphide-mineralised catchment, although concentrations were only 1.5 µg/l. Temporal variability within sites was small, and no seasonal effects (p > 0.05) were detected. Tap water samples collected from three towns (North Wales, the English Midlands, and South East England) supplied uniquely by upland reservoir water, river water, and Chalk groundwater, respectively, also showed a remarkable uniformity in Mo concentrations at each location. Within each, the variability was very small between houses (old and new), between pre-flush and post-flush samples, and between the tap water and respective source water samples. The results indicate that water distribution pipework has a negligible effect on supplied tap water Mo concentrations. The findings contrast with those for Cu, Zn, Ni, Pb, and Cd, which showed significant differences (p < 0.05) in concentrations between pre-flush and post-flush tap water samples. In two pre-flush samples, concentrations of Ni or Pb were above drinking water limits, although in all cases, post-flush waters were compliant. The high concentrations, most likely derived from metal pipework in the domestic distribution system, accumulated during overnight stagnation. The concentrations of Mo observed in British drinking water, in all cases less than 2 µg/l, were more than an order of magnitude below the WHO health-based value and suggest that Mo is unlikely to pose a significant health or water supply problem in England and Wales.

Does frequency of resistance training affect tibial cortical bone density in older women? A randomized controlled trial.

SUMMARY: This randomized controlled trial evaluated the effect of resistance training frequency (0, 1, and 2 times/week) on cortical volumetric bone mineral density (vBMD) at the tibia in older women. There was no mean difference in change in tibial cortical vBMD in older women who engaged in resistance training (RT) one or two times/week compared with the control group over 12 months after adjusting for baseline values. INTRODUCTION: National guidelines recommend RT two to three times/week to optimize bone health. Our objective was to determine the effect of a 12-month intervention of three different RT frequencies on tibial volumetric cortical density (CovBMD) in healthy older women. METHODS: We randomized participants to the following groups: (1) 2×/week balance and tone group (i.e., no resistance beyond body weight, BT), (2) 1×/week RT (RT1), and (3) 2×/week RT (RT2). Treatment allocation was concealed, and measurement team and the bone data analyst were blinded to group allocation. We used peripheral quantitative computed tomography to acquire one 2.3-mm scan at the 50 % tibia, and the primary outcome was CovBMD. Data were collected at baseline, 6 and 12 months, and we used linear mixed modeling to assess the effect at 12 months. RESULTS: We assessed 147 participants; 100 women provided data at all three points. Baseline unadjusted mean (SD) tibial CovBMD (in milligrams per cubic centimeter) at the 50 % site was 1,077.4 (43.0) (BT), 1,087.8 (42.0) (RT1), and 1,058.7 (60.4) (RT2). At 12 months, there were no statistically significant differences (-0.45 to -0.17 %) between BT and RT groups for mean difference in change in tibial CovBMD for exercise interventions (BT, RT1, RT2) after adjusting for baseline tibial CovBMD. CONCLUSION: We note no mean difference in change in tibial CovBMD in older women who engaged in RT one or two times/week compared with the control group over 12 months. It is unknown if RT of 3× or 4×/week would be enough to promote a statistically significant difference in change of bone density.

The Economic Impact of a Pilot Digital Day-Case Pathway for Knee Arthroplasty in a U.K. Setting.

Knee replacements are an increasingly common procedure in the U.K. National Health Service (NHS). Importantly, the pathway for such procedures represents a prime opportunity to leverage digital technology, modernize and streamline the approach to care, and free up resources. Methods: In this 21-patient pilot study, we assessed the impact of implementing a digital day-case pathway for knee replacement surgery at the Calderdale and Huddersfield NHS Foundation trust. Results: Fourteen (67%) of the 21 eligible patients were treated as day cases, with an average length of stay of 8.8 hours. The pilot data were utilized to model the potential impact of implementing a digital day-case program more widely across the trust. This model showed increased efficiency over the entire episode of care, with reductions in physiotherapy appointments, preoperative visits, hospital days, and face-to-face consultations. Not only would these improvements free up capacity, but they would also result in an estimated saving of £240,540 to the trust while reducing the CO2 footprint of knee replacements by 119,381 kg CO2 emitted. A sensitivity analysis revealed that, even with substantial variation of several key variables within the pathway, a trust-wide digital day-case program would still be a cost-saving measure. Conclusions: Overall, the present study supports the growing notion that digital technology can facilitate the transformation of care pathways, resulting in greater efficiency and financial savings for health-care providers while reducing the time patients spend in the hospital. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Exploring the Impact and Acceptance of Wearable Sensor Technology for Pre- and Postoperative Rehabilitation in Knee Replacement Patients: A U.K.-Based Pilot Study.

