Optimizing Filament-Based TCP Scaffold Design for Osteoconduction and Bone Augmentation: Insights from In Vivo Rabbit Models.

Additive manufacturing has emerged as a transformative tool in biomedical engineering, offering precise control over scaffold design for bone tissue engineering and regenerative medicine. While much attention has been focused on optimizing pore-based scaffold architectures, filament-based microarchitectures remain relatively understudied, despite the fact that the majority of 3D-printers generate filament-based structures. Here, we investigated the influence of filament characteristics on bone regeneration outcomes using a lithography-based additive manufacturing approach. Three distinct filament-based scaffolds (Fil050, Fil083, and Fil125) identical in macroporosity and transparency, crafted from tri-calcium phosphate (TCP) with varying filament thicknesses and distance, were evaluated in a rabbit model of bone augmentation and non-critical calvarial defect. Additionally, two scaffold types differing in filament directionality (Fil and FilG) were compared to elucidate optimal design parameters. Distance of bone ingrowth and percentage of regenerated area within scaffolds were measured by histomorphometric analysis. Our findings reveal filaments of 0.50 mm as the most effective filament-based scaffold, demonstrating superior bone ingrowth and bony regenerated area compared to larger size filament (i.e., 0.83 mm and 1.25 mm scaffolds). Optimized directionality of filaments can overcome the reduced performance of larger filaments. This study advances our understanding of microarchitecture's role in bone tissue engineering and holds significant implications for clinical practice, paving the way for the development of highly tailored, patient-specific bone substitutes with enhanced efficacy.

High-resolution three-dimensional micro-computed tomography assessment of micro-architectural patterns in non-adults with cribra orbitalia: Correlation between macro- and micro-scale bone features.

Skeletal porous lesions such as cribra orbitalia (CO) have long been of interest to bioanthropologists worldwide, mainly due to their high prevalence in osteological material. Previous studies considered CO as an external morphological manifestation, and therefore, research has mainly focused on visible (macroscopic) CO patterns. However, the understanding of CO-induced micro-scale bone changes is still scarce. Therefore, we performed high-resolution micro-computed tomography imaging to investigate three-dimensional CO-induced micro-architectural patterns in non-adults, with a particular focus on the correlation between macroscopic and micro-architectural orbital features. Cortical and trabecular micro-architectural changes in the orbital roof were analyzed in non-adults younger than 15 years, using orbital roof samples with and without macroscopic traces of CO (n = 28). A widely accepted five-grade macroscopic CO scoring system was applied to analyze CO severity. Areas affected with CO (area 1) and areas without macroscopic CO traces (area 2) were analyzed separately. The conducted high-resolution analysis showed that cortical and trabecular micro-architecture varied with CO presence, lesion severity (CO grade), and the analyzed area. Inter-grade comparisons suggested that most of the analyzed micro-architectural parameters were not significantly different between adjacent CO grades. Based on the micro-architectural evaluation of areas 1 and 2, the porous lesions were much more extensive than revealed by gross examination. In addition, micro-architectural differences were particularly pronounced in younger non-adults. In summary, our pilot study suggests that the macroscopic examination of CO reflects only the tip of the iceberg, as the micro-architectural changes seem to be much larger than macroscopically identified. RESEARCH HIGHLIGHTS: Cribra orbitalia (CO) represents orbital porous lesions. A high-resolution microscopic assessment of CO-induced changes in non-adults was done by micro-computed tomography. The microarchitecture was affected by CO presence, CO grade, area, and age.

Risk Factors for Bone Microarchitecture Impairments in Older Men with Type 2 Diabetes - The MrOS Study.

CONTEXT: Impaired bone microarchitecture, assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), may contribute to bone fragility in type 2 diabetes (T2DM) but data on men are lacking. OBJECTIVE: To investigate the association between T2DM and HR-pQCT parameters in older men. METHODS: HR-pQCT scans were acquired on 1794 participants in the Osteoporotic Fractures in Men (MrOS) study. T2DM was ascertained by self-report or medication use. Linear regression models, adjusted for age, race, BMI, limb length, clinic site, and oral corticosteroid use, were used to compare HR-pQCT parameters by diabetes status. RESULTS: Among 1777 men, 290 had T2DM (mean age 84.4 years). T2DM men had smaller total cross-sectional area (Tt.AR) at the distal tibia (p=0.028) and diaphyseal tibia (p=0.025), and smaller cortical area at the distal (p= 0.009) and diaphyseal tibia (p= 0.023). Trabecular indices and cortical porosity were similar between T2DM and non-T2DM. Among men with T2DM, in a model including HbA1c, diabetes duration, and insulin use, diabetes duration ≥ 10 years, compared with <10 years, was significantly associated with higher cortical porosity but with higher trabecular thickness at the distal radius. Insulin use was significantly associated with lower cortical area and thickness at the distal radius and diaphyseal tibia and lower failure load at all three scan sites. Lower cortical area, cortical thickness, total BMD, cortical BMD, and failure load of the distal sites were associated with increased risk of incident non-vertebral fracture in T2DM. CONCLUSIONS: Older men with T2DM have smaller bone size compared to non-T2DM, which may contribute to diabetic skeletal fragility. Longer diabetes duration was associated with higher cortical porosity and insulin use with cortical bone deficits and lower failure load.

