Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury.

Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.

Fixed and Relative Positioning of Scans for High Resolution Peripheral Quantitative Computed Tomography.

INTRODUCTION: High resolution peripheral quantitative computed tomography (HR-pQCT) imaging protocol requires defining where to position the ∼1 cm thick scan along the bone length. Discrepancies between the use of two positioning methods, the relative and fixed offset, may be problematic in the comparison between studies and participants. This study investigated how bone landmarks scale linearly with length and how this scaling affects both positioning methods aimed at providing a consistent anatomical location for scan acquisition. METHODS: Using CT images of the radius (N = 25) and tibia (N = 42), 10 anatomical landmarks were selected along the bone length. The location of these landmarks was converted to a percent length along the bone, and the variation in their location was evaluated across the dataset. The absolute location of the HR-pQCT scan position using both offset methods was identified for all bones and converted to a percent length position relative to the HR-pQCT reference line for comparison. A secondary analysis of the location of the scan region specifically within the metaphysis was explored at the tibia. RESULTS: The location of landmarks deviated from a linear relationship across the dataset, with a range of 3.6 % at the radius sites, and 4.5 % at the tibia sites. The consequent variation of the position of the scan at the radius was 0.6 % and 0.3 %, and at the tibia 2.4 % and 0.5 %, for the fixed and relative offset, respectively. The position of the metaphyseal junction with the epiphysis relative to the scan position was poorly correlated to bone length, with R2 = 0.06 and 0.37, for the fixed and relative offset respectively. CONCLUSION: The variation of the scan position by either method is negated by the intrinsic variation of the bone anatomy with respect both to total bone length as well as the metaphyseal region. Therefore, there is no clear benefit of either offset method. However, the lack of difference due to the inherent variation in the underlying anatomy implies that it is reasonable to compare studies even if they are using different positioning methods.

Accuracy of volumetric bone mineral density measurement in weight bearing, cone beam computed tomography.

BACKGROUND: Weight bearing computed tomography (WBCT) utilizes cone beam CT technology to provide assessments of lower limb joint structures while they are functionally loaded. Grey-scale values indicative of X-ray attenuation that are output from cone beam CT are challenging to calibrate, and their use for bone mineral density (BMD) measurement remains debatable. To determine whether WBCT can be reliably used for cortical and trabecular BMD assessment, we sought to establish the accuracy of BMD measurements at the knee using modern WBCT by comparing them to measurements from conventional CT. METHODS: A hydroxyapatite phantom with three inserts of varying densities was used to systematically quantify signal uniformity and BMD accuracy across the acquisition volume. We evaluated BMD in vivo (n = 5, female) using synchronous and asynchronous calibration techniques in WBCT and CT. To account for variation in attenuation along the height (z-axis) of acquisition volumes, we tested a height-dependent calibration approach for both WBCT and CT images. RESULTS: Phantom BMD measurement error in WBCT was as high as 15.3% and consistently larger than CT (up to 5.6%). Phantom BMD measures made under synchronous conditions in WBCT improved measurement accuracy by up to 3% but introduced more variability in measured BMD. We found strong correlations (R = 0.96) as well as wide limits of agreement (-324 mgHA/cm3 to 183 mgHA/cm3) from Bland-Altman analysis between WBCT and CT measures in vivo that were not improved by height-dependent calibration. CONCLUSION: Whilst BMD accuracy from WBCT was found to be dependent on apparent density, accuracy was independent of the calibration technique (synchronous or asynchronous) and the location of the measurement site within the field of view. Overall, we found strong correlations between BMD measures from WBCT and CT and in vivo measures to be more accurate in trabecular bone regions. Importantly, WBCT can be used to distinguish between anatomically relevant differences in BMD, however future work is necessary to determine the repeatability and sensitivity of BMD measures in WBCT.

C-reactive protein predicts endocortical expansion but not fracture in older men: the prospective STRAMBO study.