Knee replacement operations are common, highly successful procedures that are increasing in frequency. The COVID-19 pandemic has emphasized the need for innovative care pathways that reduce face-to-face appointments. We report on the impact of introducing a wearable sensor for pre- and postoperative rehabilitation of 21 knee replacement patients at 2 hospitals in the U.K. Methods: The sensor (BPMpathway; 270 Vision) was provided during joint school prior to knee replacement and stayed with the patient until a maximum of 9 weeks post-surgery. Participant progress and exercise were monitored remotely, with exercise regimens altered as required. Participants and clinicians could communicate remotely via the device. Results: The median range of motion during the first week post-surgery was 63° (interquartile range [IQR] = 21°) and increased to 136° (IQR = 16°) by week 7. The rate of participant compliance with exercises using the device was 32.3% for thrice-daily compliance and 52.4% for once-daily compliance. The 2-way communication channel was well utilized by both participants and clinicians. We report a 35.7% reduction in face-to-face physiotherapy appointments compared with standard practice. Finally, >80% of users who completed the feedback questionnaire reported a positive experience using the device, finding it easy to understand and reporting that it motivated them to perform their exercises. Conclusions: The use of BPMpathway was well received, effective, and reduced face-to-face physiotherapy appointments. Clinical Relevance: Remote monitoring can reduce the burden to the outpatient physiotherapy service by supporting the post-COVID-19 surgical service recovery plans of the National Health Service and allowing patients to recuperate at home.

Visualization of 3D osteon morphology by synchrotron radiation micro-CT.

Cortical bone histology has been the subject of scientific inquiry since the advent of the earliest microscopes. Histology - literally the study of tissue - is a field nearly synonymous with 2D thin sections. That said, progressive developments in high-resolution X-ray imaging are enabling 3D visualization to reach ever smaller structures. Micro-computed tomography (micro-CT), employing conventional X-ray sources, has become the gold standard for 3D analysis of trabecular bone and is capable of detecting the structure of vascular (osteonal) porosity in cortical bone. To date, however, direct 3D visualization of secondary osteons has eluded micro-CT based upon absorption-derived contrast. Synchrotron radiation micro-CT, through greater image quality, resolution and alternative contrast mechanisms (e.g. phase contrast), holds great potential for non-destructive 3D visualization of secondary osteons. Our objective was to demonstrate this potential and to discuss areas of bone research that can be advanced through the application of this approach. We imaged human mid-femoral cortical bone specimens derived from a 20-year-old male (Melbourne Femur Collection) at the Advanced Photon Source synchrotron (Chicago, IL, USA) using the 2BM beam line. A 60-mm distance between the target and the detector was employed to enhance visualization of internal structures through propagation phase contrast. Scan times were 1 h and images were acquired with 1.4-µm nominal isotropic resolution. Computer-aided manual segmentation and volumetric 3D rendering were employed to visualize secondary osteons and porous structures, respectively. Osteonal borders were evident via two contrast mechanisms. First, relatively new (hypomineralized) osteons were evident due to differences in X-ray attenuation relative to the surrounding bone. Second, osteon boundaries (cement lines) were delineated by phase contrast. Phase contrast also enabled the detection of soft tissue remnants within the vascular pores. The ability to discern osteon boundaries in conjunction with vascular and cellular porosity revealed a number of secondary osteon morphologies and provided a unique 3D perspective of the superimposition of secondary osteons on existing structures. Improvements in resolution and optimization of the propagation phase contrast promise to provide further improvements in structural detail in the future.

Relating age and micro-architecture with apparent-level elastic constants: a micro-finite element study of female cortical bone from the anterior femoral midshaft.

