Cortical Density Research Articles

The PYY/Y2R-deficient male mouse is not protected from bone loss due to Roux-en-Y gastric bypass.

Peptide YY (PYY) is an anorexigenic gut hormone that also has anti-osteogenic effects, inhibiting osteoblastic activity and inducing catabolic effects. It has been postulated that increases in PYY after Roux-en-Y gastric bypass (RYGB) contribute to declines in bone mineral density (BMD) and increases in bone turnover. The aim of this study is to determine the role of the PYY Y2-receptor in mediating bone loss post-RYGB in mice. We compared adult male wildtype (WT) and PYY Y2 receptor-deficient (KO) C57BL/6 mice that received RYGB (WT: n=8; KO: n=9), with sham-operated mice (Sham; WT: n=9; KO: n=10) and mice that were food-restricted to match the weights of the RYGB-treated group (Weight-Matched, WM; WT: n=7; KO: n=5). RYGB or sham surgery was performed at 15-16weeks of age, and mice sacrificed 21weeks later. We characterized bone microarchitecture with micro-computed tomography (μCT) at the distal femur (trabecular) and femoral midshaft (cortical). Differences in body weight, bone microarchitecture and biochemical bone markers (parathyroid hormone, PTH; C-telopeptide, CTX; and type 1 procollagen, P1NP) were compared using 2-factor ANOVA with Tukey's adjustments for multiple comparisons. Body weights were similar in the WT-RYGB, WT-WM, KO-RYGB, and KO-WM: 41-44g; these groups weighed significantly less than the Sham surgery groups: 55-57g. Trabecular BMD was 31-43% lower in RYGB mice than either Sham or WM in WT and KO groups. This deficiency in trabecular bone was accompanied by a lower trabecular number (19%-23%), thickness (22%-30%) and increased trabecular spacing (25%-34%) in WT and KO groups (p<0.001 for all comparisons vs. RYGB). RYGB led to lower cortical thickness, cortical tissue mineral density, and cortical bone area fraction as compared to Sham and WM in WT and KO groups (p≤0.004 for all). There were no interactions between genotype and bone microarchitecture, with patterns of response to RYGB similar in both WT and KO groups. CTX and P1NP were significantly higher in RYGB mice than WM in WT and KO groups. PTH did not differ among groups. RYGB induced greater trabecular and cortical deficits and high bone turnover than observed in weight-matched mice, with a similar pattern in the WT and Y2RKO mice. Thus, skeletal effects of RYGB are independent of weight loss, and furthermore, PYY signaling through Y2R is not a key mediator of bone loss post-RYGB.

Effects of four-year cyclic versus two-year daily teriparatide treatment on volumetric bone density and bone strength in postmenopausal women with osteoporosis.

To evaluate the effects of cyclic vs daily teriparatide treatment (TPTD) on volumetric bone mineral density (vBMD) and bone strength at the hip and spine in women who were previously untreated. A total of 86 women were randomized to a 24-month open label treatment of either daily TPTD (20μg daily) or cyclic TPTD (20μg daily for 3months followed by 3months off). During a 2-year extension, women in the daily TPTD group were switched to alendronate (ALN) and those in the cyclic TPTD group continued on cyclic TPTD (without any ALN). QCT images were acquired at baseline, 2-years (n=54) and 4-years (n=35) and analyzed for volumetric integral, cortical and trabecular bone mineral density (vBMD) and bone strength (by finite element analysis) at the hip and spine. The primary analysis presented here compared the responses across equal total TPTD doses (2years daily vs 4years cyclic). In the spine, integral vBMD and strength increased substantially after 2years daily and 4years cyclic TPTD, with no significant differences (vBMD +12% vs +11%, respectively, p=0.70; spine strength +21% vs +16%, respectively, p=0.35). At the hip, the gains were smaller, but again no significant differences were detected between the groups for the increases in either vBMD (+2% in both groups, p=0.97) or hip strength (3% vs 3%, p=0.91). In the spine, the vBMD increment was about twice as large in the trabecular vs peripheral compartment; in the hip, significant vBMD gain was seen only in the trabecular compartment. The gains in volumetric BMD and bone strength for an equivalent dose of TPTD did not depend on whether it was administered every day over two years or cyclically over four years.

Intrinsic Cortical Property Analysis of the Medial Column of Proximal Humerus.