TPMS Microarchitectures for Vertical Bone Augmentation and Osteoconduction: An In Vivo Study.

Triply periodic minimal surface microarchitectures (TPMS) were developed by mathematicians and evolved in all kingdoms of living organisms. Renowned for their lightweight yet robust attributes, TPMS structures find application in diverse fields, such as the construction of satellites, aircrafts, and electric vehicles. Moreover, these microarchitectures, despite their intricate geometric patterns, demonstrate potential for application as bone substitutes, despite the inherent gothic style of natural bone microarchitecture. Here, we produced three TPMS microarchitectures, D-diamond, G-gyroid, and P-primitive, by 3D printing from hydroxyapatite. We explored their mechanical characterization and, further, implanted them to study their bone augmentation and osteoconduction potential. In terms of strength, the D-diamond and G-gyroid performed significantly better than the P-primitive. In a calvarial defect model and a calvarial bone augmentation model, where osteoconduction is determined as the extent of bony bridging of the defect and bone augmentation as the maximal vertical bone ingrowth, the G-gyroid performed significantly better than the P-primitive. No significant difference in performance was observed between the G-gyroid and D-diamond. Since, in real life, the treatment of bone deficiencies in patients comprises elements of defect bridging and bone augmentation, ceramic scaffolds with D-diamond and G-gyroid microarchitectures appear as the best choice for a TPMS-based scaffold in bone tissue engineering.

Distinguishing risk of curve progression in adolescent idiopathic scoliosis with bone microarchitecture phenotyping - a 6-year longitudinal study.

Low bone mineral density and impaired bone qualities have been shown to be important prognostic factors for curve progression in Adolescent Idiopathic Scoliosis (AIS). There is no evidence-based integrative interpretation method to analyse high-resolution peripheral quantitative computed tomography (HR-pQCT) data in AIS. This study aimed to (a) utilize unsupervised machine learning to cluster bone microarchitecture phenotypes on HR-pQCT parameters in AIS girls, (b) assess the phenotypes' risk of curve progression and progression to surgical threshold at skeletal maturity (primary cohort), and (c) investigate risk of curve progression in a separate cohort of mild AIS girls whose curve severity did not reach bracing threshold at recruitment (secondary cohort). Patients were followed up prospectively for 6.22 ± 0.33 years in the primary cohort (N = 101). Three bone microarchitecture phenotypes were clustered by Fuzzy C-Means at time of peripubertal peak height velocity (PHV). Phenotype-1 had normal bone characteristics. Phenotype-2 was characterized by low bone volume and high cortical bone density, and Phenotype-3 had low cortical and trabecular bone density and impaired trabecular microarchitecture. The difference in bone qualities amongst the phenotypes was significant at peripubertal PHV and continued to skeletal maturity. Phenotype-3 had significantly increased risk of curve progression to surgical threshold at skeletal maturity (Odd Ratios (OR) = 4.88; 95% Confidence Interval (CI): 1.03-28.63). In the secondary cohort (N = 106), both Phenotype-2 (adjusted OR = 5.39; 95%CI: 1.47-22.76) and Phenotype-3 (adjusted OR = 3.67; 95%CI: 1.05-14.29) had increased risk of curve progression ≥6° with mean follow-up of 3.03 ± 0.16 years. In conclusion, three distinct bone microarchitecture phenotypes could be clustered by unsupervised machine learning on HR-pQCT generated bone parameters at peripubertal PHV in AIS. The bone qualities reflected by these phenotypes were found to have significant differentiating risk of curve progression and progression to surgical threshold at skeletal maturity in AIS.

Adolescent Idiopathic Scoliosis (AIS) is an abnormal spinal curvature commonly presents during puberty growth. Evidence has shown that low bone mineral density and impaired bone qualities are important risk factors for curve progression in AIS. High-resolution peripheral quantitative computed tomography (HR-pQCT) has improved our understanding of bone qualities in AIS. It generates a large amount of quantitative and qualitative bone parameters from a single measurement, but the data are not easy for clinicians to interpret and analyse. This study enrolled AIS girls and used unsupervised machine learning model to analyse their HR-pQCT data at first clinic visit. The model clustered the patients into 3 bone microarchitecture phenotypes (i.e. Phenotype-1: normal, Phenotype-2: low bone volume and high cortical bone density, and Phenotype-3: low cortical and trabecular bone density and impaired trabecular microarchitecture). They were longitudinally followed up for 6 years until skeletal maturity. We observed the three phenotypes were persistent, and Phenotype-3 had a significantly increased risk of curve progression to severity that requires invasive spinal surgery (Odds Ratio = 4.88, P = 0.029). The difference in bone qualities reflected by these 3 distinct phenotypes could aid clinicians to differentiate risk of curve progression and surgery at early stages of AIS.

