Deterioration of Cortical Bone Microarchitecture: Critical Component of Renal Osteodystrophy Evaluation

Background: Cortical bone is a significant determinant of bone strength and its deterioration contributes to bone fragility. Thin cortices and increased cortical porosity have been noted in patients with chronic kidney disease (CKD), but the “Turnover Mineralization Volume” classification of renal osteodystrophy does not emphasize cortical bone as a key parameter. We aimed to assess trabecular and cortical bone microarchitecture by histomorphometry and micro-CT in patients with CKD G5 and 5D (dialysis). Methods: Transiliac bone biopsies were performed in 14 patients undergoing kidney transplantation (n = 12) and parathyroidectomy (n = 2). Structural parameters were analysed by histomorphometry and micro-CT including trabecular bone volume, thickness (TbTh), number (TbN) and separation and cortical thickness (CtTh) and porosity (CtPo). Indices of bone remodelling and mineralisation were obtained and relationships to bone biomarkers examined. Associations were determined by Spearman’s or Pearson’s rank correlation coefficients. Results: By micro-CT, trabecular parameters were within normal ranges in most patients, but all patients showed very low CtTh (127 ± 44 µm) and high CtPo (60.3 ± 22.5%). CtPo was inversely related to TbN (r = –0.56; p = 0.03) by micro-CT and to TbTh (r = –0.60; p = 0.024) by histomorphometry and correlated to parathyroid hormone values (r = 0.62; p = 0.021). By histomorphometry, bone turnover was high in 50%, low in 21% and normal in 29%, while 36% showed abnormal patterns of mineralization. Significant positive associations were observed between osteoblast surface, osteoclast surface, mineralization surface and bone turnover markers. Conclusions: Deterioration of cortical microarchitecture despite predominantly normal trabecular parameters reinforces the importance of comprehensive cortical evaluation in patients with CKD.

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FC 124PATTERNS OF RENAL OSTEODYSTROPHY ONE YEAR AFTER KIDNEY TRANSPLANTATION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab147.003 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Hanne Skou Jørgensen ◽

Geert Behets ◽

Patrick D'Haese ◽

Pieter Evenepoel

Keyword(s):

Kidney Transplantation ◽

Bone Turnover ◽

Kidney Transplant ◽

Renal Osteodystrophy ◽

Bone Disease ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Post Transplant ◽