Adequate mechanical support of the medial column is paramount to maintain fracture reduction in locking plating of proximal humerus fractures. However, intrinsic cortical properties of the medial column are rarely discussed. The purpose of the study is to describe regional variation of cortex in the medial column. A total of 147 healthy participants were eligible for enrollment between December 2016 and December 2018. Subjects were divided into three groups: group A (20-39 years), group B (40-59 years), and group C (>60 years). For each individual, a color 3D thickness map for proximal humerus was created by cortical bone mapping (CBM) technique after bilateral shoulders were imaged by computed tomography. Measurement Indices including the cortical thickness (CTh), cortical mass surface density (CM) and the endocortical trabecular density (ECTD) were determined, after six regions of interest (ROI) were defined in metaphyseal region. Regional parameter variations were analyzed by one-way ANOVA. The CTh, CM and ECTD values were approximately equivalent between genders in the proximal part of the medial column across all ages (P> 0.05).The greatest difference between sexes was found in CTh and CM values of middle and distal part (P< 0.05). The CTh and CM within medial column were negatively associated with age (P< 0.05). The proximal cortical bone of the medial column was thicker and more dense, compared to the lateral column (P< 0.05). Significant regional variation was found in all measured parameters in group A, but not in groups B and C. Our finding proved that regional differences in the distribution of cortical bone in the medial column The attenuation of cortical bone heterogeneity in the medial column was found after the age of 40 years.

MRI Quantification of Cortical Bone Porosity, Mineralization, and Morphologic Structure in Postmenopausal Osteoporosis.

Background Preclinical studies have suggested that solid-state MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are useful measures of bone health. Purpose To explore whether MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are affected in postmenopausal osteoporosis (OP) and to examine associations between MRI markers and bone mineral density (BMD) in postmenopausal women. Materials and Methods In this single-center study, postmenopausal women were prospectively recruited from January 2019 to October 2020 into two groups: participants with OP who had not undergone treatment, defined as having any dual-energy x-ray absorptiometry (DXA) T-score of -2.5 or less, and age-matched control participants without OP (hereafter, non-OP). Participants underwent MRI in the midtibia, along with DXA in the hip and spine, and peripheral quantitative CT in the midtibia. Specifically, MRI measures of cortical bone porosity (pore water and total water), osteoid density (bound water [BW]), morphologic structure (cortical bone thickness), and mineralization (phosphorous [P] density [31P] and 31P-to-BW concentration ratio) were quantified at 3.0 T. MRI measures were compared between OP and non-OP groups and correlations with BMD were assessed. Results Fifteen participants with OP (mean age, 63 years ± 5 [SD]) and 19 participants without OP (mean age, 65 years ± 6) were evaluated. The OP group had elevated pore water (11.6 mol/L vs 9.5 mol/L; P = .007) and total water densities (21.2 mol/L vs 19.7 mol/L; P = .03), and had lower cortical bone thickness (4.8 mm vs 5.6 mm; P < .001) and 31P density (6.4 mol/L vs 7.5 mol/L; P = .01) than the non-OP group, respectively, although there was no evidence of a difference in BW or 31P-to-BW concentration ratio. Pore and total water densities were inversely associated with DXA and peripheral quantitative CT BMD (P < .001), whereas cortical bone thickness and 31P density were positively associated with DXA and peripheral quantitative CT BMD (P = .01). BW, 31P density, and 31P-to-BW concentration ratio were positively associated with DXA (P < .05), but not with peripheral quantitative CT. Conclusion Solid-state MRI of cortical bone was able to help detect potential impairments in parameters reflecting porosity, morphologic structure, and mineralization in postmenopausal osteoporosis. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bae in this issue.

Differential Cortical Volumetric Bone Mineral Density within the Human Rib

Introduction: The human rib provides a vital role in the protection of thoracic contents. Rib fractures are linked to injuries and health complications that can be fatal. Current clinical methods to assess fracture risk and bone quality are insufficient to quantify intra-element differences in bone mineral density (BMD) or to identify at-risk populations. Utilizing quantitative computed tomography (QCT) provides accurate measures of volumetric BMD (vBMD) along the length of the rib which can help delineate factors influencing differential fracture risk. Methodology: One mid-level rib was obtained from 54 post-mortem human subjects (PMHS) and scanned using QCT. Volumes of interest (VOIs) were created for sites at 30%, 50%, and 75% of rib total curve length. Mean Hounsfield units (HU) from each VOI were converted to vBMD using a scan-specific cortical phantom calibration curve. Additionally, rib and lumbar areal BMD (aBMD) were obtained from a sub-sample of 33 PMHS. Results: Significant differences in vBMD were found between all sites within the rib (p<0.01). When analyzed by sex, vBMD between the 30% and 50% site were no longer different in either males or females (p>0.05). Separating the sample into discrete age groups demonstrated the relative differences in vBMD between sites diminished with age. Further, age as a continuous variable significantly predicted rib vBMD at all sites (p<0.05), but with little practical or clinical utility (R2, 14.7- 22.8%). Similarly, only small amounts of variation in rib vBMD were explained from DXA lumbar and rib aBMD (R2 , 1.1-21.8%). Conclusions: vBMD significantly decreased from the posterior (30%) site to the anterior (75%) site within the rib which may represent adaptation to localized mechanical loading. These differences could result in differential fracture risk across the rib. As thoracic injury can be fatal, using comprehensive assessments of bone quality that accounts for variation within the rib may provide more accurate identification of at-risk populations.