In older men, higher high-sensitivity C-reactive protein (hsCRP) concentrations were associated with faster prospectively assessed endocortical expansion (distal radius, distal tibia) and slightly higher cortical bone loss at distal tibia, but not with the fracture risk. High hsCRP level has a limited impact on bone decline in older men. PURPOSE: Data on the link of the high-sensitivity C-reactive protein (hsCRP) with bone loss and fracture risk are discordant. We studied the association of the hsCRP with the prospectively assessed decrease in areal bone mineral density (aBMD), bone microarchitecture decline, and fracture risk in older men. METHODS: At baseline, hsCRP was measured in 823 men aged 60-88. Areal BMD and bone microarchitecture (distal radius, distal tibia) were assessed by dual-energy X-ray absorptiometry and high-resolution peripheral QCT, respectively, at baseline and after 4 and 8 years. Data on incident fractures were collected for 8 years. RESULTS: Higher hsCRP concentration was associated with faster increase in aBMD at the whole body and lumbar spine, but not other sites. Higher hsCRP levels were associated with faster decrease in cortical area and more rapid increase in trabecular area at the distal radius (0.048 mm2/year/SD, p < 0.05) and distal tibia (0.123 mm2/year/SD, p < 0.001). At the distal tibia, high hsCRP level was associated with greater decrease in total and cortical volumetric BMD (vBMD) and in failure load. The hsCRP levels were not associated with the fracture risk, even after accounting for competing risk of death. CONCLUSION: Higher hsCRP levels were associated with greater endocortical expansion at the distal radius and tibia. Higher hsCRP was associated with slightly faster decrease in total and cortical vBMD and failure load at distal tibia, but not with the fracture risk. Thus, high hsCRP levels are associated with faster cortical bone loss, but not with fracture risk in older men.

Comparison of Bone Quality Among Winter Endurance Athletes with and Without Risk Factors for Relative Energy Deficiency in Sport (REDs): A Cross-Sectional Study.

Relative Energy Deficiency in Sport (REDs) is a syndrome describing the relationship between prolonged and/or severe low energy availability and negative health and performance outcomes. The high energy expenditures incurred during training and competition put endurance athletes at risk of REDs. The objective of this study was to investigate differences in bone quality in winter endurance athletes classified as either low-risk versus at-risk for REDs. Forty-four participants were recruited (M = 18; F = 26). Bone quality was assessed at the distal radius and tibia using high resolution peripheral quantitative computed tomography (HR-pQCT), and at the hip and spine using dual X-ray absorptiometry (DXA). Finite element analysis was used to estimate bone strength. Participants were grouped using modified criteria from the REDs Clinical Assessment Tool Version 1. Fourteen participants (M = 3; F = 11), were classified as at-risk of REDs (≥ 3 risk factors). Measured with HR-pQCT, cortical bone area (radius) and bone strength (radius and tibia) were 6.8%, 13.1% and 10.3% lower (p = 0.025, p = 0.033, p = 0.027) respectively, in at-risk compared with low-risk participants. Using DXA, femoral neck areal bone density was 9.4% lower in at-risk compared with low-risk participants (p = 0.005). At-risk male participants had 21.9% lower femoral neck areal bone density (via DXA) than low-risk males (p = 0.020) with no significant differences in females. Overall, 33.3% of athletes were at-risk for REDs and had lower bone quality than those at low-risk.

Bone Quality in Competitive Athletes: A Systematic Review.

The study objective was to assess bone quality measured by high resolution peripheral quantitative computed tomography (HR-pQCT) in competitive athletes. Medline, EMBASE and Sport Discus were searched through May 2022. Prior to submission, a follow-up database search was performed (January 2023). Studies of competitive athletes using HR-pQCT to assess bone quality were included. Athletes were aged between 14 and 45 years. Data extraction included study design and location (country), skeletal imaging modality and site, bone variables and any additional musculoskeletal-related outcome. Information identifying sports and athletes were also extracted. This review included 14 manuscripts and a total of 928 individuals (male: n=75; female: n=853). Athletes comprised 78% (n=722) of the included individuals and 93% of athletes were female. Assessment scores indicate the studies were good to fair quality. The athletes included in this review can be categorized into three groups: 1) healthy athletes, 2) athletes with compromised menstrual function (e.g., amenorrhoea), and 3) athletes with compromised bone health (e.g., bone stress injuries). When assessing bone quality using HR-pQCT, healthy competitive athletes had denser, stronger and larger bones with better microarchitecture, compared with controls. However, the same cannot be said for athletes with amenorrhoea or bone stress injuries.

