Age- and gender-related differences in vertebral bone mass, density, and strength.

This study was designed to evaluate age- and gender-related differences in vertebral bone mass, density, and strength by dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), peripheral QCT (pQCT), ash measurements, and biomechanical testing. The material comprised human lumbar vertebral bodies (L3) from 51 females and 50 males (age-range: 18-96 years). The results showed that females had significantly lower vertebral body bone mass (ash weight) than males at any given age. The decline in bone mass with age was parallel for females and males. The different bone density measurements-cancellous ash density, total vertebral body ash density, DXA bone mineral density, QCT, and pQCT-showed no gender-related difference concerning numeric value or changes with age. Morphometrical measurements showed that females had smaller vertebral bodies (volumes) than males. Hence the females had significantly smaller cross-sectional area (CSA) of L3 than males (11.6 cm2 and 14.4 cm2, respectively). This led to females having lower maximum compressive load (N) than males at all ages, whereas maximum compressive stress (load/CSA) showed no gender-related difference. In conclusion, females have lower vertebral body bone mass than males at any given age, due to smaller vertebral bodies. Hence, maximum compressive load (strength not corrected for size) was lower in females. Vertebral body cancellous bone density and total-vertebral body density were equal when comparing genders, and no gender differences were found in the size-corrected strength: maximum compressive stress. The decrease with age in vertebral body compressive strength decrease was twice as large as the age decrease in density.     

Age- and gender-related differences in bone mineral status and biochemical markers of bone metabolism in Northern Chinese men and women

The aim of this study was to provide insight into the bone mineral status and biochemical markers of bone metabolism in a Chinese population from Shenyang, in the north of China, where hip fracture incidence is low. A total of 194 healthy men and women, aged 25-35 years and 65-75 years, were studied. Bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) was measured using dual-energy X-ray absorptiometry. Fasting blood and 24 h urine samples were collected for bone alkaline phosphatase (bAP), osteocalcin, calcium, phosphate, and free deoxypyridinoline (Dpd). Both older women and men had lower BMD compared with younger women and men by 27.2 +/- 3.0% (mean +/- SE) and 9.8 +/- 3.0% at the LS and 22.0 +/- 3.4% and 12.8 +/- 3.4% at the FN, respectively, after adjusting for bone and body size (p < 0.01). BMD at the two sites was lower in older women than in older men by 10.7 +/- 4.1% and 10.2 +/- 4.2%, respectively, after size correction (p < 0.05). Plasma bAP, osteocalcin, calcium, and phosphate concentrations were higher in older women than younger women by 69.3 +/- 9.7%, 77.2 +/- 11.1%, 7.5 +/- 2.3%, and 8.0 +/- 3.8%, respectively, and older men by 67.6 +/- 11.1%, 72.1 +/- 11.0%, 7.7 +/- 2.3%, and 23.8 +/- 3.8%, respectively (p < 0.01). However, plasma osteocalcin, calcium, and phosphate concentrations were lower in older men compared with their younger counterparts by 35.6 +/- 11.0%, 8.7 +/- 2.3%, and 14.1 +/- 3.8%, respectively (p < 0.05). Urinary calcium and phosphate output were lower in older men compared with younger men by 48.0 plus minus 10.3% and 27.6 +/- 6.9%, respectively (p < 0.01), whereas there were no differences between older and younger women. No differences in Dpd between older and younger groups were found. This study demonstrates that bone mineral status is lower in older people in Shenyang, as has been shown in populations elsewhere. The pronounced low bone mineral status in older women may be associated with increased bone turnover, which was not observed in older men.     

Age- and gender-dependent changes in three-dimensional microstructure of cortical and trabecular bone at the human femoral neck

Summary  

We investigated age- and gender-related variation of both cortical and trabecular microstructure in human femoral neck. We found that age-related change of cortical porosity is more noticeable than that of trabecular parameter. Our data may help to gain more insight into the potential mechanism of osteoporotic femoral neck fractures.     