Photon-Counting Computed Tomography for Microstructural Imaging of Bone and Joints.

PURPOSE OF REVIEW: Recently, photon-counting computed tomography (PCCT) has been introduced in clinical research and diagnostics. This review describes the technological advances and provides an overview of recent applications with a focus on imaging of bone. RECENT FINDINGS: PCCT is a full-body scanner with short scanning times that provides better spatial and spectral resolution than conventional energy-integrating-detector CT (EID-CT), along with an up to 50% reduced radiation dose. It can be used to quantify bone mineral density, to perform bone microstructural analyses and to assess cartilage quality with adequate precision and accuracy. Using a virtual monoenergetic image reconstruction, metal artefacts can be greatly reduced when imaging bone-implant interfaces. Current PCCT systems do not allow spectral imaging in ultra-high-resolution (UHR) mode. Given its improved resolution, reduced noise and spectral imaging capabilities PCCT has diagnostic capacities in both qualitative and quantitative imaging that outperform those of conventional CT. Clinical use in monitoring bone health has already been demonstrated. The full potential of PCCT systems will be unlocked when UHR spectral imaging becomes available.

Association between sleep microarchitecture and cognition in obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) increases the risk of cognitive impairment. Measures of sleep microarchitecture from EEG may help identify patients at risk of this complication. METHODS: Participants with suspected OSA (n=1142) underwent in-laboratory polysomnography and completed sleep and medical history questionnaires, and tests of global cognition (Montreal Cognitive Assessment, MoCA), memory (Rey Auditory Verbal Learning Test, RAVLT) and information processing speed (Digit-Symbol Coding, DSC). Associations between cognitive scores and stage 2 NREM sleep spindle density, power, frequency and %-fast (12-16Hz), odds-ratio product (ORP), normalized EEG power (EEGNP) and the delta:alpha ratio were assessed using multivariable linear regression (MLR) adjusted for age, sex, education, and total sleep time. Mediation analyses were performed to determine if sleep microarchitecture indices mediate the negative effect of OSA on cognition. RESULTS: All spindle characteristics were lower in participants with moderate and severe OSA (p≤0.001, versus no/mild OSA) and positively associated with MoCA, RAVLT and DSC scores (false discovery rate corrected p-value, q≤0.026), except spindle power which was not associated with RAVLT (q=0.185). ORP during NREM sleep (ORPNREM) was highest in severe OSA participants (p≤0.001) but neither ORPNREM (q≥0.230) nor the delta:alpha ratio were associated with cognitive scores in MLR analyses (q≥0.166). In mediation analyses, spindle density and EEGNP (p≥0.048) mediated moderate-to-severe OSA's negative effect on MoCA scores while ORPNREM, spindle power and %-fast spindles mediated OSA's negative effect on DSC scores (p≤0.018). CONCLUSION: Altered spindle activity, ORP and normalized EEG power may be important contributors to cognitive deficits in patients with OSA.

Investigating the three-dimensional myocardial micro-architecture in the laminar structure using X-ray phase-contrast microtomography.

A comprehensive grasp of the myocardial micro-architecture is essential for understanding diverse heart functions. This study aimed to investigate three-dimensional (3D) cardiomyocyte arrangement in the laminar structure using X-ray phase-contrast microtomography. Using the ID-19 beamline at the European Synchrotron Radiation Facility, we imaged human left ventricular (LV) wall transparietal samples and reconstructed them with an isotropic voxel edge length of 3.5 µm. From the reconstructed volumes, we extracted different regions to analyze the orientation distribution of local cardiomyocyte aggregates, presenting findings in terms of helix and intrusion angles. In regions containing one sheetlet population, we observed cardiomyocyte aggregates running along the local LV wall's radial direction at the border of sheetlets, branching and merging into a complex network around connecting points of different sheetlets, and bending to accommodate vessel passages. In regions with two sheetlet populations, the helix angle of local cardiomyocyte aggregates experiences a nonmonotonic change, and some cardiomyocyte aggregates run along the local radial direction. X-ray phase-contrast microtomography is a valuable technique for investigating the 3D local myocardial architecture at microscopic level. The arrangement of local cardiomyocyte aggregates in the LV wall proves to be both regional and complex, intricately linked to the local laminar structure.

Prior Nonmelanoma Skin Cancer is Associated with Fewer Fractures, More Vitamin D Sufficiency, Greater Bone Mineral Density, and Improved Bone Microarchitecture in Older Adults.