Diagnostic accuracy of a dual-energy computed tomography-based post-processing method for imaging bone marrow edema following an acute ligamentous knee injury.

OBJECTIVE: This study evaluated the ability of a custom dual-energy CT (DECT) post-processing material decomposition method to image bone marrow edema after acute knee injury. Using an independent validation cohort, the DECT method was compared to gold-standard, fluid-sensitive MRI. By including both quantitative voxel-by-voxel validation outcomes and semi-quantitative radiologist scoring-based assessment of diagnostic accuracy, we aimed to provide insight into the relationship between quantitative metrics and the clinical utility of imaging methods. MATERIALS AND METHODS: Images from 35 participants with acute anterior cruciate ligament injuries were analyzed. DECT material composition was applied to identify bone marrow edema, and the DECT result was quantitatively compared to gold-standard, registered fluid-sensitive MRI on a per-voxel basis. In addition, two blinded readers rated edema presence in both DECT and fluid-sensitive MR images for evaluation of diagnostic accuracy. RESULTS: Semi-quantitative assessment indicated sensitivity of 0.67 and 0.74 for the two readers, respectively, at the tibia and 0.55 and 0.57 at the femur, and specificity of 0.87 and 0.89 for the two readers at the tibia and 0.58 and 0.89 at the femur. Quantitative assessment of edema segmentation accuracy demonstrated mean dice coefficients of 0.40 and 0.16 at the tibia and femur, respectively. CONCLUSION: The custom post-processing-based DECT method showed similar diagnostic accuracy to a previous study that assessed edema associated with ligamentous knee injury using a CT manufacturer-provided, built-in edema imaging application. Quantitative outcome measures were more stringent than semi-quantitative scoring methods, accounting for the low mean dice coefficient scores.

Pre-flight exercise and bone metabolism predict unloading-induced bone loss due to spaceflight.

OBJECTIVES: Bone loss remains a primary health concern for astronauts, despite in-flight exercise. We examined changes in bone microarchitecture, density and strength before and after long-duration spaceflight in relation to biochemical markers of bone turnover and exercise. METHODS: Seventeen astronauts had their distal tibiae and radii imaged before and after space missions to the International Space Station using high-resolution peripheral quantitative CT. We estimated bone strength using finite element analysis and acquired blood and urine biochemical markers of bone turnover before, during and after spaceflight. Pre-flight exercise history and in-flight exercise logs were obtained. Mixed effects models examined changes in bone and biochemical variables and their relationship with mission duration and exercise. RESULTS: At the distal tibia, median cumulative losses after spaceflight were -2.9% to -4.3% for bone strength and total volumetric bone mineral density (vBMD) and -0.8% to -2.6% for trabecular vBMD, bone volume fraction, thickness and cortical vBMD. Mission duration (range 3.5-7 months) significantly predicted bone loss and crewmembers with higher concentrations of biomarkers of bone turnover before spaceflight experienced greater losses in tibia bone strength and density. Lower body resistance training volume (repetitions per week) increased 3-6 times in-flight compared with pre-spaceflight. Increases in training volume predicted preservation of tibia bone strength and trabecular vBMD and thickness. CONCLUSIONS: Findings highlight the fundamental relationship between mission duration and bone loss. Pre-flight markers of bone turnover and exercise history may identify crewmembers at greatest risk of bone loss due to unloading and may focus preventative measures.

Maintained Bone Density in Young Hypoestrogenized Women with a High BMI: Case Series.