Steroid Dose ◽

Bone Biopsies

Abstract Background and Aims Bone disease after kidney transplantation is an issue of growing concern, as prolonged graft survival and older age of recipients necessitate focus on long-term health burdens such as osteoporosis and fractures. Pre-existing type of renal osteodystrophy, post-transplant immunosuppressive treatment, and de novo disturbances of mineral metabolism all contribute to bone disease in kidney transplant recipients. The current pattern of renal osteodystrophy after kidney transplantation is not well characterized. This study reports histomorphometric findings of protocolled bone biopsies in a large cohort of kidney transplant recipients 1 year post-transplant. Method Histomorphometric analysis of transiliac bone biopsies with prior tetracycline labelling was performed in 141 kidney transplant recipients. Biochemical measurements included bioactive parathyroid hormone (PTH), total calcium, phosphate, calcidiol, bicarbonate, and sclerostin. Kruskal-Wallis and Wilcoxon signed rank tests were used to evaluate differences across categories and between groups, respectively. Stepwise multivariate linear regression was performed to identify key demographic and biochemical determinants of bone turnover (bone formation rate, BFR), mineralization (mineralization lag time, Mlt), and volume (Bone area, BAr). Results Mean age was 57±11 years, 71% were men, and all were Caucasian. Mean eGFR was 49±16 (range 19 to 106) ml/min/1.73 m². Hyperparathyroidism (PTH > 1.5xUNL) was seen in 48%, hypercalcemia (>10.3 mg/dL) in 18%, hypophosphatemia (<2.3 mg/dl) in 12%, and vitamin D deficiency (<15 ng/mL) in 4% of patients. Categorization of bone turnover, mineralization, and volume is shown in Figure 1. Bone turnover was normal in the vast majority (71%). Patients with low turnover (26%) had received a higher cumulative steroid dose (2.78 vs 2.34g in low vs non-low turnover; p=0.02). Patients with delayed mineralization (16%) were younger (52 vs 58 yrs, p=0.02) and had received a higher cumulative steroid dose (2.85 vs 2.36g, p=0.003). They had higher levels of PTH (124 vs 53 ng/L, p<0.001), and lower levels of phosphate (2.68 vs 3.18 mg/dL, p<0.001), calcidiol (29 vs 37ug/L, p=0.02), bicarbonate (21.3 vs 23.3 mmol/L, p=0.004), and sclerostin (493 vs 594 pg/mL, p=0.03) compared to patients with normal mineralization. Patients with low bone volume tended to be older (61 vs 56 years, p=0.07). Independent determinants of BFR were PTH (β=0.68, p<0.001) and cumulative steroid dose (β = -0.22, p=0.02). Determinants of Mlt were phosphate (β=-0.48, p=0.001) and cumulative steroid dose (β=0.18, p=0.004), and determinants of BAr were age (β=-0.15, p=0.002), and BMI (β=0.33, p=0.002). Conclusion Bone turnover is normal in the majority of kidney transplant recipients at 1 year post-transplant, despite a high prevalence of hyperparathyroidism. Low levels of bicarbonate, phosphate, and calcidiol may contribute to delayed bone mineralization in kidney transplant recipients.

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A Comparison of Micro-CT and Dental CT in Assessing Cortical Bone Morphology and Trabecular Bone Microarchitecture

PLoS ONE ◽

10.1371/journal.pone.0107545 ◽

2014 ◽

Vol 9 (9) ◽

pp. e107545 ◽

Cited By ~ 19

Author(s):

Jui-Ting Hsu ◽

Ying-Ju Chen ◽

Jung-Ting Ho ◽

Heng-Li Huang ◽

Shun-Ping Wang ◽

...

Keyword(s):

Trabecular Bone ◽

Cortical Bone ◽

Bone Microarchitecture ◽

Micro Ct ◽

Bone Morphology ◽

Trabecular Bone Microarchitecture ◽

Dental Ct

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Technetium-99 Conjugated with Methylene Diphosphonate Ameliorates Glucocorticoid Induced Osteoporosis by Inhibiting Osteoclastogenesis

BioMed Research International ◽

10.1155/2018/7902760 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9

Author(s):

Lianjie Shi ◽

Ying Ning ◽

Liling Xu ◽

Jianhong Li ◽

Xuewu Zhang

Keyword(s):