Age- and gender-related differences of the immune function in a murine model of hemorrhagic shock: IL-10 restores immunodepression in aged females without reduction of mortality

Introduction Interleukin-10 (IL-10) treatment has been shown to have beneficial effects on the immune function after hemorrhagic shock and to improve survival after subsequent sepsis in young male mice, but not in young females. Although it was demonstrated that the immune function under these conditions is reversed with age, it remains unclear whether the observed gender-related effect of IL-10 treatment continues to exist in aged mice. Materials and methods Aged male and female CBA/J mice (18–19 months) were subjected to hemorrhage (35 ± 5 mmHg for 90 min) or sham operation. At resuscitation, each received either 10-μg recombinant murine (rm)IL-10 or placebo i.p. At 48 h after resuscitation, either the mice were killed and the plasma, splenic macrophages (sMϕ), and splenocytes were harvested or polymicrobial sepsis was induced by cecal ligation and puncture (CLP). After CLP, either survival over 10 days was determined or, 4 h after CLP, tissues were again harvested and cytokine-released in vitro were assessed by enzyme-linked immunosorbent assay. Results Early IL-10 treatment restored depressed proinflammatory immune response (TNF-α, IL-1β) and Th1 response of splenocytes in aged females after hemorrhage, whereas having no effects or having suppressive effects in aged males. Subsequent sepsis combined with placebo treatment led to a significant suppression of proinflammatory cytokine release of sMϕ and a significant increase of Th2 response in both males and females associated with high mortality (80–100%, respectively) after CLP. These effects were not influenced by early rmIL-10 treatment. Conclusion After hemorrhage, early rmIL-10 treatment restored immune function in aged females, but not in males. However, in contrast to young mice, rmIL-10 treatment had no effect on survival and immune function after CLP in aged mice. The paper was presented at the first joint meeting of the Surgical Infection Society (SIS–NA) and the Surgical Infection Society–Europe (SIS–E), 02.-04.05.2002, Madrid, Spain, and published as an abstract in Surgical Infections 3(1):70, 2002.     

Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors.

Bone marrow harvested by aspiration contains connective tissue progenitor cells which can be induced to express a bone phenotype in vitro. The number of osteoblastic progenitors can be estimated by counting the colony-forming units which express alkaline phosphatase (CFU-APs). This study was undertaken to test the hypothesis that human aging is associated with a significant change in the number or prevalence of osteoblastic progenitors in the bone marrow. Four 2-ml bone marrow aspirates were harvested bilaterally from the anterior iliac crest of 57 patients, 31 men (age 15-83) and 26 women (age 13-79). A mean of 64 million nucleated cells was harvested per aspirate. The mean prevalence of CFU-APs was found to be 55 per million nucleated cells. These data revealed a significant age-related decline in the number of nucleated cells harvested per aspirate for both men and women (P = 0.002). The number of CFU-APs harvested per aspirate also decreased significantly with age for women (P = 0.02), but not for men (P = 0.3). These findings are relevant to the harvest of bone marrow derived connective tissue progenitors for bone grafting and other tissue engineering applications, and may also be relevant to the pathophysiology of age-related bone loss and post-menopausal osteoporosis.     

Sex hormones and gender-related differences: their influence on chronic renal allograft rejection

BACKGROUND: Renal hemodynamics and immune responses differ between males and females. Thus, sex hormones and genetically determined gender differences may determine the process of chronic rejection to some extent. METHODS: Female (F) or male (M) F344 kidneys were orthotopically transplanted into ovariectomized female Lewis recipients and were treated for 16 weeks with either estradiol, testosterone, or vehicle. RESULTS: Testosterone treatment resulted in increased urinary protein excretion independently of the donor gender, as well as extended glomerular sclerosis, interstitial fibrosis, and severe vascular lesions. Additionally, mononuclear cell infiltration was most pronounced in these animals, in parallel to an increased expression of intercellular adhesion molecule-1 (ICAM-1), fibronectin, laminin, and transforming growth factor-beta (TGF-beta) in the grafts. Estradiol treatment resulted in an improved graft function, reduced glomerular sclerosis, and a diminished cellular infiltration, in parallel to a reduced ICAM-1, fibronectin, laminin, and TGF-beta expression. In animals treated with vehicle, the gender of the donor influenced the outcome. Grafts of male origin had good graft function and histology, whereas grafts from female donors developed severe proteinuria and glomerular, interstitial, and vascular damage. CONCLUSIONS: These results suggest that a protective effect of estradiol on the progression of chronic rejection exists that is independent of donor gender. Additionally, a male kidney may benefit from the absence of testosterone, whereas the function of a female kidney deteriorates in the absence of estradiol.     