Estrogen deficiency and obesity are factors that affect bone mass in a manner that is independent and in opposing directions. Obesity favours higher bone mass and increased bone formation whereas estrogen deficiency leads to significant bone loss in leaner individuals. To report the impact of the competing effects of a hypoestrogenized state and obesity on long-term bone health, we present two cases of young chronically hypoestrogenized females whose bone parameters were assessed with high-resolution peripheral quantitative computed tomography (HR-pQCT) and revealed a bone mineral density and microstructure that did not change despite the long history of a low estrogen state. As evidenced by the outcomes for these patients, the obesity-related effect on bone mass may be dominant when obesity is marked and appears to be highly protective even in the setting of sub-physiologic circulating estrogen. Recognition of this interaction should be considered in decisions around estrogen replacement therapy in such cases.

Contrast-enhanced x-ray microscopy of articular cartilage.

Osteoarthritis is a common chronic disease of joints characterized by degenerative changes of articular cartilage. An early diagnosis of osteoarthritis may be possible when imaging excised tissue for research in situ at the cellular-molecular scale. Whereas cartilage histopathology is destructive, time-consuming, and limited to 2D views, contrast-enhanced x-ray microscopy (XRM) can image articular cartilage and subchondral bone in 3D. This study evaluates articular cartilage structure ex vivo using both techniques.Osteochondral plugs were excised from non-diseased bovine knees and stained in phosphotungstic acid for 0 to 32 h. XRM imaging revealed an optimal staining time of 16 h and a saturated staining time of 24 h. Histology sections were cut and analyzed by polarized light microscopy (PLM) and second-harmonic-generation dual-photon (SHG-DP) microscopy. Histology photomicrographs were aligned with matching XRM slices and evaluated for features relevant in histopathological scoring of osteoarthritis cartilage, including the tidemark, collagen architecture and chondrocyte morphology.The cartilage collagen network and chondrocytes from the 3D contrast-enhanced XRM were correlated with the 2D histology. This technique has two distinct advantages over routine histopathology: (1) the avoidance of dehydration, demineralization, and deformation of histological sectioning, thereby preserving the intact articular cartilage and subchondral bone plate ex vivo, and (2) the ability to evaluate the entire osteochondral volume in 3D. This work explores several diagnostic features of imaging cartilage, including: visualization of the tidemark in XRM and SHG-DP microscopy, validating the morphology of chondrocytes and nuclei with XRM, SHG-DP and PLM, and correlating collagen birefringence with XRM image intensity.

The Assessment of Skeletal Muscle and Cortical Bone by Second-generation HR-pQCT at the Tibial Midshaft.

BACKGROUND: Peripheral quantitative computed tomography (pQCT) is the current densitometric gold-standard for assessing skeletal muscle at the 66% proximal tibia site. High resolution peripheral quantitative computed tomography (HR-pQCT) is a leading technology for quantifying bone microarchitecture at the distal extremities, and with the second-generation HR-pQCT it is possible to measure proximal limb sites. Therefore, the objectives of this study were to: (1) assess the feasibility of using HR-pQCT to assess skeletal muscle parameters at the 66% proximal tibia site, and (2) test HR-pQCT skeletal muscle measurement reproducibility at this site. METHODS: Adult participants (9 males; 7 females; ages 31-75) received 1 pQCT scan and 2 HR-pQCT scans at the 66% proximal site of the nondominant tibia. Participants were repositioned between HR-pQCT scans to test reproducibility. HR-pQCT and pQCT scans were analyzed to quantify muscle cross-sectional area (CSA) and muscle density. Coefficients of determination and Bland-Altman plots compared muscle parameters between pQCT and HR-pQCT. For short-term reproducibility, root-mean-square of coefficient of variance and least significant change were calculated. RESULTS: HR-pQCT and pQCT measured muscle density and muscle CSA were positively correlated (R2 = 0.66, R2 = 0.95, p < 0.001, respectively). Muscle density was equivalent between HR-pQCT and pQCT; however, there was systematic and directional bias for muscle CSA, such that muscle CSA was 11% lower with HR-pQCT and bias increased with larger muscle CSA. Root-mean-square of coefficient of variance was 0.67% and 0.92% for HR-pQCT measured muscle density and muscle CSA, respectively, while least significant change was 1.4 mg/cm3 and 174.0 mm2 for muscle density and muscle CSA, respectively. CONCLUSION: HR-pQCT is capable of assessing skeletal muscle at the 66% site of the tibia with good precision. Measures of muscle density are comparable between HR-pQCT and pQCT.