Cortical Bone ◽

Bone Microarchitecture ◽

Osteoclast Differentiation ◽

Bone Geometry ◽

Negative Control ◽

High Dose ◽

Micro Ct ◽

Sprague Dawley ◽

Blank Group ◽

Methylene Diphosphonate

Technetium-99 conjugated with methylene diphosphonate (99Tc-MDP) is an effective anti-inflammatory drug in treating rheumatoid arthritis (RA) for over 15 years in China. However, as a special form of bisphosphonate, the antiosteoporotic effect of99Tc-MDP is unclear. We systematically investigated the effects of99Tc-MDP on cancellous and cortical bone, respectively, in glucocorticoid induced osteoporosis (GIO) animal models. Forty-eight Sprague-Dawley rats were randomly divided into six groups: blank, negative control, high dose, medium dose, low dose, and positive control groups. After dexamethasone was given to all groups except the blank group to induce osteoporosis, the rats in different groups were treated with saline, MDP, or different doses of99Tc-MDP. After treatment, all rats were sacrificed, and their tibiae and femora were analyzed with microcomputed tomography (micro-CT), histology and biomechanics. Micro-CT analyses showed that (1)99Tc-MDP reversed glucocorticoid induced bone microarchitecture destruction by increasing BV/TV, Tb.Th, and Tb.N and decreasing BS/BV, Tb.Sp, and TBPf; (2) effect of99Tc-MDP increased as its dosage increased; and (3)99Tc-MDP could improve cortical bone thickness while MDP failed to do so. Micro-CT spatial structure analysis and histology also yielded consistent results, indicating that99Tc-MDP increased trabecular number and connectivity morphologically. Secondly, biomechanics revealed that99Tc-MDP can enhance the extrinsic stiffness of bone by changing bone geometry. Finally,99Tc-MDP could inhibit osteoclastogenesis in PBMCs in human. In conclusion,99Tc-MDP exerted antiosteoporotic effect by improving both cancellous and cortical bone, as well as increasing extrinsic bone stiffness which might be attributed to the its inhibition of osteoclast differentiation. The antiosteoporotic effect of99Tc-MDP may suggest a potential clinical application for patients with GIO.

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Determination of dynamical ages of open clusters through the A+ parameter – I

Monthly Notices of the Royal Astronomical Society ◽

10.1093/mnras/stab2894 ◽

2021 ◽

Author(s):

Khushboo K Rao ◽

Kaushar Vaidya ◽

Manan Agarwal ◽

Souradeep Bhattacharya

Keyword(s):

Globular Clusters ◽

Structural Parameters ◽

Statistical Tests ◽

Rank Correlation ◽

Correlation Coefficients ◽

Reference Population ◽

Open Clusters ◽

Velocity Information ◽

Red Giant ◽

Giant Branch Stars

Abstract The sedimentation level of blue straggler stars (BSS) has been shown to be a great tool to investigate the dynamical states of globular clusters (GCs). The area enclosed between the cumulative radial distributions of BSS and a reference population up to the half-mass radius of the clusters, $A^+_{\mathrm{rh}}$, is known to be a measure of the sedimentation of BSS in GCs. In this work, we calculate $A^+_{\mathrm{rh}}$ for 11 open clusters (OCs) using a combined list of main-sequence turn-off stars, sub-giant branch stars, and red-giant branch stars as reference population. The BSS, the reference populations, and the cluster members are identified using the proper motions and parallaxes from the Gaia DR2 data. In a subset of clusters, the BSS are confirmed cluster members on the basis of radial velocity information available in the literature. Using the Pearson and Spearman rank correlation coefficients, we find weak correlations between the estimated values of $A^+_{\mathrm{rh}}$ and other markers of dynamical ages of the clusters, i.e. the number of central relaxations a cluster has experienced since its formation, and the structural parameters of the clusters. Based on statistical tests, we find that these correlations are similar to the corresponding correlations among the less evolved GCs, albeit within large errors.

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FC 076DIAGNOSTIC ACCURACY OF BONE TURNOVER MARKERS IN RENAL OSTEODYSTROPHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab123.001 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Hanne Skou Jørgensen ◽

Geert Behets ◽

Etienne Cavalier ◽

Patrick D'Haese ◽

Pieter Evenepoel

Keyword(s):