BACKGROUND: Prior nonmelanoma skin cancer (NMSC), a biomarker of cumulative lifetime sun exposure, is associated with reduced fracture risk later in life. The mechanism is unknown. METHODS: Prospective cohort analysis of 1099 community-dwelling adults aged 50-80 years with baseline and 10-year follow-up assessments. Histopathologically-confirmed NMSC diagnosis was established by linkage with the Tasmanian Cancer Registry. Bone mineral density (BMD) and vertebral deformity were quantified by DXA, 25-hydroxyvitamin D (25(OH)D) by radioimmunoassay, bone microarchitecture by high-resolution peripheral quantitative CT, melanin density by spectrophotometry, and skin photosensitivity and clinical fracture by questionnaire. 25(OH)D <50 nmol/L was considered deficient. RESULTS: Participants with an NMSC reported prior to baseline were less likely to sustain an incident vertebral deformity over 10 years (RR = 0.74, P = .036). There were similar reductions for other fracture types but these did not reach significance. Prior NMSC was associated with baseline (RR = 1.23, P = .005) and 10-year longitudinal (RR = 5.9, P = .014) vitamin D sufficiency and greater total body BMD (ß = 0.021g/cm2, P = .034), but not falls risk or muscle strength. The relationship between prior NMSC and bone microarchitecture was age-dependent (pinteraction < 0.05). In the oldest age tertile, prior NMSC was associated with greater volumetric BMD (ß = 57.8-62.6, P = .002-0.01) and less porosity (ß = -4.6 to -5.2, P = .002-0.009) at cortical, compact cortical and outer transitional zones. CONCLUSIONS: Prior NMSC was associated with fewer incident fractures in community-dwelling older adults. This protective association is most likely mediated by modifiable fracture risk factors associated with an outdoor lifestyle, including 25(OH)D, BMD, and bone microarchitecture.

Impact of pheochromocytoma or paraganglioma on bone metabolism: A systemic review and meta-analysis.

INTRODUCTION: Preclinical and animal studies have suggested that excess catecholamines can lead to bone mineral loss. However, to date, no systematic review is available that has analyzed the impact of catecholamine excess in the context of pheochromocytoma/paraganglioma (PPGL) on bone metabolism. We conducted this meta-analysis to address this knowledge gap. METHODS: Electronic databases were searched for studies evaluating bone metabolism, including assessments of bone mineral density (BMD), quantitative computed tomography (qCT), trabecular bone score (TBS), or bone turnover markers in patients with PPGL. These markers included those of bone resorption, such as tartrate-resistant acid phosphatase 5b (TRACP-5b) and cross-linked C-telopeptide of type I collagen (CTx), as well as markers of bone formation, such as bone-specific alkaline phosphatase (BS ALP). RESULTS: Out of the initially screened 1614 articles, data from six studies published in four different patient cohorts with PPGL that met all criteria were analysed. Individuals with PPGL had significantly lower TBS [Mean Difference (MD) -0.04 (95% CI: -0.05--0.03); p < 0.00001; I2 = 0%], higher serum CTx [MD 0.13 ng/ml (95% CI: 0.08-0.17); p < 0.00001; I2 = 0%], and higher BS-ALP [MD 1.47 U/L (95% CI: 0.30-2.64); p = 0.01; I2 = 1%]. TBS at 4-7 months post-surgery was significantly higher compared to baseline [MD 0.05 (95% CI: 0.02-0.07); p < 0.0001]. A decrease in CTx has been documented post-surgery. CONCLUSION: Bone health deterioration is a major concern in patients with PPGL. In addition to providing a definitive cure for catecholamine excess, monitoring and treating osteoporosis is essential for individuals with secondary osteoporosis due to PPGL. Long-term studies on bone health outcomes in PPGL are warranted.

Associations of marrow fat fraction with MR imaging based trabecular bone microarchitecture in first-time diagnosed type 1 diabetes mellitus.

Purpose: To determine whether there are alterations in marrow fat content in individuals first-time diagnosed with type 1 diabetes mellitus (T1DM) and to explore the associations between marrow fat fraction and MRI-based findings in trabecular bone microarchitecture. Method: A case-control study was conducted, involving adults with first-time diagnosed T1DM (n=35) and age- and sex-matched healthy adults (n=46). Dual-energy X-ray absorptiometry and 3 Tesla-MRI of the proximal tibia were performed to assess trabecular microarchitecture and vertebral marrow fat fraction. Multiple linear regression analysis was used to test the associations of marrow fat fraction with trabecular microarchitecture and bone density while adjusting for potential confounding factors. Results: In individuals first-time diagnosed with T1DM, the marrow fat fraction was significantly higher (p < 0.001) compared to healthy controls. T1DM patients also exhibited higher trabecular separation [median (IQR): 2.19 (1.70, 2.68) vs 1.81 (1.62, 2.10), p < 0.001], lower trabecular volume [0.45 (0.30, 0.56) vs 0.53 (0.38, 0.60), p = 0.013], and lower trabecular number [0.37 (0.26, 0.44) vs 0.41 (0.32, 0.47), p = 0.020] compared to controls. However, bone density was similar between the two groups (p = 0.815). In individuals with T1DM, there was an inverse association between marrow fat fraction and trabecular volume (r = -0.69, p < 0.001) as well as trabecular number (r = -0.55, p < 0.001), and a positive association with trabecular separation (r = 0.75, p < 0.001). Marrow fat fraction was independently associated with total trabecular volume (standardized ß = -0.21), trabecular number (ß = -0.12), and trabecular separation (ß = 0.57) of the proximal tibia after adjusting for various factors including age, gender, body mass index, physical activity, smoking status, alcohol consumption, blood glucose, plasma glycated hemoglobin, lipid profile, and bone turnover biomarkers. Conclusions: Individuals first-time diagnosed with T1DM experience expansion of marrow adiposity, and elevated marrow fat content is associated with MRI-based trabecular microstructure.