Validation of Bone Density and Microarchitecture Measurements of the Load-Bearing Femur in the Human Knee Obtained Using In Vivo HR-pQCT Protocol.

High resolution peripheral quantitative computed tomography (HR-pQCT) was designed to study bone mineral density (BMD) and microarchitecture in peripheral sites at the distal radius and tibia. With the introduction of the second generation HR-pQCT scanner (XtremeCT II, Scanco Medical) that has a larger, longer gantry it is now possible to study the human knee in vivo using HR-pQCT. Previous validation of HR-pQCT measurements at the distal radius and tibia against micro-CT is not representative of the knee because the increased cross-sectional area, greater amount of soft tissue surrounding the scan region, and different imaging protocol result in potentially increased beam hardening effects and photon scatter and different signal-to-noise ratio. The objective of this study is to determine the accuracy of density and microarchitecture measurements in the human knee measured by HR-pQCT using an in vivo protocol. Twelve fresh-frozen cadaver knees were imaged using in vivo HR-pQCT (60.7 µm) protocol. Subsequentially, distal femurs were extracted and imaged using a higher resolution (30.3 µm) ex vivo protocol, replicating micro-CT imaging. Scans were registered so that agreement of density and bone microarchitecture measurements could be determined using linear regression and Bland-Altman plots. All density and microarchitecture outcomes were highly correlated between the 2 protocols (R2 > 0.89) albeit with statistically significant differences between absolute measures based on paired t tests. All parameters showed accuracy between 4.5% and 8.7%, and errors were highly systematic, particularly for trabecular BMD and trabecular thickness (R2 > 0.93). We found that BMD and microarchitecture measurements in the distal femur obtained using an in vivo HR-pQCT knee protocol contained systematic errors, and accurately represented measurements obtained using a micro-CT equivalent imaging protocol. This work establishes the validity and limitations of using HR-pQCT to study the BMD and microarchitecture of human knees in future clinical studies.

Associations Between Breastfeeding History and Early Postmenopausal Bone Loss.

This study aimed to evaluate associations of parity and breastfeeding history with postmenopausal bone loss. Early postmenopausal women from the Canadian Multicentre Osteoporosis Study were divided into three groups based on their reproductive histories: nulliparous (NP, n = 10), parous with < 6 months breastfeeding (P-NBF, n = 14), and parous with > 6 months breastfeeding (P-BF, n = 21). Women underwent dual X-ray absorptiometry and high-resolution peripheral quantitative computed tomography imaging at baseline and after 6 years to evaluate bone mineral density (BMD), bone microstructure, and finite element-estimated failure load. Average age at baseline was 57 years. Baseline density, microstructure, and failure load were not different among groups. In all women, total and cortical BMD decreased significantly at the tibia and radius. P-BF women only experienced a significant decline in tibial trabecular BMD, with a greater magnitude of change for P-BF than NP women (p = 0.002). Overall, results suggest that early postmenopausal bone health did not differ based on parity or breastfeeding history. Over the 6-year follow-up period, postmenopausal bone loss was evident in all women, with subtle differences in the rate of postmenopausal change among women with varying breastfeeding histories. Parous women who had breastfed for at least 6 months showed an elevated rate of trabecular BMD loss at the tibia. Meanwhile, correlation analyses suggest that longer durations of breastfeeding may be associated with reduced cortical bone loss at the radius. The lack of differences among groups in FE-derived failure load suggests that parity and breastfeeding history is unlikely to significantly affect postmenopausal risk of fracture.