Electrical injury: a long-term analysis with review of regional differences

Due to its relatively small share among burn injuries, published data on electrical injuries remain scarce, and differ in patient collectives due to infrastructural differences. We have retrospectively analyzed records of 56 patients who were admitted because of electrical injury to our burn center from 1994 to 2008, compared results with the current literature, and focused our review on regional differences. Patients in our collective were predominantly young men (71%, n = 40/56) and those who resulted from work-related accidents (59%, n = 33/56). The mean total burn surface area was 26%. In all, 93% of patients needed at least 1 operation, with 43% of patients requiring at least 1 surgical intervention during a follow-up hospital stay. The mean length-of-stay was 44 days. Two patients died, accounting for a mortality rate of 3.6%. When comparing high to low-voltage injuries, patients in the former group were significantly younger, had more operations, and required a longer length-of-stay. With respect to work-related high-voltage injuries, job-specific male-predominance explains for the demographic distribution of admissions. Low-voltage injuries continue to have low mortality rates in this part of Europe, most likely as a result of established high security standards as well as access to emergency treatment with subsequent intensive and specialist surgical care.     

Strain-based regional traumatic brain injury intensity in controlled cortical impact: a systematic numerical analysis

Regional strain-based brain injury intensity during controlled cortical impact (CCI) was studied using a three-dimensional numerical rat brain model. A full factorial design of CCI computer experiments was performed using two typical impactor shapes (flat or hemispherical) at a fixed impact velocity of 4?m/s with various impact depths (1, 1.5, 1.6, 2, 2.5, 2.7, and 3?mm) and various impactor diameters (4, 5, 6, 8, and 9.5?mm). In total, 70 CCI cases were simulated numerically. Two injury assessment measures, the cumulative strain damage measure (CSDM), which accounts for the volume of brain tissue with elevated strains, and cumulative strain damage percentage measure (CSDPM), which is a strain-based estimate of the neuronal cell loss percentage, were used to evaluate the risk of brain injury. Results demonstrated positive nonlinear relationships between impact depth and these injury assessment measures in six regions of interest: ipsilateral cortex, ipsilateral corpus callosum, ipsilateral hippocampus, ipsilateral thalamus, cerebellum, and brainstem. However, the impactor diameter was not always positively correlated with regional tissue strains. For the flat impactor group, the 5?mm diameter impactor induced more tissue strain in the corpus callosum/hippocampus, and a smaller impactor induced more strain in the thalamus. For the hemispherical impactor group, a larger impactor tended to induce more tissue strain in subcortical regions, with the exception of the 6?mm diameter impactor. This study systematically predicts regional intensity of primary brain injury according to tissue strain distributions in the hope that strain distribution maps may become a common platform to compare CCI severities with different configurations.     

Differences in sensitivity to microstructure between cyclic‐ and impact‐based microindentation of human cortical bone

Unlike the known relationships between traditional mechanical properties and microstructural features of bone, the factors that influence the mechanical resistance of bone to cyclic reference point microindention (cRPI) and impact microindention (IMI) have yet to be identified. To determine whether cRPI and IMI properties depend on microstructure, we indented the tibia mid‐shaft, the distal radius, and the proximal humerus from 10 elderly donors using the BioDent and OsteoProbe (neighboring sites). As the only output measure of IMI, bone material strength index (BMSi) was significantly different across all three anatomical sites being highest for the tibia mid‐shaft and lowest for the proximal humerus. Total indentation distance (inverse of BMSi) was higher for the proximal humerus than for the tibia mid‐shaft but was not different between other anatomical comparisons. As a possible explanation for the differences in BMSi, pore water, as determined by ¹H nuclear magnetic resonance, was lowest for the tibia and highest for the humerus. Moreover, the local intra‐cortical porosity, as determined by micro‐computed tomography, was negatively correlated with BMSi for both arm bones. BMSi was also positively correlated with peak bending stress of cortical bone extracted from the tibia mid‐shaft. Microstructural correlations with cRPI properties were not significant for any of the bones. The one exception was that average energy dissipated during cRPI was negatively correlated with local tissue mineral density in the tibia mid‐shaft. With higher indentation force and larger tip diameter than cRPI, only IMI appears to be sensitive to the underlying porosity of cortical bone. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1442–1452, 2017.