Homogenized elastic properties are often assumed for macro-finite element (FE) models used in orthopaedic biomechanics. The accuracy of material property assignments may have a strong effect on the ability of these models to make accurate predictions. For cortical bone, most macro-scale FE models assume isotropic elastic material behaviour and do not include variation of material properties due to bone micro-architecture. The first aim of the present study was to evaluate the variation of apparent-level (homogenized) orthotropic elastic constants of cortical bone with age and indices of bone micro-architecture. Considerable age-dependent differences in porosity were noted across the cortical thickness in previous research. The second aim of the study was to quantify the resulting differences in elastic constants between the periosteum and endosteum. Specimens were taken from the anterior femoral midshaft of 27 female donors (age 53.4 +/- 23.6 years) and micro-FE (gFE) analysis was used to derive orthotropic elastic constants. The variation of orthotropic elastic constants (Young's moduli, shear moduli, and Poisson's ratios) with various cortical bone micro-architectural indices was investigated. The ratio of canal volume to tissue volume, Ca.V/TV, analogous to porosity, was found to be the strongest predictor (r2(ave) = 0.958) of the elastic constants. Age was less predictive (r2(ave) = 0.385) than Ca.V/TV. Elastic anisotropy increased with increasing Ca.V/TV, leading to lower elastic moduli in the transverse, typically less frequently loaded, directions. Increased Ca.V/TV led to a more substantial reduction in elastic constants at the endosteal aspect than at the periosteal aspect. The results are expected to be most applicable in similar midshaft locations of long bones; specific analysis of other sites would be necessary to evaluate elastic properties elsewhere. It was concluded that Ca.V/TV was the most predictive of cortical bone elastic constants and that considerable periosteal-endosteal variations in these constants can develop with bone loss.

3D visualization and quantification of rat cortical bone porosity using a desktop micro-CT system: a case study in the tibia.

Although micro-computed tomography (micro-CT) has become the gold standard for assessing the 3D structure of trabecular bone, its extension to cortical bone microstructure has been relatively limited. Desktop micro-CT has been employed to assess cortical bone porosity of humans, whereas that of smaller animals, such as mice and rats, has thus far only been imaged using synchrotron-based micro-CT. The goal of this study was to determine if it is possible to visualize and quantify rat cortical porosity using desktop micro-CT. Tibiae (n = 10) from 30-week-old female Sprague-Dawley rats were imaged with micro-CT (3 µm nominal resolution) and sequential ground sections were then prepared. Bland-Altman plots were constructed to compare per cent porosity and mean canal diameter from micro-CT (3D) versus histology (2D). The mean difference or bias (histology-micro-CT; ±95% confidence interval) for per cent porosity was found to be -0.15% (±2.57%), which was not significantly different from zero (P= 0.720). Canal diameter had a bias (±95% confidence interval) of -5.73 µm (±4.02 µm) which was found to be significantly different from zero (P < 0.001). The results indicated that cortical porosity in rat bone can indeed be visualized by desktop micro-CT. Quantitative assessment of per cent porosity provided unbiased results, whereas direct analysis of mean canal diameter was overestimated by micro-CT. Thus, although higher resolution, such as that available from synchrotron micro-CT, may ultimately be required for precise geometric measurements, desktop micro-CT--which is far more accessible--is capable of yielding comparable measures of porosity and holds great promise for assessment of the 3D arrangement of cortical porosity in the rat.

Quantifying Subresolution 3D Morphology of Bone with Clinical Computed Tomography.

The aim of this study was to quantify sub-resolution trabecular bone morphometrics, which are also related to osteoarthritis (OA), from clinical resolution cone beam computed tomography (CBCT). Samples (n = 53) were harvested from human tibiae (N = 4) and femora (N = 7). Grey-level co-occurrence matrix (GLCM) texture and histogram-based parameters were calculated from CBCT imaged trabecular bone data, and compared with the morphometric parameters quantified from micro-computed tomography. As a reference for OA severity, histological sections were subjected to OARSI histopathological grading. GLCM and histogram parameters were correlated to bone morphometrics and OARSI individually. Furthermore, a statistical model of combined GLCM/histogram parameters was generated to estimate the bone morphometrics. Several individual histogram and GLCM parameters had strong associations with various bone morphometrics (|r| > 0.7). The most prominent correlation was observed between the histogram mean and bone volume fraction (r = 0.907). The statistical model combining GLCM and histogram-parameters resulted in even better association with bone volume fraction determined from CBCT data (adjusted R2 change = 0.047). Histopathology showed mainly moderate associations with bone morphometrics (|r| > 0.4). In conclusion, we demonstrated that GLCM- and histogram-based parameters from CBCT imaged trabecular bone (ex vivo) are associated with sub-resolution morphometrics. Our results suggest that sub-resolution morphometrics can be estimated from clinical CBCT images, associations becoming even stronger when combining histogram and GLCM-based parameters.

Anterior-posterior bending strength at the tibial shaft increases with physical activity in boys: evidence for non-uniform geometric adaptation.