The Influence of Reconstruction Kernel on Bone Mineral and Strength Estimates Using Quantitative Computed Tomography and Finite Element Analysis.

Quantitative computed tomography has been posed as an alternative imaging modality to investigate osteoporosis. We examined the influence of computed tomography convolution back-projection reconstruction kernels on the analysis of bone quantity and estimated mechanical properties in the proximal femur. Eighteen computed tomography scans of the proximal femur were reconstructed using both a standard smoothing reconstruction kernel and a bone-sharpening reconstruction kernel. Following phantom-based density calibration, we calculated typical bone quantity outcomes of integral volumetric bone mineral density, bone volume, and bone mineral content. Additionally, we performed finite element analysis in a standard sideways fall on the hip loading configuration. Significant differences for all outcome measures, except integral bone volume, were observed between the 2 reconstruction kernels. Volumetric bone mineral density measured using images reconstructed by the standard kernel was significantly lower (6.7%, p < 0.001) when compared with images reconstructed using the bone-sharpening kernel. Furthermore, the whole-bone stiffness and the failure load measured in images reconstructed by the standard kernel were significantly lower (16.5%, p < 0.001, and 18.2%, p < 0.001, respectively) when compared with the image reconstructed by the bone-sharpening kernel. These data suggest that for future quantitative computed tomography studies, a standardized reconstruction kernel will maximize reproducibility, independent of the use of a quantitative calibration phantom.

Concurrent Assessment of Cartilage Morphology and Bone Microarchitecture in the Human Knee Using Contrast-Enhanced HR-pQCT Imaging.

Osteoarthritis (OA) is a prevalent articular disease characterized by whole joint degradation, including articular cartilage and bone. Presently, no single imaging modality is well suited to concurrently capture these changes. Recent ex vivo animal studies have demonstrated the efficacy of utilizing contrast agents in conjunction with micro-CT as a means of evaluating cartilage and bone alterations concurrently, though no work as of yet has been performed in large animal models or humans. This study sought to develop and validate a novel joint imaging technique, contrast enhanced high resolution peripheral quantitative computed tomography (CEHR-pQCT), to concurrently assess bone microarchitecture and cartilage morphology in the whole human knee. Fresh frozen cadaveric knees were harvested (n = 10) and scanned using magnetic resonance imaging (MRI), HR-pQCT without contrast, and HR- pQCT following intra-articular injection of nonionic contrast media. Cartilage morphology and bone microarchitecture were evaluated in weight bearing regions of interest in both the tibia and femur. Joints were then disarticulated, and the articular cartilage thickness measured by needle probe. Measures of cartilage morphology, thickness and volume, were found to be significantly less when measured by CEHR- pQCT compared to magnetic resonance imaging in all regions. Compared to needle probing, cartilage thickness measured by CEHR-pQCT was less in the lateral tibia and greater in the medial tibia. Bone microarchitecture was found to be significantly different when measured with CEHR-pQCT compared to HR-pQCT, where cortical bone mineral density (BMD) was depressed, and trabecular bone mineral density was greater. This study demonstrates that CEHR-pQCT can be used to concurrently measure cartilage morphology and bone microarchitecture; however, systematic errors impact both measures. This is the first study using contrast media in combination with HR-pQCT in whole joints. Additionally, all imaging parameters, as well as the contrast media, were selected to be directly transferable to in vivo studies, laying the foundation to perform in vivo scanning of knee cartilage and bone.

Trabecular Bone Score at the Distal Femur and Proximal Tibia in Individuals With Spinal Cord Injury.