     

Analyzing cortical bone cross-sectional geometry by peripheral QCT: comparison with bone histomorphometry.

A distinct advantage of peripheral quantitative computed tomography (pQCT) is its ability to assess bone strength by measuring cross-sectional geometry and density of cortical bone. For accurate determination of cortical bone cross-sectional area (CoA), it is important to select the appropriate analysis mode and thresholds. No study has assessed which analysis protocol best represents tibial bone geometry--as determined by histomorphometry. We measured bone geometry from 16 human cadaver tibiae (mean age 74 [SD 6] yr) with pQCT (XCT 2000) at the 25% site, measured proximally from the distal tibia plafond. We conducted histomorphometry at the same site as the criterion standard. Scans were analyzed using modes and thresholds recommended by the manufacturer (Norland Stratec Medizintechnic GmbH, Pforzheim, Germany). We also investigated agreement of two additional thresholds (calculated by half-maximum height and inflection point methods) to define the endosteal border of cortical bone. Compared to the criterion, the smallest error (-1.0%, p=0.002) in total cross-sectional area (ToA) was obtained using Contour mode 3 with an outer threshold of 169 mg/cm(3). The smallest error (0.1%, NS) in CoA was obtained with Separation mode 4 (outer threshold 200mg/cm(3), inner threshold 670 mg/cm(3)). CoA was overestimated by 5-7% (p<0.001) from the criterion when an inner threshold of 480 mg/cm(3) was used in combination with any of the recommended outer thresholds. pQCT measurements of bone geometry in vitro vary to some extent between modes and thresholds selected. The effect of variation in bone geometry measurements on the predictive ability of bone strength indices derived from CoA needs to be assessed.     

Improved insulin sensitivity by GLUT12 overexpression in mice

OBJECTIVE

Evidence suggests that insulin-sensitive glucose transporters (GLUTs) other than GLUT4 may exist. To investigate whether GLUT12 may represent another insulin-sensitive GLUT, transgenic (TG) mice that overexpress GLUT12 were characterized.

RESEARCH DESIGN AND METHODS

TG mice that overexpressed GLUT12 under a β-actin promoter were generated. Glucose metabolism in TG and wild-type control mice was compared using glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. In addition, basal and insulin-stimulated glucose clearance rates into insulin-sensitive peripheral tissues were measured using [³H]-2-deoxy-d-glucose.

RESULTS

GLUT12 was overexpressed by 40–75% in TG compared with wild-type mice in insulin-sensitive tissues with no change in GLUT4 content. Body weight and fasting blood glucose did not differ between wild-type and TG mice; however, insulin concentrations were reduced in TG mice. Enhanced oral glucose tolerance was noted in TG mice by a reduced blood glucose excursion compared with wild-type mice (P < 0.05). Enhanced insulin sensitivity was noted by a greater decrease in blood glucose in TG mice during insulin tolerance testing. Hyperinsulinemic-euglycemic clamps confirmed enhanced insulin sensitivity in GLUT12-overexpressing mice (P < 0.01). Tissues of TG mice exhibited normal basal glucose clearance rates; however, under insulin-stimulated conditions, glucose clearance was significantly increased (P < 0.01) in tissues of TG mice.

CONCLUSIONS

Increased expression of GLUT12 results in improved whole-body insulin sensitivity mediated by an increased glucose clearance rate in insulin-responsive tissues under insulin-stimulated, but not basal, conditions. These findings provide evidence that GLUT12 represents a novel, second insulin-sensitive GLUT.The glucose transporter (GLUT) responsible for insulin-stimulated glucose uptake in peripheral tissues, such as skeletal muscle and fat, is GLUT4. Interestingly, the GLUT4 knockout mouse does not develop hyperglycemia (1), and soleus muscle from GLUT4 knockout mice retains its ability to increase glucose uptake in response to insulin (2). These findings have led to an interest in identifying other insulin-sensitive GLUTs. The class III facilitative GLUT, GLUT12, was first identified by Rogers et al. (3) in MCF7 cells. Experiments in Xenopus oocytes showed that GLUT12 preferentially transported d-glucose and 2-deoxy-d-glucose over other hexoses (4). The presence of targeting motifs similar to GLUT4 and GLUT8 (5,6), and localization primarily in insulin-sensitive tissues (6–10), has led to research into whether GLUT12 may represent a second insulin-sensitive GLUT. Stuart et al. (11) recently demonstrated that in human skeletal muscle, GLUT12 translocates to the plasma membrane following euglycemic insulin infusion. The authors also reported that insulin-induced GLUT12 translocation to the plasma membrane in L6 cells required phosphatidyl inositol-3 kinase activity. To further assess the function of GLUT12 as an insulin-sensitive GLUT, transgenic (TG) mice were generated to study the effects of GLUT12 overexpression on whole-animal glucose homeostasis and insulin-stimulated glucose clearance into peripheral tissues.     