Changes in tibial cortical dimensions and density associated with long-term locking plate fixation in goats

PurposeCortical porosis, secondary to either vascular injury or stress-shielding, is a comorbidity of fracture fixation using compression bone plating. Locking plate constructs have unique mechanics of load transmission and lack of reliance on contact pressures for fixation stability, so secondary cortical porosis adjacent to the plate has not been widely investigated. Therefore, this study aimed to assess the effects of long-term locking plate fixation on cortical dimensions and density in a caprine tibial segmental ostectomy model.MethodsData was acquired from a population of goats enrolled in ongoing orthopedic research which utilized locking plate fixation of 2 cm tibial diaphyseal segmental defects to evaluate bone healing over periods of 3, 6, 9, and 12 months. Quantitative data included tibial cortical width measurements and three-dimensionally reconstructed slab density measurements, both assessed using computed tomographic examinations performed at the time of plate removal. Additional surgical and demographic variables were analyzed for effect on cortical widths and density, and all cis-cortex measurements were compared to both the trans-cortex and to the contralateral limbs.ResultsThe tibial cis-cortex was significantly wider and more irregular than the trans-cortex at the same level. This width asymmetry differed in both magnitude and direction from the contralateral limb. The bone underlying the plate was significantly less dense than the trans-cortex, and this cortical density difference was significantly greater than that of the contralateral limb. These cortical changes were independent of both duration of fixation and degree of ostectomy bone healing.ConclusionsThis study provides evidence that cortical bone loss consistent with cortical porosity is a comorbidity of locking plate fixation in a caprine tibial ostectomy model. Further research is necessary to identify risk factors for locking-plate-associated bone loss and to inform clinical decisions in cases necessitating long-term locking plate fixation.

PS-BPB07-4: LONG-TERM PATHOLOGICAL CHANGES IN ABLATED RENAL NERVES FOLLOWING CATHETER-BASED RADIOFREQUENCY RENAL DENERVATION IN A NORMOTENSIVE SWINE MODEL

Objective: Randomized, sham-controlled clinical trials with catheter-based radiofrequency (RF) renal denervation (RDN) have demonstrated safety and efficacy of the procedure through 3 years. However, pre-clinical reports of functional renal nerve regrowth are inconsistent. In this analysis in normotensive swine, we assessed the specificity of RF ablation around the renal arteries out to 28 days and quantified the long-term pathophysiological outcomes through 180 days. Design and method: RF ablations were delivered to the renal arteries of normotensive swine using the Symplicity SpyralTM catheter (Medtronic, Santa Rosa, CA, USA). For the tissue specificity analysis, RF RDN was performed in 14 swine, and serial sections of the renal artery were harvested from 6 pigs at day 7, and 8 pigs at day 28. Surrounding anatomic tissues of the treated areas (including ureter, kidney, lymph nodes, skeletal muscle, adrenal glands, and renal nerves) were evaluated in response to RDN using a semi-quantitative scoring system (Figure). To assess durability, RF RDN was performed in a separate group of 14 normotensive swine, with an additional 14 pigs serving as control. Serial sections of renal artery were harvested at day 7 (n = 6 animals per group) and day 180 (n = 8 per group) post-procedure. In addition, matrixed samples from renal cortex were collected for each pig in both studies and subjected to bioanalytical quantification of cortical norepinephrine (NE) levels and immunohistochemical analysis of renal cortical axon density. Results: At 7 and 28 days, cell disruption in non-target perivascular tissues (ureter, kidney, lymph nodes, skeletal muscle and adrenal glands) were rare/absent, whereas renal artery nerve disruption and axonal loss were sustained through 28 days (Figure). Through 180 days, nerve atrophy due to axonal destruction was apparent within and downstream to the ablation regions. Consistent nerve necrosis at the ablation sites was evident at day 7, but not day 180. Fibrosis was confined to the ablated regions at 7 and 180 days. Renal cortical axon density and corresponding cortical NE levels were significantly reduced at 7 and 180 days in the RF RDN group vs. control. Conclusion: RF RDN specifically disrupted the renal nerves around the renal artery leading to downstream axonal loss in the renal cortex. Renal cortical axon density, associated NE reduction, and nerve atrophy due to axonal destruction were sustained through 180 days post-RDN in a normotensive swine model. These results support the existing clinical evidence of specific and durable effects of RF RDN in lowering blood pressure.