Rapid declines in bone mineral density (BMD) at the knee after spinal cord injury (SCI) are associated with an increased risk of fracture. Evaluation of bone quality using the trabecular bone score (TBS) may provide a complimentary measure to BMD assessment to examine bone health and fracture risk after SCI. The purpose of this study was to assess bone mineral density (BMD) and trabecular bone score (TBS) at the knee in individuals with and without SCI. Nine individuals with complete SCI (mean time since SCI 2.9 ± 3.8 yr) and 9 non-SCI controls received dual-energy X-ray absorptiometry scans of the right knee using the lumbar spine protocol. BMD and TBS were quantified at epiphyseal, metaphyseal, diaphyseal, and total bone regions of the distal femur and proximal tibia. Individuals with SCI illustrated significantly lower total BMD at the distal femur (23%; p = 0.029) and proximal tibia (19%; p = 0.02) when compared with non-SCI controls. Despite these marked differences in BMD from both locations, significant differences in total TBS were observed at the distal femur only (6%; p = 0.023). The observed differences in total BMD and TBS could be attributed to reductions in epiphyseal rather than metaphyseal or diaphysis measurements. The relationship between TBS and duration of SCI was well explained by a logarithmic trend at the distal femoral epiphysis (r2 = 0.54, p = 0.025). The logarithmic trend would predict that after 3 yr of SCI, TBS would be approximately 6% lower than the non-SCI controls. Further evaluation is needed to determine if TBS measures at the knee provide important information about bone quality that is not captured by traditional BMD.

The Correction of Systematic Error due to Plaster and Fiberglass Casts on HR-pQCT Bone Parameters Measured In Vivo at the Distal Radius.

Due to difficulty assessing healing of distal radius fractures using conventional radiography, there is interest in using high resolution peripheral quantitative computed tomography (HR-pQCT) to track healing at the microarchitectural level. Unfortunately, the plaster-of-Paris and fiberglass casts used to immobilize fractures affect HR-pQCT measurements due to beam hardening, and increased noise. The challenge is compounded because casts have variable thickness, and an individual patient will often have their cast changed 2-3 times during the course of treatment. This study quantifies the effect of casts within a clinically relevant range of thicknesses on measured bone parameters at the distal radius, and establishes conversion equations to correct for systematic error in due to cast presence. Eighteen nonfractured participants were scanned by HR-pQCT in three conditions: no cast, plaster-of-Paris cast, and fiberglass cast. Measured parameters were compared between the baseline scan (no cast) and each cast scan to evaluate if systematic error exists due to cast presence. A linear regression model was used to determine an appropriate conversion for parameters that were found to have systematic error. Plaster-of-Paris casts had a greater range of thicknesses (3.2-9.5 mm) than the fiberglass casts (3.0-5.4 mm), and induced a greater magnitude of systematic error overall. Key parameters of interest were bone mineral density (total, cortical, and trabecular) and trabecular bone volume fraction, all of which were found to have systematic error due to presence of either cast type. Linear correlations between baseline and cast scans for these parameters were excellent (R2 > 0.98), and appropriate conversions could be determined within a margin of error less than a ±6% for the plaster-of-Paris cast, and ±4% for the fiberglass cast. We have demonstrated the effects of cast presence on bone microarchitecture measurements, and presented a method to correct for systematic error, in support of future use of HR-pQCT to study fracture healing.

Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial.

