Effects of insulin therapy on porosity,non-enzymatic glycation and mechanical competence in the bone of rats with type 2 diabetes mellitus

Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and optimal treatment strategies remain unclear. We studied the effects of diabetes and insulin therapy on non-enzymatic glycation (NEG), cortical porosity (Ct.Po) and biomechanics of the bone tissue in Zucker Diabetic Fatty (ZDF) rats.Eleven-week old ZDF diabetic and non-diabetic rats were given insulin to achieve glycaemic control or vehicle seven days per week over twelve weeks (insulin dose adapted individually 0.5 international units (IU) at week 1 to 13.0 IU at week 12). The right femora were excised, micro-CT scanned, and tested in 3-point bending to measure biomechanics. NEG of the midshaft was determined from bulk fluorescence.Diabetes led to increased NEG (+ 50.1%, p = 0.001) and Ct.Po (+ 22.9%, p = 0.004), as well as to reduced mechanical competence (max. stress: − 14.2%, p = 0.041, toughness: − 29.7%, p = 0.016) in the bone tissue. NEG and Ct.Po both correlated positively to serum glucose (NEG: R² = 0.41, p < 0.001, Ct.Po: R² = 0.34, p = 0.003) and HbA1c (NEG: R² = 0.42, p < 0.001, Ct.Po: R² = 0.28, p = 0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R² = 0.21, p = 0.023, yield stress: R² = 0.17, p = 0.047). Twelve weeks of insulin therapy had no significant effect on NEG or Ct.Po, and was unable to improve the mechanical competence of the bone tissue.A reduction of mechanical competence was observed in the bone tissue of the diabetic rats, which was explained in part by increased collagen NEG. Twelve weeks of insulin therapy did not alter NEG, Ct.Po or bone biomechanics. However, significant correlations between NEG and serum glucose and HbA1c were observed, both of which were reduced with insulin therapy. This suggests that a longer duration of insulin therapy may be required to reduce the NEG of the bone collagen and restore the mechanical competence of diabetic bone.     

Age and Sex Differences in Estimated Tibia Strength: Influence of Measurement Site

Variability in peripheral quantitative computed tomography (pQCT) measurement sites and outcome variables limit direct comparisons of results between studies. Furthermore, it is unclear what estimates of bone strength are most indicative of changes due to aging, disease, or interventions. The purpose of this study was to examine age and sex differences in estimates of tibia strength. An additional purpose of this study was to determine which tibia site or sites are most sensitive for detecting age and sex differences in tibia strength. Self-identifying Caucasian men (n = 55) and women (n = 59) aged 20–59 yr had their tibias measured with pQCT from 5% to 85% of limb length in 10% increments distal to proximal. Bone strength index, strength strain index (SSI), moments of inertia (I_p, I_max, and I_min), and strength-to-mass ratios (polar moment of inertia to total bone mineral content [BMC] ratio [I_p:Tot.BMC] and strength strain index to total BMC ratio [SSI:Tot.BMC]) were quantified. There were significant (p < 0.01) site effects for all strength variables and strength-to-mass ratios. Site × sex interaction effects were significant (p < 0.05) for all strength variables. Men had greater (p < 0.01) values than women for all strength variables. Sex differences in I_p, I_max, I_p:Tot.BMC, SSI, and SSI:Tot.BMC ratios were the smallest at the 15% site and peaked at various sites, depending on variable. Site × age interactions existed for I_max, I_p:Tot.BMC, and SSI:Tot.BMC. There were significant age effects, I_max, I_p:Tot.BMC, and SSI:Tot.BMC, as values were the lowest in the 20–29 age group. Age and sex differences varied by measurement site and variable, and larger sex differences existed for moments of inertia than SSI. Strength-to-mass ratios may reflect efficiency of the whole bone architecture.     