Super-resolution of clinical CT: Revealing microarchitecture in whole bone clinical CT image data.

Osteoporotic fractures, prevalent in the elderly, pose a significant health and economic burden. Current methods for predicting fracture risk, primarily relying on bone mineral density, provide only modest accuracy. If better spatial resolution of trabecular bone in a clinical scan were available, a more complete assessment of fracture risk would be obtained using microarchitectural measures of bone (i.e. trabecular thickness, trabecular spacing, bone volume fraction, etc.). However, increased resolution comes at the cost of increased radiation or can only be applied at small volumes of distal skeletal locations. This study explores super-resolution (SR) technology to enhance clinical CT scans of proximal femurs and better reveal the trabecular microarchitecture of bone. Using a deep-learning-based (i.e. subset of artificial intelligence) SR approach, low-resolution clinical CT images were upscaled to higher resolution and compared to corresponding MicroCT-derived images. SR-derived 2-dimensional microarchitectural measurements, such as degree of anisotropy, bone volume fraction, trabecular spacing, and trabecular thickness were within 16 % error compared to MicroCT data, whereas connectivity density exhibited larger error (as high as 1094 %). SR-derived 3-dimensional microarchitectural metrics exhibited errors <18 %. This work showcases the potential of SR technology to enhance clinical bone imaging and holds promise for improving fracture risk assessments and osteoporosis detection. Further research, including larger datasets and refined techniques, can advance SR's clinical utility, enabling comprehensive microstructural assessment across whole bones, thereby improving fracture risk predictions and patient-specific treatment strategies.

Impaired bone mineral density and microarchitecture in female adolescents with IgE-mediated cow's milk allergy.

This study compared the bone parameters of adolescents with persistent cow's milk allergy (CMA) with those of healthy adolescents. Adolescents with CMA had compromised bone parameters (lower bone mineral density, impaired trabecular microarchitecture, and lower bone strength). Partial exclusion diet was associated with better bone parameters than total exclusion diet. BACKGROUND: Persistent immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) may impair bone parameters and increase the risk of fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a novel methodology that not only assesses trabecular and cortical bone compartments and volumetric density measurements, but also evaluates bone microarchitecture and estimates biomechanical properties through finite element analysis (FEA). Both HR-pQCT and bone strength parameters derived from FEA have shown a strong correlation with fracture risk. PURPOSE: To assess the bone density, microarchitecture, and bone strength of adolescents with persistent IgE-mediated CMA (IgE-CMA). METHODS: This was an observational, cross-sectional study with female adolescents with persistent IgE-CMA and healthy control participants matched by female sex and sexual maturation. Bone parameters were assessed by areal bone mineral density (aBMD) through dual-energy X-ray absorptiometry (DXA), bone microarchitecture by HR-pQCT at the radius and tibia, and laboratory markers related to bone metabolism. RESULTS: The median age of adolescents with persistent IgE-CMA (n = 26) was 13.0 years (interquartile range (IQR) 11.4-14.7) and of healthy control participants (n = 28) was 13.6 years (IQR 11.9-14.9). Adolescents with IgE-CMA ingested 27.4% less calcium (p = 0.012) and 28.8% less phosphorus (p = 0.009) than controls. Adolescents with IgE-CMA had lower bone mineral content (BMC) (38.83 g vs. 44.50 g) and aBMD (0.796 g/cm2 vs. 0.872 g/cm2) at lumbar spine, and lower BMC (1.11 kg vs. 1.27 kg) and aBMD (0.823 g/cm2 vs. 0.877 g/cm2) at total body less head (TBLH) (p < 0.05). However, Z-scores BMC and Z-scores aBMD at lumbar spine and TBLH, when adjusted for Z-score height/age, were not significantly different between the groups. Moreover, CMA adolescents had lower bone strength at the distal tibia (S 169 kN/mm vs. 194 kN/mm; F Load 8030 N vs. 9223 N) (p < 0.05). Pairing of groups by the presence of menarche showed compromised parameters at the tibia-lower total volumetric BMD (Tt.vBMD) (293.9 mg HA/cm3 vs. 325.9 mg HA/cm3) and trabecular vBMD (Tb.vBMD) (170.8 mg HA/cm3 vs. 192.2 mg HA/cm3), along with lower cortical thickness (Ct.th) (1.02 mm vs. 1.16 mm) and bone strength (S 174 kN vs. 210 kN; F Load 8301 N vs. 9950 N)-and at the radius (S 61 kN/mm vs. 71 kN/mm; F Load 2920 N vs. 3398 N) (p < 0.05) among adolescents with IgE-CMA. Adolescents with IgE-CMA on a total exclusion diet (n = 12) showed greater impairment of bone features than those on a partial exclusion diet (n = 14), with lower lumbar spine Z-score BMC (- 0.65 vs. 0.18; p = 0.013), lumbar spine trabecular bone score (TBS) (1.268 vs. 1.383; p = 0.005), Z-score TBS (0.03 vs. 1.14; p = 0.020), TBLH Z-score BMC (- 1.17 vs. - 0.35; p = 0.012), TBLH Z-score aBMD (- 1.13 vs. - 0.33; p = 0.027), Tt.vBMD at the tibia (259.0 mg HA/cm3 vs. 298.7 mg HA/cm3; p = 0.021), Ct.th at the tibia (0.77 mm vs. 1.04 mm; p = 0.015) and Ct.th at the radius (0.16 mm vs. 0.56 mm; p = 0.033). CONCLUSION: Adolescents with persistent IgE-CMA had lower aBMD and compromised microarchitecture (impaired trabecular microarchitecture and lower bone strength). Adolescents on a partial exclusion diet had better bone parameters than those on a total exclusion diet.