UNLABELLED: We investigated bone structural adaptations to a 16-month school-based physical activity intervention in 202 young boys using a novel analytical method for peripheral quantitative computed tomography scans of the tibial mid-shaft. Our intervention effectively increased bone bending strength in the anterior-posterior plane as estimated with the maximum second moment of area (I(max)). INTRODUCTION: We previously reported positive effects of a physical activity intervention on peripheral quantitative computed tomography (pQCT)-derived bone strength at the tibial mid-shaft in young boys. The present study further explored structural adaptations to the intervention using a novel method for pQCT analysis. METHODS: Participants were 202 boys (aged 9-11 years) from 10 schools randomly assigned to control (CON, 63 boys) and intervention (INT, 139 boys) groups. INT boys participated in 60 min/week of classroom physical activity, including a bone-loading program. We used ImageJ to process pQCT images of the tibial mid-shaft and determine the second moments of area (I(max), I(min)) and cortical area (CoA) and thickness (CTh) by quadrant (anterior, medial, lateral, posterior). We defined quadrants according to pixel coordinates about the centroid. We used mixed linear models to compare change in bone outcomes between groups. RESULTS: The INT boys had a 3% greater gain in I(max) than the CON boys (p = 0.04) and tended to have a greater gain in I(min) ( approximately 2%, NS). Associated with the greater gain in I(max) was a slightly greater (NS) gain (1-1.4%) in CoA and CTh in the anterior, medial, and posterior (but not lateral) quadrants. CONCLUSION: Our results suggest regional variation in bone adaptation consistent with patterns of bone formation induced by anterior-posterior bending loads.

Cortical and trabecular bone in the femoral neck both contribute to proximal femur failure load prediction.

UNLABELLED: We examined the contributions of femoral neck cortical and trabecular bone to proximal femur failure load. We found that trabecular bone mineral density explained a significant proportion of variance in failure load after accounting for total bone size and cortical bone mineral content or cortical area. INTRODUCTION: The relative contribution of femoral neck trabecular and cortical bone to proximal femur failure load is unclear. OBJECTIVES: Our primary objective was to determine whether trabecular bone mineral density (TbBMD) contributes to proximal femur failure load after accounting for total bone size and cortical bone content. Our secondary objective was to describe regional differences in the relationship among cortical bone, trabecular bone, and failure load within a cross-section of the femoral neck. MATERIALS AND METHODS: We imaged 36 human cadaveric proximal femora using quantitative computed tomography (QCT). We report total bone area (ToA), cortical area (CoA), cortical bone mineral content (CoBMC), and TbBMD measured in the femoral neck cross-section and eight 45 degrees regions. The femora were loaded to failure. RESULTS AND OBSERVATIONS: Trabecular bone mineral density explained a significant proportion of variance in failure load after accounting for ToA and then either CoBMC or CoA respectively. CoBMC contributed significantly to failure load in all regions of the femoral neck except the posterior region. TbBMD contributed significantly to failure load in all regions of the femoral neck except the inferoanterior, superoposterior, and the posterior regions. CONCLUSION: Both cortical and trabecular bone make significant contributions to failure load in ex vivo measures of bone strength.

Skeletal muscle growth in young rats is inhibited by chronic exposure to IL-6 but preserved by concurrent voluntary endurance exercise.

Childhood diseases are often accompanied by chronic inflammation, which is thought to negatively impact growth. Interleukin-6 (IL-6) is typically cited as an indicator of inflammation and is linked to impaired growth. This study was designed to isolate and identify potential effects of chronic IL-6 exposure on skeletal muscle growth during development. A second aim was to determine if endurance exercise, thought to antagonize chronic inflammation, would interact with any effects of IL-6. The muscles of one leg of rapidly growing rats were exposed to IL-6 or vehicle for 14 days. Subgroups of IL-6-infused rats were provided access to running wheels. Local IL-6 infusion resulted in approximately 13% muscle growth deficit (myofibrillar protein levels). Exercise (>4,000 m/day) prevented this deficit. IL-6 infusion increased mRNA for suppressor of cytokine signaling-3 (SOCS3) and tumor necrosis factor-alpha (TNF-alpha), and this was not prevented by exercise. IL-6 infusion increased the mRNAs for atrogin, insulin-like growth factor-I (IGF-I), and IGF binding protein-4 (IGFBP4), and these effects were mitigated by exercise. Exercise stimulated an increase in total RNA ( approximately 19%) only in the IL-6-infused muscle, suggesting that a compensatory increase in translational capacity was required to maintain muscle growth. This study indicates that IL-6 exposure during periods of rapid growth in young animals can retard growth possibly via interactions with key growth factors. Relatively high volumes of endurance-type exercise do not exacerbate the negative effects of IL-6 and in fact were found to be beneficial in protecting muscle growth.