Computational biomechanics of the distal tibia from high-resolution MR and micro-CT images

The mechanical properties of bone estimated by micro-finite element (μFE) analysis on the basis of in vivo micro-MR images (μMRIs) of the distal extremities provide a new tool for direct assessment of the mechanical consequences of intervention. However, the accuracy of the method has not previously been investigated. Here, we compared μFE-derived mechanical parameters obtained from μMRIs at 160 μm isotropic voxel size now achievable in vivo with those derived from 25 μm isotropic (reference) μCT images of 30 cadaveric tibiae from 15 donors (4 females and 11 males, aged 55–84 years). Elastic and shear moduli estimated from 5 mm³ subvolumes of trabecular bone (TB) derived from μMRIs were significantly correlated with those derived from volume-matched reference μCT images (R² = 0.60–0.67). Axial stiffness of whole-bone sections (including both cortical and trabecular compartments) derived from μMR-based models were highly correlated (R² = 0.85) with those from high-resolution reference images. Further, μFE models generated from μCT images after downsampling to lower resolutions relevant to in vivo μMRI (100–160 μm) showed mechanical parameters to be strongly correlated (R² > 0.93) with those derived at reference resolution (25 μm). Incorporation of grayscale image information into the μMR-based μFE model yielded slopes closer to unity than binarized models (1.07 ± 0.15 vs. 0.71 ± 0.11) when correlated with reference subregional elastic and shear moduli. This work suggests that elastic properties of distal tibia can be reliably estimated by μFE analysis from μMRIs obtainable at in vivo resolution.     

Effects of soy isoflavone supplements on bone turnover markers in menopausal women: Systematic review and meta-analysis of randomized controlled trials

IntroductionEffects of soy isoflavone supplements on bone turnover markers remain unclear. This up-to-date systematic review and meta-analysis of randomized controlled trials (RCTs) was performed primarily to more completely and precisely clarify the effects on urinary deoxypyridinoline (DPD) and serum bone alkaline phosphatase (BAP) and secondarily to evaluate the effects on other bone turnover markers, compared with placebo in menopausal women.MethodsPubMed, CENTRAL, ICHUSHI, and CNKI were searched in June 2009 for relevant studies of RCTs. Data on study design, participants, interventions, and outcomes were extracted and methodological quality of each included trial was assessed.ResultsFrom 3740 identified relevant articles, 10 (887 participants), 10 (1210 participants), and 8 (380 participants) RCTs were selected for meta-analysis of effects on DPD, BAP, and serum osteocalcin (OC), respectively, using Review Manager 5.0.22. Daily ingestion of an average 56 mg soy isoflavones (aglycone equivalents) for 10 weeks to 12 months significantly decreased DPD by 14.1% (95% CI: ? 26.8% to ? 1.5%; P = 0.03) compared to baseline (heterogeneity: P < 0.00001; I² = 93%; random effects model). The overall effect of soy isoflavones on DPD compared with placebo was a significant decrease of ? 18.0% (95% CI: ? 28.4% to ? 7.7%, P = 0.0007; heterogeneity: P = 0.0001; I² = 73%; random effects model). Subgroup analyses and meta-regressions revealed that isoflavone dose and intervention duration did not significantly relate to the variable effects on DPD. Daily supplementation of about 84 mg and 73 mg of soy isoflavones for up to 12 months insignificantly increased BAP by 8.0% (95% CI: ? 4.2% to 20.2%, P = 0.20; heterogeneity: P < 0.00001; I² = 98%) and OC by 10.3% (95% CI: ? 3.1% to 23.7%, P = 0.13; heterogeneity: P = 0.002; I² = 69%) compared with placebo (random effects model), respectively.ConclusionsSoy isoflavone supplements moderately decreased the bone resorption marker DPD, but did not affect bone formation markers BAP and OC in menopausal women. The effects varied between studies, and further studies are needed to address factors relating to the observed effects of soy isoflavones on DPD and to verify effects on other bone turnover markers.     

The impact of osteoporosis and vertebral compression fractures on mortality and association with pulmonary function in COPD: A meta-analysis