Osseous microarchitecture in frequent fracture zones of the distal clavicle.

Fracture classifications of the distal clavicle are based on ligamentous integrity. The influence of osseous microarchitecture on fracture occurrence, morphology, and the lesion's stability has not yet been investigated. We aimed to characterize osseous microarchitecture according to common fracture classification systems based on ligamentous integrity and investigated the possible effects of age, gender, and osteoporosis in distal clavicle fractures. N=20 human cadaveric distal clavicles were scanned using XtremeCT with an isometric voxel size of 82 μm. In the sagittal plane, each data set was evaluated in 11 sections of approximately 7 mm thickness. Three topographic regions were defined: the bone lateral to the trapezoid (LTR), intertubercular (ITR), and medial to the conoid (MCR) ligament. Cortical bone mineral density (BMD) [mgHA/cm3] and cortical porosity (1- (BV/TV) [%]) were determined and evaluated relative to age and gender. Along the mediolateral axis, there was an >20-fold increase in median cortical porosity (P≤.001). There were significant differences in cortical porosity between LTR and ITR (P≤.001) but not between ITR and MCR (P=.09). In ITR, cortical porosity was significantly greater in >60-year-old compared to younger donors (P=.01). For BMD, there was an >2-fold decrease toward the distal apex (P≤.001). BMD was significantly greater in ITR compared to LTR (P≤.001) and in MCR compared to ITR (P=.02). In ITR and MCR, clavicles of >60-year-old donors had significantly lower BMD values compared to younger donors (P<.01). Across all 3 regions, frequency distribution of low bone mass did not significantly differ between <60-year-olds and >60-year-olds (P>.6). The distal clavicle features a characteristic bony microarchitecture. The present study revealed a significant difference in bone quality of lateral, intertubercular, and medial zones of the distal clavicle and could specify target areas and strategies for surgical treatment of unstable fractures. Age, gender, and osteoporosis have a limited effect on bone quality and fracture genesis. In contrast, ligamentous quality is supposed to exert a substantial influence on fracture characteristics, especially in ITR. Fracture morphology of the distal clavicle is determined by a bony-ligamentous conjunction, which remains to be characterized.

Chromolaena odorata (L.) R. M. King and H. Robinson Leaves Aqueous Extract Improves the Femoral Head in Ethanol-Induced Osteonecrosis in Rats.

Chronic alcohol consumption damages bone formation and causes bone pathology, including osteonecrosis of the femoral head. The aim of this work was to evaluate the effects of the leaf aqueous extract of Chromolaena odorata (C. odorata) on the femoral head in ethanol-induced osteonecrosis in rats. Animals received alcohol (40°) at 3 g/kg for 12 weeks. A group of animals were sacrificed to attest to the instalment of osteonecrosis by using histopathological analysis. The remaining animals received alcohol concomitantly with the plant extract (150, 300, or 600 mg/kg) or diclofenac (1 mg/kg) for 28 additional days. At the end of the experimental period, biochemical parameters including total cholesterol, triglycerides, calcium, alkaline phosphatase (ALP), reduced glutathione (GSH), malondialdehyde (MDA), nitrite, superoxide dismutase (SOD), and catalase activities were measured. Histopathological and histomorphometry analyses of femurs were also assessed. The administration of alcohol, irrespective of the experimental period, induced a significant increase in total cholesterol (p < 0.05) and triglyceride (p < 0.01) and a decrease in ALP (p < 0.05) and calcium (p < 0.05-p < 0.001) levels. Intoxicated animals showed an alteration in oxidative stress parameters accompanied by a significant drop in bone cortical thickness and density with necrosis and marked bone resorption. The concomitant administration of the plant with ethanol reversed the alcohol-induced bone defect, characterized by the improvement of the lipid profile (p < 0.001), bone calcium concentration (p < 0.05), bone ALP activity (p < 0.001), oxidative stress parameters, improved cortical bone thickness (p < 0.01), and bone density (p < 0.05). These results are supported by the absence of bone resorption with an obvious effect at a dose of 300 mg/kg. The pharmacological effect of the extract on ethanol-induced osteonecrosis of the femoral head is probably due to its osteogenic, hypolipidemic, and antioxidant properties, justifying its use in Cameroonian folk medicine for articulation and bone pain management.

Cortical microarchitecture and remodeling-associated gene expression related to oral cancer prognosis.