Vascular function and skeletal fragility: A study of tonometry, brachial hemodynamics, and bone microarchitecture.

Osteoporosis and cardiovascular disease frequently occur together in older adults; however, a causal relationship between these two common conditions has not been established. By the time clinical cardiovascular disease develops, it is often too late to test whether vascular dysfunction developed before or after the onset of osteoporosis. Therefore, we assessed the association of vascular function, measured by tonometry and brachial hemodynamic testing, with bone density, microarchitecture, and strength, measured by high-resolution peripheral quantitative computed tomography (HR-pQCT), in 1391 individuals in the Framingham Heart Study. We hypothesized that decreased vascular function (pulse wave velocity, primary pressure wave, brachial pulse pressure, baseline flow amplitude and brachial flow velocity) contributes to deficits in bone density, microarchitecture and strength, particularly in cortical bone, which is less protected from excessive blood flow pulsatility than the trabecular compartment. We found that individuals with increased carotid-femoral pulse wave velocity had lower cortical volumetric bone mineral density (tibia: -0.21 [-0.26,-0.15] standardized beta [95% confidence interval], radius: -0.20 [-0.26,-0.15]), lower cortical thickness (tibia: -0.09 [-0.15,-0.04], radius: -0.07 [-0.12,-0.01]) and increased cortical porosity (tibia: 0.20 [0.15,0.25], radius: 0.21 [0.15,0.27]). However, these associations did not persist after adjustment for age, sex, height, and weight. These results suggest that vascular dysfunction with aging may not be an etiologic mechanism that contributes to the co-occurrence of osteoporosis and cardiovascular disease in older adults. Further study employing longitudinal measures of HR-pQCT parameters is needed to fully elucidate the link between vascular function and bone health.

Osteoporosis and heart disease are both medical conditions that commonly develop in older age. It is not known whether abnormal functioning of blood vessels contributes to the development of bone fragility with aging. In this study, we investigated the relationship between impaired blood vessel function and bone density and micro-structure in a group of 1391 people enrolled in the Framingham Heart Study. Blood vessel function was measured using specialized tools to assess blood flow and pressure. Bone density and micro-structure were measured using advanced imaging called high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that people with impaired blood vessel function tended to have lower bone density and worse deterioration in bone micro-structure. However, once we statistically controlled for age and sex and other confounders, we did not find any association between blood vessel function and bone measures. Overall, our results showed that older adults with impaired blood vessel function do not exhibit greater deterioration in the skeleton.

Mild hyponatremia is not associated with degradation of trabecular bone microarchitecture despite bone mass loss.