Muscle power is related to tibial bone strength in older women.

UNLABELLED: We enrolled 65 to 75 year-old community-dwelling women and measured muscle power, strength, physical activity using accelerometry and tibial bone strength using peripheral quantitative computed tomography (pQCT). Muscle power contributed 6.6% of the variance in the bone strength-strain index and 8.9% in the section modulus after accounting for age, height, weight, and physical activity; moderate to vigorous physical activity was related to muscle power in the lower extremity. INTRODUCTION: Muscle power is associated with DXA measurements of bone mass, but it is not known whether muscle power is associated with bone strength. There are no reports of investigations that have tested the effect of muscle power on bone compartments using advanced imaging. METHODS: We enrolled 74 community-dwelling women aged 65-75 years. We measured muscle power and strength of leg extension using Keiser air-pressure resistance equipment. All participants wore a waist-mounted Actigraph accelerometer to record physical activity. We used peripheral quantitative computed tomography (pQCT) to measure tibial mid-shaft (50% of the site) bone strength (strength-strain index, section modulus). We used Pearson correlations and multi-level linear regression to investigate the associations between muscle and bone. RESULTS: Muscle power contributed 6.6% (p = 0.007) of the variance in the bone strength-strain index and 8.9% (p = 0.001) the variance in the section modulus in older women after accounting for age, height, weight, and physical activity. Moderate to vigorous physical activity was significantly related to muscle power in the lower extremity (r = 0.260; p = 0.041). CONCLUSION: Muscle power significantly contributed to the variance in estimated bone strength. Whether power training will prove to be a more effective stimulus for bone strength than conventional strength training will require further studies.

Characterising cortical density in the mid-tibia: intra-individual variation in adolescent girls and boys.

BACKGROUND: Inter-individual differences in cortical bone volumetric density (CoD), such as those related to sex, are a product of differences in remodelling rates. While cortical bone is often treated as a uniform tissue, remodelling rates also vary within individual bones. This level of adaptation has largely been overlooked in analyses of peripheral quantitative computed tomography (pQCT) images. Further, such variation in CoD has never been assessed in growing bones. We hypothesised that CoD varied significantly within the same cross-section of the mid-tibia of adolescents. We further hypothesised that due to the profound impact of oestrogen on remodelling, this variation would be different between sexes. METHODS: Subjects were 183 adolescents (99 girls and 84 boys) in grade 6 and 7 with a mean age of 12.1 years. We used age at peak height velocity to adjust for maturational differences between sexes. Image data from a mid-tibia pQCT scan of each subject were assessed regionally within eight sectors distributed about the cortex and aligned by the anterior tibial crest. We used a repeated measures general linear model to assess intra-individual variation in CoD while controlling for differences in ethnicity, maturity, height, weight, physical activity level and total cross-sectional bone area (ToA). RESULTS: Sector based variation in CoD was significant (p<0.001), with the anterior cortex having lower density than the posterior cortex. The largest percentage difference (anterior vs posteromedial sectors) was 12.2%. A significant sector*sex interaction (p = 0.018) was detected; however, its impact was relatively small with girls having 1.1-3.6% denser bones than boys depending on the sector (2.7% average difference). CONCLUSIONS: The magnitude of the variation in CoD across sectors within individuals of both sex was far greater than the mean differences between the sexes. This finding indicates that the microstructural variation within the mid-tibia is detectable by pQCT and its magnitude suggests an important level of adaptation to loading.

Influence of cortical canal architecture on lacunocanalicular pore pressure and fluid flow.

Bone is a dynamic tissue that undergoes structural modification in response to its mechanical environment, but how bone cells sense and respond to loading conditions remains incompletely understood. Current theories focus on strain-induced fluid flow for the primary means of mechanotransduction. To examine the influence of age-related cortical rarefaction on lacunocanalicular fluid characteristics, coupled fluid flow and mechanical computational models of bone specimens representing young, mid-age and aged samples were derived artificially from the same original micro-computed tomography image data. Simulated mechanical loading was applied to the bone models to induce pressure-driven interstitial fluid flow. Results demonstrated a decrease in pore pressure and fluid velocity magnitudes with age as a result of increased cortical porosity. Mean canal separation, as opposed to canal size, was implicated as a primary factor affecting age-related fluid dynamics. Future investigations through refinement of the model may implicate fluid stasis or inadequate nutrient transport experienced by osteocytes as a key factor in the initiation of cortical remodelling events.