Obesity alters cortical and trabecular bone density and geometry in women

Summary

The goal in this study was to determine the relationship between body mass index and trabecular and cortical bone using quantitative computed tomography. A higher body mass index (BMI) was positively associated with trabecular and cortical bone parameters, and serum parathyroid hormone, and negatively associated with cortical volumetric bone mineral density (vBMD) and serum 25-hydroxy-vitamin D. When BMI is greater than 35 kg/m², adiposity affects vBMD and may explain the higher fracture risk in this population without low BMD.

Introduction

The influence of adult obesity on the trabecular and cortical bone, geometry, and strength has not been fully addressed. The goal in this study was to determine the relationship between body mass index and trabecular and cortical bone mass and geometry, over a wide range of body weights.

Methods

We examined 211 women (25–71 years; BMI 18–57 kg/m²) who were classified into three categories of BMI (kg/m²) including normal-weight (BMI?<?25), overweight and obese-class I (BMI 25–35) and obese-class II–III (BMI?>?35), and also by menopausal status. Volumetric bone mineral density (mg/cm³), trabecular, and cortical components as well as geometric characteristics at the 4%, 38%, and 66% from the distal tibia were measured by peripheral quantitative computed tomography, and serum was analyzed for parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25OHD).

Results

Higher BMI was associated with greater values of trabecular bone and cortical BMC and area and PTH (r?>?0.39, p?<?0.001), but lower cortical vBMD and 25OHD (r?>??0.27, p?<?0.001). When controlling for lower leg muscle area, fat area was inversely associated with cortical vBMD (r?=??0.16, p?<?0.05). Premenopausal obese women with both higher BMI and PTH had lower cortical vBMD (r?<??0.40, p?<?0.001). While age is a predictor for most bone variables, fat mass explains more variance for vBMD, and lean mass and 25OHD explain greater variance in geometric and strength indices (p?<?0.05).

Conclusions

Severe obesity (BMI?>?35) increases trabecular vBMD and in the presence of a higher PTH is associated with a lower cortical vBMD without compromising bone geometry and strength. Whether or not a lower cortical vBMD in obesity influences fracture risk over time needs to be further explored.     

Three-dimensional characterization of cortical bone microstructure by microcomputed tomography: validation with ultrasonic and microscopic measurements

Background The porosity of human cortical bone is one of the major parameters conditioning bone strength. The purpose of this study was to validate the characterization of human cortical bone microarchitecture using microcomputed tomography (μCT). To validate this μCT technique, the structural measurements were compared with other methods such as ultrasonic techniques and scanning electron microscopy (SEM). Methods Nineteen cortical samples were extracted from the superior, middle, and inferior shaft of three human femurs (FI, FII, FIII). The samples were scanned by μCT with an isotropic resolution of 8 μm. Most of the structural parameters used for trabecular microarchitecture were calculated to characterize the network of pores. On the same cortical samples, (1) ultrasound measurements were performed using contact transmission emitter-receptor to determine elastic coefficient and Young's modulus; (2) SEM was performed on femoral cross sections from FII to evaluate the porosity. Results The morphological parameters showed a wide range of variation depending of the level of the diaphysis. Porosity measured by μCT was significantly correlated with porosity measured by SEM (r = 0.91, P < 0.05). Moreover, all the morphological parameters showed high correlation coefficients with the elastic coefficient and Young's modulus, leading to validation of our three-dimensional analysis. Conclusions The strong correlations between the structural and mechanical properties obtained with the three techniques allowed us to validate the μCT technique used to characterize cortical bone microstructure. Porosity measurements might be of importance for clinicians and researchers to obtain a better understanding and evaluation of bone fracture in elderly patients.