CONTEXT: Hyponatremia is associated with increased risk of osteoporosis and fractures. The impact of hyponatremia on non-invasive indices of bone quality, however, is unknown. OBJECTIVE: To evaluate whether trabecular bone microarchitecture, assessed non-invasively by trabecular bone score (TBS), is altered in patients with hyponatremia. METHODS: We conducted a cross-sectional analysis of the population-based 2005-2008 cycles of the National Health and Nutrition Examination Survey (NHANES), in which TBS measurement was performed. The main outcome measures were TBS values and bone mineral density (BMD) T-scores at the lumbar spine, total hip and femoral neck. RESULTS: A total of 4204 subjects aged 50 years or older were included (4041 normonatremic, 163 hyponatremic - 90.8% with mild hyponatremia). Univariate analyses did not show any difference in TBS between patients with and without hyponatremia (1.308 ± 0.145 vs 1.311 ± 0.141, p = 0.806). Hyponatremic subjects had lower BMD T-score at total hip (-0.70 ± 1.46 vs -0.13 ± 1.32, p < 0.001) and femoral neck (-1.11 ± 1.26 vs -0.72 ± 1.14, p = 0.004), while no difference was observed at lumbar spine (-0.27 ± 1.63 vs -0.31 ± 1.51, p = 0.772). After adjustment for relevant confounders, hyponatremia was confirmed as an independent predictor of lower BMD T-score at the total hip (ß=-0.20, 95%CI:[-0.39, -0.02], p = 0.029), while the significance was lost at the femoral neck (p = 0.308). Again, no association between hyponatremia and lumbar spine BMD (p = 0.236) or TBS (p = 0.346) was observed. CONCLUSIONS: Hyponatremia, at least in mild forms, is not associated with a degradation of trabecular microarchitecture, assessed non-invasively by TBS. An independent association between hyponatremia and loss of bone mass is confirmed, particularly at the total hip.

Evaluation of Trabecular Bone Microarchitecture and Bone Mineral Density in Young Women, Including Selected Hormonal Parameters.

The absence of non-invasive methods for assessing bone material and structural changes is a significant diagnostic challenge. Dual-energy X-ray absorptiometry (DXA) bone mineral density (BMD) testing is the gold standard for osteoporosis diagnosis. BMD and the trabecular bone score (TBS) have facilitated targeted osteoporosis prevention and treatment in clinical settings. The findings from this study indicate that BMD modulation in young women is influenced by various hormones, potentially compromising the diagnostic precision of BMD for subclinical bone demineralization. A total of 205 women aged 19 to 37 underwent anthropometric measurements and hormonal tests. BMD was determined using DXA, and TBS values were computed from the lumbar spine L1-L4 segment. The multivariate analysis findings suggest that BMD might not be determined by hormones. The relationship between TBS and TSH was statistically significant in the univariate analysis, which indicates the efficacy of further studies to determine the link between TBS and specific hormones. Analyzing the strength of the correlation between TBS and hormones in the univariate analysis shows which factors are worth considering in further analyses. This makes it possible to create better techniques that will help identify young women who are at a higher risk of developing osteoporosis.

Trabecular bone score (TBS) in Cushing's disease: TBS gain after hypercortisolism normalization.

CONTEXT: Hypercortisolism frequently induces trabecular bone loss, more pronounced at the lumbar spine, resulting in osteoporosis, and thus an increase in fracture risk. Several studies have shown bone mass recovery in patients with Cushing's disease (CD) after treatment. OBJECTIVE: To examine treatment effects on TBS (trabecular bone score) in addition to aBMD (areal bone mineral density) in a cohort of patients with CD. DESIGN AND SETTING: Single-center retrospective longitudinal study in patients diagnosed with CD and successfully treated following surgery and/or medical treatment. PATIENTS: We included 31 patients with median age and BMI (body mass index) of 37.7 [28.4;43.3] years old and 27.7 [25.8;30.4] kg/m2, respectively. Median 24 h urinary cortisol before treatment was 213.4 [168.5;478.5] µg/24 h. All subjects were completely biochemically controlled or cured after treatment. MAIN OUTCOME MEASURES: aBMD and TBS were evaluated at AP Spine (L1-L4) with DXA prodigy (GE-Lunar), QDR 4500 (Hologic), and TBS iNsight® (Med-Imaps) before and after treatment. RESULTS: Absolute TBS and aBMD gains following cure of CD were significant (p < 0.0001, and p < 0.001, respectively). aBMD and TBS increased by +3.9 and 8.2 % respectively after cure of CD. aBMD and TBS were not correlated before (p = 0.43) and after treatment (p = 0.53). Linear regression analyses showed that TBS gain was independent of baseline BMI and that low TBS at baseline was predictive of TBS gain after treatment. CONCLUSION: The more significant improvement of microarchitecture assessed by TBS than aBMD and the absence of correlation between TBS and aBMD suggest that TBS may be an adequate marker of bone restoration after cure of CD. To support this conclusion, future studies with larger sample sizes and longer follow-up periods should be carried out.

Rapid bone microarchitecture decline in older men with high bone turnover-the prospective STRAMBO study.