The objective of this study was to assess the remodeling-associated gene expression in the mandible of patients diagnosed with oral squamous cell carcinoma (OSCC), investigating the cortical microarchitecture, and their influence on disease-free survival (DFS) and overall survival (OS) rates. A total of twenty-four patients who underwent mandibulectomy for OSCC treatment had two bone fragments harvested from the mandible for gene expression (RANK, RANKL, OPG, and SOST), and microarchitecture analysis, including bone volume, surface, mineral density, degree of anisotropy, and fractal dimension. The prognosis of the patients was assessed. The results revealed that RANK, RANKL, and SOST were predominantly downregulated, while OPG was completely downregulated. Tumors located adjacent to the posterior region of the mandible (p = 0.02), with a bone mineral density below 1.03 g/cm3 HA (p = 0.001), and a bone volume less than 86.47% (p = 0.03) were associated with poor outcomes. In conclusion, bone-remodeling-associated genes exhibited downregulation in the cortex of the mandible in OSCC patients. Additionally, the tumor's location within the mandible, bone volume, and cortical bone mineral density were identified as factors impacting DFS.

Peripheral quantitative computed tomography-derived bone parameters in men with impaired fasting glucose and diabetes.

Individuals with type 2 diabetes mellitus (T2DM) are at higher risk of fracture, but paradoxically do not have reduced bone mineral density. We investigated associations between peripheral quantitative computed tomography (pQCT) and glycaemia status. Participants were men (n = 354, age 33-92year) from the Geelong Osteoporosis Study. Diabetes was defined by fasting plasma glucose (FPG) ≥ 7.0mmol/L, self-report of diabetes and/or antihyperglycaemic medication use and impaired fasting glucose (IFG) as FPG 5.6-6.9mmol/L. Bone measures were derived using pQCT (XCT2000) at 4% and 66% radial and tibial sites. Linear regression was used, adjusting for age, body mass index and socio-economic status. At the 4% site, men with T2DM had lower adjusted bone total area, trabecular area and cortical area at the radius (all -6.2%) and tibia (all -6.4%) compared to normoglycaemia. Cortical density was higher for T2DM at the radius (+ 5.8%) and tibia (+ 8.0%), as well as adjusted total bone density at the tibial site (+ 6.1%). At the 66% site, adjusted total bone area and polar stress strain index were lower for T2DM at the radius (-4.3% and -8.0%). Total density was also higher for T2DM (+ 1.2%). Only cortical density at the 4% tibial site was different between IFG and normoglycaemia in adjusted analyses (+ 4.5%). Men with T2DM had lower total bone area, trabecular area, cortical area and polar stress strain index than the other two groups; however, total density and cortical density were higher. Only one difference was observed between IFG and normoglycaemia; increased tibial cortical density.

Longitudinal evolution of neuropathological substrates of Alzheimer’s disease in obese patients

AbstractBackgroundObesity is a metabolic condition with increasing prevalence all over the world. Patients with a body mass index (BMI) higher than 30 are considered obese. Obesity is also a risk factor for chronic morbidities such as type 2 diabetes and may increase the risk of developing Alzheimer's disease (AD). Not much is known about longitudinal changes in Alzheimer’s pathology in these patients. We hypothesised that BMI would predict longitudinal pathological alterations derived from imaging parameters.Method252 participants (n=107 obese non‐diabetic patients with BMI&gt;30) cognitively normal (n=80) and with mild cognitive impairment (n=172) were evaluated from the Alzheimer’s Disease Neuroimaging Initiative (Mean age = 73.6 years, SD = 8.0). All participants had two T1‐weighted MPRAGE MRI scans within two‐years (Mean gap=718 days, SD=107). Regional cortical thickness was measured on T1‐MPRAGE using FreeSurfer v.6.0. Individual gray matter density maps were computed using voxel‐based morphometry (VBM) and regional values were sampled in various cortical regions. Regional cortical thickness and gray matter density are expressed as delta values between baseline and followup (Value followup ‐ Value Baseline). Spearman’s correlation coefficients were calculated to assess the relationship between BMI and imaging biomarkers.ResultIn the whole cohort, we found that BMI is significantly negatively correlated with longitudinal changes in cortical thickness in anterior cingulate (ACC, p=0.0073, r=‐0.17) and posterior cingulate (PCC, p=0.0147, r=‐0.15) cortical thickness. We also found that BMI is significantly negatively correlated with longitudinal changes in frontal (p=0.0184, r=‐0.15), parietal (p=0.0057, r=‐0.18) and temporal (p=0.0141, r=‐0.16) gray matter density. When looking only at MCI participants, we found similar results with even stronger correlations. BMI is significantly negatively correlated with delta anterior cingulate (ACC, p=0.0008, r=‐0.25) and posterior cingulate (PCC, p=0.004, r=‐0.22) cortical thickness.ConclusionIn this cohort of obese and non‐obese participants cognitively normal and with MCI, we found that obesity was associated with a longitudinal 2‐years worsening of macrostructural changes. Higher BMI was associated with a higher reduction of cortical thickness and with a decreased gray matter density in several brain regions.