Bone Turnover ◽

Kidney Transplant ◽

Renal Osteodystrophy ◽

Type I Collagen ◽

Tartrate Resistant Acid Phosphatase ◽

Type I ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Predictive Values ◽

Bone Biopsies

Abstract Background and Aims A transiliac bone biopsy is the gold standard for diagnosing renal osteodystrophy, but is not recommended as part of routine clinical workup due to its invasive nature. Suitable non-invasive alternatives have yet to be established. The aim of this study was to investigate the diagnostic accuracy novel biochemical markers of bone remodeling compared to that of biointact parathyroid hormone (PTH) for bone turnover as evaluated by histomorphometry. Method Protocolled bone biopsies were performed in end-stage kidney disease patients (ESKD, n = 80) and kidney transplant recipients (n = 119). Full-length (1-84) PTH, bone-specific alkaline phosphatase (BsAP), intact N-terminal propeptide of type I collagen (P1NP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) were measured. Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC). Optimal diagnostic cutoffs were established in an exploration cohort (n=100), and subsequently validated in a separate subset of patients (n=99). Results Mean age was 55±13 years, two-thirds were men (67%), and 23% had diabetes mellitus. Post-transplant eGFR was 49 [IQR 39, 59] ml/min/1.73m². Bone turnover was low in 47 (24%), normal in 119 (60%), and high in 33 (17%) patients. All biomarkers differed significantly across categories of bone turnover (p < 0.001). The AUC of biointact PTH for high turnover was 0.82 (0.73, 0.91), which was not significantly different from AUC values for BsAP, Intact P1NP, and TRAP5b (0.87, 0.90, and 0.86, respectively). AUC of biointact PTH for low turnover was 0.71 (0.63, 0.78), which was significantly lower than the values for BsAP, Intact P1NP, and TRAP5b (0.79, 0.83, and 0.79, respectively; p < 0.05, all). Calculated optimal diagnostic cutoffs in the exploration cohort are shown in Table 1. Applying these cutoffs in the validation cohort revealed high negative predictive values for both high (92 - 96%) and low (82 - 90%) bone turnover. Positive predictive values were consistently low. Conclusion The diagnostic accuracies of BsAP, Intact P1NP and TRAP5b are sufficient to rule out both high and low bone turnover in CKD. Biointact PTH shows inferior performance, particularly in kidney transplant recipients.

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Cortical Bone Microarchitecture in Dialysis Patients

American Journal of Nephrology ◽

10.1159/000510064 ◽

2020 ◽

Vol 51 (10) ◽

pp. 833-838 ◽

Cited By ~ 1

Author(s):

Eva Benillouche ◽

Agnes Ostertag ◽

Caroline Marty ◽

Pablo Ureña Torres ◽

Martine Cohen-Solal

Keyword(s):

Cortical Bone ◽

Bone Microarchitecture ◽

Quantitative Computed Tomography ◽

Peripheral Quantitative Computed Tomography ◽

Microcomputed Tomography ◽

Bone Fragility ◽

Bone Volume ◽

Dialysis Patients ◽

Dialysis Therapy ◽

Bone Biopsies

Background: The incidence of skeletal fractures is high in dialysis patients. Current available tools are insufficient to predict bone fragility. We analyzed the microarchitecture in patients on dialysis therapy using bone biopsies and peripheral microcomputed tomography. Methods: We analyzed 12 trans-iliac bone biopsies of patients with recent fractures. Bone microarchitecture was assessed in the bone cores by histology (2D-), microcomputed tomography (3D-µCT), and high-resolution peripheral quantitative computed tomography (HR-pQCT) at the tibia. Results: Trabecular bone volume/tissue volume was similar in 2D histology and 3D-µCT (p = 0.40), while lower in HR-pQCT (p < 0.01). There was no correlation in trabecular microarchitectural indices between 2-histology and 3D-µCT, or HR-pQCT. The 3D-µCT cortical thickness (Ct.Th) were positively correlated with 2D (p < 0.05), but with HR-pQCT (p = 0.33). Ct.Th was lower in patients with ≥2 vertebral fractures than with one fracture. Conclusions: 3D-µCT is a reliable method for the measurement of cortical bone in bone biopsies. Prospective studies are awaited to address its value in discriminating fracture risk.