Older men with high bone turnover have faster bone loss. We assessed the link between the baseline levels of bone turnover markers (BTMs) and the prospectively assessed bone microarchitecture decline in men. In 825 men aged 60-87 yr, we measured the serum osteocalcin (OC), bone alkaline phosphatase (BAP), N-terminal propeptide of type I procollagen (PINP), and C-terminal telopeptide of type I collagen (CTX-I), and urinary total deoxypyridinoline (tDPD). Bone microarchitecture and strength (distal radius and distal tibia) were estimated by high-resolution pQCT (XtremeCT, Scanco Medical) at baseline and then after 4 and 8 yr. Thirty-seven men took medications affecting bone metabolism. Statistical models were adjusted for age and BMI. At the distal radius, the decrease in the total bone mineral density (Tt.BMD), cortical BMD (Ct.BMD), cortical thickness (Ct.Thd), and cortical area (Ct.Ar) and failure load was faster in the highest vs the lowest CTX-I quartile (failure load: -0.94 vs -0.31% yr-1, P < .001). Patterns were similar for distal tibia. At the distal tibia, bone decline (Tt.BMD, Ct.Thd, Ct.Ar, Ct.BMD, and failure load) was faster in the highest vs the lowest tDPD quartile. At each skeletal site, the rate of decrease in Tb.BMD differed between the extreme OC quartiles (P < .001). Men in the highest BAP quartile had a faster loss of Tt.BMD, Tb.BMD, reaction force, and failure load vs the lowest quartile. The link between PINP and bone decline was poor. The BTM score is the sum of the nos. of the quartiles for each BTM. Men in the highest quartile of the score had a faster loss of cortical bone and bone strength vs the lowest quartile. Thus, in the older men followed prospectively for 8 yr, the rate of decline in bone microarchitecture and estimated bone strength was 50%-215% greater in men with high bone turnover (highest quartile, CTX-I above the median) compared to the men with low bone turnover (lowest quartile, CTX-I below the median).

Predicting the Fracture Toughness of Human Cancellous Bone in Fractured Neck of Femur Patients Using Bone Volume and Micro-Architecture.

The current protocol used to determine if an individual is osteoporotic relies on assessment of the individual's bone mineral density (BMD), which allows clinicians to judge the condition of a patient with respect to their peers. This, in essence, evaluates a person's fracture risk, because BMD is a good surrogate measure for strength and stiffness. In recent studies, the authors were the first to produce fracture toughness (FT) data from osteoporotic (OP) and osteoarthritic (OA) patients, by using a testing technique which basically analyzes the prerequisite stress conditions for the onset of growth of a major crack through cancellous bone tissue. FT depends mainly on bone quantity (BV/TV, bone volume/tissue volume), but also on bone micro-architecture (mArch), the inner trabecular design of the bone. The working research hypothesis of the present study is that mArch offers added prediction power to BV/TV in determining FT parameters. Consequently, our aim was to investigate the use of predictive models for fracture toughness and also to investigate if there are any significant differences between the models produced from samples loaded across (AC, transverse to) the main trabecular orientation and along (AL, in parallel) the trabeculae. In multilinear regression analysis, we found that the strength of the relationships varied for a crack growing in these two orthogonal directions. Adding mArch variables in the Ac direction helped to increase the R2 to 0.798. However, in the AL direction, adding the mArch parameters did not add any predictive power to using BV/TV alone; BV/TV on its own could produce R2 = 0.730. The present results also imply that the anisotropic layout of the trabeculae makes it more difficult for a major crack to grow transversely across them. Cancellous bone models and remodels itself in a certain way to resist fracture in a specific direction, and thus, we should be mindful that architectural quality as well as bone quantity are needed to understand the resistance to fracture.

Calcified Cartilage-Guided Identification of Osteogenic Molecules and Geometries.

Calcified cartilage digested by chondroclasts provides an excellent scaffold to initiate bone formation. We analyzed bioactive proteins and microarchitecture of calcified cartilage either separately or in combination and evaluated biomimetic osteogenic culture conditions of surface-coated micropatterning. To do so, we prepared a crude extract from porcine femoral growth plates, which enhanced in vitro mineralization when coated on flat-bottom culture dishes, and identified four candidate proteins by fractionation and mass spectrometry. Murine homologues of two candidates, desmoglein 4 (DSG4) and peroxiredoxin 6 (PRDX6), significantly promoted osteogenic activity based on in vitro mineralization and osteoblast differentiation. Moreover, we observed DSG4 and PRDX6 protein expression in mouse femur. In addition, we designed circular, triangular, and honeycomb micropatterns with 30 or 50 µm units, either isolated or connected, to mimic hypertrophic chondrocyte-sized compartments. Isolated, larger honeycomb patterns particularly enhanced osteogenesis in vitro. Mineralization on micropatterns was positively correlated with the reduction of osteoblast migration distance in live cell imaging. Finally, we evaluated possible combinatorial effects of coat proteins and micropatterns and observed an additive effect of DSG4 or PRDX6 coating with micropatterns. These data suggest that combining a bioactive surface coating with osteogenic micropatterns may recapitulate initiation of bone formation during endochondral ossification.