Treatment of Diaphyseal Tibial Fractures Distal to a Total Knee Arthroplasty by Intramedullary Nailing Is Safe and Effective.

To report the clinical result of a series of patients who underwent intramedullary nailing (IMN) of tibial shaft fractures distal to a total knee arthroplasty (TKA). Retrospective case series. Level-1 trauma center. Patients who sustained a tibial shaft fracture distal to a TKA treated with an IMN. IMN of tibial shaft fractures distal to a TKA. Postoperative weight-bearing status, readmissions, and complications or failure of treatment within 90 days; Knee Injury and Osteoarthritis Outcome Scores at the final follow-up; failure of treatment; and revision surgery. Nine patients were included. The average age was 71.4 years (range 55-87 years). All TKAs were cemented. The average distance between the tibial keel and the cortical density of the tibial tubercle was 24.1 mm (range 19.5-26.7 mm). Six nails were inserted using an infrapatellar portal, 2 were inserted using a suprapatellar portal, and 1 was inserted using a lateral parapatellar approach. The median nail diameter was 10 mm (range 9-12 mm). All fractures were healed at the final follow-up. There were no infections or arthroplasty-related complications. Knee Injury and Osteoarthritis Outcome Scores ranged from 100% to 74% (median 82%). Overall, we report on the largest cohort in the literature undergoing IMN of a tibial shaft fracture distal to a TKA. We demonstrate that IMN of diaphyseal tibial fractures distal to a TKA can be performed safely. We additionally demonstrate that this treatment is highly effective in achieving fracture union with no arthroplasty-related complications. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Cortical synapses of the world's smallest mammal: An FIB/SEM study in the Etruscan shrew.

The main aim of the present study was to determine if synapses from the exceptionally small brain of the Etruscan shrew show any peculiarities compared to the much larger human brain. We analyzed the cortical synaptic density and a variety of structural characteristics of 7,239 3D reconstructed synapses, using using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM). We found that someof the general synaptic characteristics are remarkably similar to those found in the human cerebral cortex. However, the cortical volume of the human brain is about 50,000 times larger than the cortical volume of the Etruscan shrew, while the total number of cortical synapses in human is only 20,000 times the number of synapses in the shrew, and synaptic junctions are 35% smaller in the Etruscan shrew. Thus, the differences in the number and size of synapses cannot be attributed to a brain size scaling effect but rather to adaptations of synaptic circuits to particular functions.

Urinary and Daily Assumption of Polyphenols and Hip-Fracture Risk: Results from the InCHIANTI Study.

A high polyphenol intake has been associated with higher bone-mineral density. In contrast, we recently demonstrated that the urinary levels of these micronutrients were associated with the long-term accelerated deterioration of the bone. To expand on the health consequences of these findings, we assessed the association between urinary level and dietary intake of polyphenols and the 9-year risk of hip fractures in the InCHIANTI study cohort. The InCHIANTI study enrolled representative samples from two towns in Tuscany, Italy. Baseline data were collected in 1998 and at follow-up visits in 2001, 2004, and 2007. Of the 1453 participants enrolled at baseline, we included 817 participants in this study who were 65 years or older at baseline, donated a 24 hour urine sample, and underwent a quantitative computerized tomography (pQCT) of the tibia. Fracture events were ascertained by self-report over 9 years of follow-up. Thirty-six hip fractures were reported over the 9-year follow-up. The participants who developed a hip fracture were slightly older, more frequently women, had a higher dietary intake of polyphenols, had higher 24-hour urinary polyphenols excretion, and had a lower fat area, muscle density, and cortical volumetric Bone Mineral Density (vBMD) in the pQCT of the tibia. In logistic regression analyses, the baseline urinary excretion of total polyphenols, expressed in mg as a gallic acid equivalent, was associated with a higher risk of developing a hip fracture. Dietary intake of polyphenols was not associated with a differential risk of fracture. In light of our findings, the recommendation of an increase in dietary polyphenols for osteoporosis prevention should be considered with caution.