Importance: Few studies have assessed the effects of daily vitamin D doses at or above the tolerable upper intake level for 12 months or greater, yet 3% of US adults report vitamin D intakes of at least 4000 IU per day. Objective: To assess the dose-dependent effect of vitamin D supplementation on volumetric bone mineral density (BMD) and strength. Design, Setting, and Participants: Three-year, double-blind, randomized clinical trial conducted in a single center in Calgary, Canada, from August 2013 to December 2017, including 311 community-dwelling healthy adults without osteoporosis, aged 55 to 70 years, with baseline levels of 25-hydroxyvitamin D (25[OH]D) of 30 to 125 nmol/L. Interventions: Daily doses of vitamin D3 for 3 years at 400 IU (n = 109), 4000 IU (n = 100), or 10 000 IU (n = 102). Calcium supplementation was provided to participants with dietary intake of less than 1200 mg per day. Main Outcomes and Measures: Co-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis. Results: Of 311 participants who were randomized (53% men; mean [SD] age, 62.2 [4.2] years), 287 (92%) completed the study. Baseline, 3-month, and 3-year levels of 25(OH)D were 76.3, 76.7, and 77.4 nmol/L for the 400-IU group; 81.3, 115.3, and 132.2 for the 4000-IU group; and 78.4, 188.0, and 144.4 for the 10 000-IU group. There were significant group × time interactions for volumetric BMD. At trial end, radial volumetric BMD was lower for the 4000 IU group (-3.9 mg HA/cm3 [95% CI, -6.5 to -1.3]) and 10 000 IU group (-7.5 mg HA/cm3 [95% CI, -10.1 to -5.0]) compared with the 400 IU group with mean percent change in volumetric BMD of -1.2% (400 IU group), -2.4% (4000 IU group), and -3.5% (10 000 IU group). Tibial volumetric BMD differences from the 400 IU group were -1.8 mg HA/cm3 (95% CI, -3.7 to 0.1) in the 4000 IU group and -4.1 mg HA/cm3 in the 10 000 IU group (95% CI, -6.0 to -2.2), with mean percent change values of -0.4% (400 IU), -1.0% (4000 IU), and -1.7% (10 000 IU). There were no significant differences for changes in failure load (radius, P = .06; tibia, P = .12). Conclusions and Relevance: Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful. Trial Registration: ClinicalTrials.gov Identifier: NCT01900860.

Assessment of Bone Mineral Density at the Distal Femur and the Proximal Tibia by Dual-Energy X-ray Absorptiometry in Individuals With Spinal Cord Injury: Precision of Protocol and Relation to Injury Duration.

Spinal cord injury (SCI) is characterized by marked bone loss at the knee, and there is a need for established dual-energy X-ray absorptiometry (DXA) protocols to examine bone mineral density (BMD) at this location to track therapeutic progress and to monitor fracture risk. The purpose of this study was to quantify the precision and reliability of a DXA protocol for BMD assessment at the distal femur and the proximal tibia in individuals with SCI. The protocol was subsequently used to investigate the relationship between BMD and duration of SCI. Nine individuals with complete SCI and 9 able-bodied controls underwent 3 repeat DXA scans in accordance with the short-term precision methodology recommended by the International Society of Clinical Densitometry. The DXA protocol demonstrated a high degree of precision with the root-mean-square standard deviation ranging from 0.004 to 0.052 g/cm2 and the root-mean-square coefficient of variation ranging from 0.6% to 4.4%, depending on the bone, the region of interest, and the rater. All measurements of intra- and inter-rater reliability were excellent with an intraclass correlation of ≥0.950. The relationship between the BMD and the duration of SCI was well described by a logarithmic trend (r2 = 0.68-0.92). Depending on the region of interest, the logarithmic trends would predict that, after 3 yr of SCI, BMD at the knee would be 43%-19% lower than that in the able-bodied reference group. We believe the DXA protocol has the level of precision and reliability required for short-term assessments of BMD at the distal femur and the proximal tibia in people with SCI. However, further work is required to determine the degree to which this protocol may be used to assess longitudinal changes in BMD after SCI to examine clinical interventions and to monitor fracture risk.

Premature changes in trabecular and cortical microarchitecture result in decreased bone strength in hemophilia.

Low bone density is a growing concern in aging men with hemophilia and may result in high-morbidity fragility fractures. Using high-resolution peripheral quantitative computed tomography (HR-pQCT), we demonstrate low trabecular and cortical bone density contributing to lower volumetric bone mineral density (BMD) at both distal radius and tibia in patients with hemophilia compared with age- and sex-matched controls. The low trabecular bone density found in hemophilia is attributed to significantly decreased trabecular number and increased separation; the lower cortical bone density results from thinner cortices, whereas cortical porosity is maintained. Microfinite element analysis from three-dimensional HR-pQCT images demonstrates that these microarchitectural deficits seen in patients with hemophilia translate into significantly lower estimated failure load (biomechanical bone strength) at the distal tibia and radius when compared with controls. In addition, an inverse association of joint score with BMD and failure load suggests the negative role of hemophilic arthropathy in bone density loss.