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MO568STATIC PARAMETERS OF HISTOMORPHOMETRY FOR THE EVALUATION OF BONE TURNOVER IN RENAL OSTEODYSTROPHY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab086.006 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Hanne Skou Jørgensen ◽

Geert Behets ◽

Patrick D'Haese ◽

Pieter Evenepoel

Keyword(s):

Bone Turnover ◽

Diagnostic Accuracy ◽

Renal Osteodystrophy ◽

Bone Biopsy ◽

Bone Formation Rate ◽

Suitable Alternative ◽

Predictive Values ◽

Bone Biopsies ◽

Low Bone Turnover ◽

Tetracycline Labeling

Abstract Background and Aims A full histomorphometric analysis of a transiliac bone biopsy with prior tetracycline labeling remains the gold standard to diagnose renal osteodystrophy. Bone turnover is primarly evaluated by the dynamic parameter bone formation rate, calculated from the incorporation of tetracycline in bone. In cases of failed tetracycline labels, however, an evaluation of bone turnover based on static parameters is warranted. This study investigates the diagnostic accuracy of static histomorphometric parameters for the diagnosis of high and low bone turnover. Method Bone biopsies with prior tetracycline labeling of sufficient quality for a full histomorpometric analysis were included (n = 205). Mean age of participants was 56±13 years, 67% were men, and 22% had diabetes mellitus. Diagnostic accuracy of static histomorphometric parameters for bone turnover was evaluated by area under the receiver operator characteristics curve (AUC) statistics, against the full set of static and dynamic histomorphometric parameters. The cohort was randomly split to allow calculation of optimal diagnostic cutoffs in an exploration cohort (n=105), with subsequent validation in a separate subset of patients (n=100). Results All histomorphometric parameters were significantly different across categories of low (24%), normal (60%), and high (16%) bone turnover (p < 0.01), and all were significant predictors of both high and low bone turnover (Figure 1). Calculated optimal cutoffs and their sensitivities and specificities in the validation cohort are shown in Table 1. Diagnostic accuracy was very good for high turnover, as the combination of presence of fibrosis with ObPm>5.4%, OcPm>1.5%, and OAr>2.4% provided a correct diagnosis in 94% of patients, with positive (PPV) and negative (NPV) predictive values of 80% and 96%, respectively. Using the same predefined combination, an accuracy of 80% was achieved for low turnover (no fibrosis, ObPm≤1.9% OcPm≤0.9% and OAr≤1.6%), with a PPV of 71% and a NPV of 82%. Conclusion Static histomorphometric parameters provide an acceptable alternative for the diagnosis of high and low bone turnover. In the absence of successful tetracycline labeling, the proposed cutoffs may provide a suitable alternative for the evaluation of bone turnover in renal osteodystrophy.

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Integrated Numerical and Experimental Data-Driven Parameter Identification of Electrode Properties in All-Vanadium Redox Flow Batteries

10.26434/chemrxiv.11936124.v1 ◽

2020 ◽

Author(s):

Ziqiang Cheng ◽

Kevin M. Tenny ◽

Alberto Pizzolato ◽

Antoni Forner-Cuenca ◽

Vittorio Verda ◽

...

Keyword(s):

Parameter Identification ◽

Structural Parameters ◽

Rank Correlation ◽

Correlation Coefficients ◽

Vanadium Redox Flow Battery ◽

Data Driven ◽

Cell Current ◽

Power And Energy ◽

The Impact ◽

Vanadium Redox

The vanadium redox flow battery (VRFB) is a promising energy storage technology for stationary applications (e.g., renewables integration) that offers a pathway to cost-effectiveness through independent scaling of power and energy as well as longevity. Many current research efforts are focused on improving battery performance through electrode modifications, but high-throughput, laboratory-scale testing can be time- and material-intensive. Advances in multiphysics-based numerical modeling and data-driven parameter identification afford a computational platform to expand the design space by rapidly screening a diverse array of electrode configurations. Herein, a 3D VRFB model is first developed and validated against experimental results. Subsequently, a new 2D model is composed, yielding a computationally light simulation framework, which is used to generate a dataset of 16800 electrode property combinations under four different cell voltages to track the impact of different structural parameters on the cell current density. These structure-performance relationships are quantified using Kendall $\tau$ rank correlation coefficients to highlight the dependence of cell performance on bulk electrode morphology and to identify improved property sets. This statistical framework may serve as a general guideline for parameter identification for more advanced electrode designs.

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