Reduced cortical neuron number and neuron density in schizophrenia with focus on area 24: a post-mortem case–control study

Structural and functional abnormalities of the anterior cingulate cortex (ACC) have frequently been identified in schizophrenia. Alterations of von Economo neurons (VENs), a class of specialized projection neurons, have been found in different neuropsychiatric disorders and are also suspected in schizophrenia. To date, however, no definitive conclusions can be drawn about quantitative histologic changes in the ACC in schizophrenia because of a lack of rigorous, design-based stereologic studies. In the present study, the volume, total neuron number and total number of VENs in layer V of area 24 were determined in both hemispheres of postmortem brains from 12 male patients with schizophrenia and 11 age-matched male controls. To distinguish global from local effects, volume and total neuron number were also determined in the whole area 24 and whole cortical gray matter (CGM). Measurements were adjusted for hemisphere, age, postmortem interval and fixation time using an ANCOVA model. Compared to controls, patients with schizophrenia showed alterations, with lower mean total neuron number in CGM (− 14.9%, P = 0.007) and in layer V of area 24 (− 21.1%, P = 0.002), and lower mean total number of VENs (− 28.3%, P = 0.027). These data provide evidence for ACC involvement in the pathophysiology of schizophrenia, and complement neuroimaging findings of impaired ACC connectivity in schizophrenia. Furthermore, these results support the hypothesis that the clinical presentation of schizophrenia, particularly deficits in social cognition, is associated with pathology of VENs.

Denosumab treatment is associated with decreased cortical porosity and increased bone density and strength at the proximal humerus of ovariectomized cynomolgus monkeys.

Upper extremity fractures, including those at the humerus, are common among women with postmenopausal osteoporosis. Denosumab was shown to reduce humeral fractures in this population; however, no clinical or preclinical studies have quantified the effects of denosumab on humerus bone mineral density or bone microarchitecture changes. This study used micro-computed tomography (μCT) and computed tomography (CT), alongside image-based finite element (FE) models derived from both modalities, to quantify the effects of denosomab (DMAb) and alendronate (ALN) on humeral bone from acutely ovariectomized (OVX) cynomolgus monkeys. Animals were treated with 12 monthly injections of s.c. vehicle (VEH; n=10), s.c. denosumab (DMAb; 25mg/kg, n=9), or i.v. alendronate (ALN; 50μg/kg, n=10). Two more groups received 6months of VEH followed by 6months of DMAb (VEH-DMAb; n=7) or 6months of ALN followed by 6months of DMAb (ALN-DMAb; n=9). After treatment, humeri were harvested and μCT was used to quantify tissue mineral density, trabecular morphology, and cortical porosity at the humeral head. Clinical CT imaging was also used to quantify trabecular and cortical bone mineral density (BMD) at the ultra-proximal, proximal, 1/5 proximal and midshaft of the bone. Finally, μCT-based FE models in compression, and CT-based FE models in compression, torsion, and bending, were developed to estimate differences in strength. Compared to VEH, groups that received DMAb at any time demonstrated lower cortical porosity and/or higher tissue mineral density via μCT; no effects on trabecular morphology were observed. FE estimated strength based on μCT was higher after 12-months DMAb (p=0.020) and ALN-DMAb (p=0.024) vs. VEH; respectively, FE predicted mean (SD) strength was 4649.88 (710.58) N, and 4621.10 (1050.16) N vs. 3309.4 (876.09) N. All antiresorptive treatments were associated with higher cortical BMD via CT at the 1/5 proximal and midshaft of the humerus; however, no differences in CT-based FE predicted strength were observed. Overall, these results help to explain the observed reductions in humeral fracture rate following DMAb treatment in women with postmenopausal osteoporosis.

Menopause is associated with bone loss, particularly at the distal radius, in black South African women: Findings from the Study of Women Entering and in Endocrine Transition (SWEET).

Radius and tibia peripheral QCT data were collected for Black South African women (n=430) aged 40-61years with verified menopause and HIV status. pQCT outcomes were distal 4% radius and tibia total cross-sectional area (CSA), total volumetric bone mineral density (vBMD), and compressive bone strength (BSIc); proximal 66% radius and 38% tibia cortical vBMD, total CSA, cortical thickness, and Stress-strain Index (SSI). Linear regression assessed associations between pre, peri-, and postmenopausal groups and pQCT outcomes adjusting for age, height, and weight, and then stratified by HIV status. Mean [95%CI] and tests for trend (p-trend) across menopausal groups are presented. Women were mean (SD) age 49.2 (5.3) years, with a body mass index (BMI) of 32.4 (6.3) m/kg2, and 18% were living with HIV. After adjustment, later menopause stage was associated with lower 4% radius total mean [95%CIs] vBMD (premenopause: 345.7 [335.8,355.5] vs. postmenopause: 330.1 [322.7,337.6] mg/cm3, p-trend=0.017) and BSIc (premenopause: 0.39 [0.37,0.41] vs. postmenopause: 0.36 [0.35,0.37] g2/cm4; p-trend=0.012). Similar trends were observed at the 66% radius for cortical vBMD (premenopause: 1146.8 [1138.9,1154.6] vs. postmenopause: 1136.1 [1130.1,1142.0] mg/cm3; p-trend=0.028) and cortical thickness (premenopause: 2.01 [1.95,2.06] vs. postmenopause: 1.93 [1.89,1.98] mm; p-trend=0.036). After stratification by HIV status a similar patten was observed in women with HIV (cortical vBMD premenopause: 1152.9 [1128.5,1177.2] mg/cm3 vs. postmenopause: 1123.6 [1106.0,1141.2] mg/cm3, p-trend=0.048). Total CSA varied little by menopause or HIV status at either radius sites; few differences were found at the tibia. In black South African women, menopause is associated with lower bone density and strength at the distal radius, a common site of osteoporotic fracture, in addition to lower cortical density and thickness at the proximal radius. Although the sample size was small, following stratification by HIV, women living with HIV had evidence of lower cortical density across menopause stages, unlike those without HIV. These findings raise concern for the incidence of Colles' fractures in postmenopausal women in South Africa; longitudinal studies of fracture incidence and implications of living with HIV are required.

Clinical observation of diminished bone quality and quantity through longitudinal HR-pQCT-derived remodeling and mechanoregulation

High resolution peripheral quantitative computed tomography (HR-pQCT) provides methods for quantifying volumetric bone mineral density and microarchitecture necessary for early diagnosis of bone disease. When combined with a longitudinal imaging protocol and finite element analysis, HR-pQCT can be used to assess bone formation and resorption (i.e., remodeling) and the relationship between this remodeling and mechanical loading (i.e., mechanoregulation) at the tissue level. Herein, 25 patients with a contralateral distal radius fracture were imaged with HR-pQCT at baseline and 9–12 months follow-up: 16 patients were prescribed vitamin D3 with/without calcium supplement based on a blood biomarker measures of bone metabolism and dual-energy X-ray absorptiometry image-based measures of normative bone quantity which indicated diminishing (n = 9) or poor (n = 7) bone quantity and 9 were not. To evaluate the sensitivity of this imaging protocol to microstructural changes, HR-pQCT images were registered for quantification of bone remodeling and image-based micro-finite element analysis was then used to predict local bone strains and derive rules for mechanoregulation. Remodeling volume fractions were predicted by both average values of trabecular and cortical thickness and bone mineral density (R2 > 0.8), whereas mechanoregulation was affected by dominance of the arm and group classification (p < 0.05). Overall, longitudinal, extended HR-pQCT analysis enabled the identification of changes in bone quantity and quality too subtle for traditional measures.

Analysis of Bone Histomorphometry in Rat and Guinea Pig Animal Models Subject to Hypoxia.

Hypoxia may be associated with alterations in bone remodeling, but the published results are contradictory. The aim of this study was to characterize the bone morphometry changes subject to hypoxia for a better understanding of the bone response to hypoxia and its possible clinical consequences on the bone metabolism. This study analyzed the bone morphometry parameters by micro-computed tomography (μCT) in rat and guinea pig normobaric hypoxia models. Adult male and female Wistar rats were exposed to chronic hypoxia for 7 and 15 days. Additionally, adult male guinea pigs were exposed to chronic hypoxia for 15 days. The results showed that rats exposed to chronic constant and intermittent hypoxic conditions had a worse trabecular and cortical bone health than control rats (under a normoxic condition). Rats under chronic constant hypoxia were associated with a more deteriorated cortical tibia thickness, trabecular femur and tibia bone volume over the total volume (BV/TV), tibia trabecular number (Tb.N), and trabecular femur and tibia bone mineral density (BMD). In the case of chronic intermittent hypoxia, rats subjected to intermittent hypoxia had a lower cortical femur tissue mineral density (TMD), lower trabecular tibia BV/TV, and lower trabecular thickness (Tb.Th) of the tibia and lower tibia Tb.N. The results also showed that obese rats under a hypoxic condition had worse values for the femur and tibia BV/TV, tibia trabecular separation (Tb.Sp), femur and tibia Tb.N, and BMD for the femur and tibia than normoweight rats under a hypoxic condition. In conclusion, hypoxia and obesity may modify bone remodeling, and thus bone microarchitecture, and they might lead to reductions in the bone strength and therefore increase the risk of fragility fracture.