ObjectiveOsteoporosis is highly prevalent among patients with chronic obstructive pulmonary disease (COPD) and most commonly presents as a vertebral compression fracture (VCF). Our objective was to quantify the effect of osteoporosis and VCFs on the mortality and pulmonary function tests (PFTs), such as forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC), of patients with COPD.MethodsA PubMed/Medline search was conducted using the search terms “chronic obstructive pulmonary disease”, “osteoporosis” and “vertebral compression fracture”. Meta-analyses were conducted to evaluate the differences in mortality and PFTs between patients with COPD with and without osteoporosis or VCFs, according to PRISMA guidelines. PROSPERO registration: CRD42019120335.ResultsOf the 896 abstracts identified, 27 studies describing 7662 patients with COPD of which 1883 (24.6%) had osteoporosis or VCFs, were included. Random effects model analysis demonstrated that patients with COPD and osteoporosis or VCFs had an increased OR for mortality of 2.40 (95% CI: 1.24; 4.64, I² = 89%, P < 0.01), decreased FEV₁/FVC with a mean difference of ?4.80% (95% CI: ?6.69; ?2.90, I² = 83%, P < 0.01) and decreased FEV₁, with a mean difference of ?4.91% (95% CI: ?6.51; ?3.31, I² = 95%, P < 0.01) and ?0.41 L (95% CI: ?0.59; ?0.24, I² = 97%, P < 0.01), compared to control subjects. Apart from FEV₁ (liters) in subgroup 1 (P = 0.06), all subgroup analyses found significant differences between groups, as did sensitivity analysis of low risk of bias studies.ConclusionOsteoporosis and VCFs are associated with a significant reduction in survival and pulmonary function among patients with COPD.     

Correlation of pQCT bone strength index with mechanical testing in distraction osteogenesis

Distraction osteogenesis is an established method of treatment of non-unions and limb length discrepancies. Despite improvements in surgical techniques and fixation devices there is still a considerable possibility of failure of the regenerate bone after frame removal. The hypothesis of the present experimental study was that a noninvasive bone strength marker, the strength–strain index (SSI) measured by peripheral quantitative computerized tomography (pQCT), could be significantly correlated with a biomechanical bone strength index, the maximum load at bone failure (F_max), assessed in a three-point bending test. The right tibias of fifteen male New Zealand White rabbits were subjected to gradual lengthening using an external fixator. At the end of the consolidation phase (55th day) the animals were sacrificed and the lengthened tibiae were collected free of soft tissue, after removal of the lengthener, for immediate scanning and mechanical testing. The values of cortical bone mineral density, cortical bone area, and the corresponding SSIy, as measured by pQCT, were assessed for statistically significant correlation relative to the values of the F_max and stiffness as evaluated by the three-point bending test were assessed. SSIy showed a statistically significant positive correlation with the maximum load (F_max) with a correlation value R = 0.846 (p < 0.001), and it was a good predictor of F_max since it was able to describe the 71.6% of variability of F_max(R² = 0.716). Furthermore, cortical bone area appeared to be highly correlated with F_max (p < 0.005), but it was a less efficient predictor of F_max (R² = 0.471). There was, also, a statistically significant correlation between SSIy and bone stiffness as assessed in the 3-point bending test (p < 0.005). In conclusion, the present study reveals that the SSI can be used as a sensitive index of adequate consolidation of the regenerate bone, possibly able to reduce mechanical failure due to premature frame removal. In clinical relevance, the aforementioned hypothesis should be applied in studies of human populations and possible confirmation of its validity would establish pQCT as a valuable diagnostic tool not only in distraction osteogenesis but also in other techniques of bone healing.     

Human trabecular bone microarchitecture can be assessed independently of density with second generation HR-pQCT

The second generation HR-pQCT scanner (XtremeCTII, Scanco Medical) can assess human bone microarchitecture of peripheral limbs with a 61 μm nominal isotropic voxel size. This is a marked improvement from the first generation HR-pQCT that had a nominal isotropic voxel size of 82 μm, which is at the limit to accurately determine the thickness of individual human trabeculae. We sought to determine the accuracy of a direct morphometric approach to measure trabecular bone microarchitecture with three-dimensional morphological techniques using second generation HR-pQCT, and to compare this with the approach currently applied by the first generation HR-pQCT scanner based on derived indices using ex vivo scans of human cadaveric radii. We also compared images acquired and resampled to mimic the first generation HR-pQCT with those obtained directly from the first generation HR-pQCT.We evaluated 20 human cadaveric radii and a micro-CT performance phantom using the first (XtremeCT, Scanco Medical) and second generation HR-pQCT scanner (XtremeCTII) and compared a patient evaluation (XCTII, 61 μm) with a high resolution ex vivo protocol (HR, 30 μm). We generated 82 μm scans of the same specimens to mimic a first-generation HR-pQCT evaluation (XCTIM, 82 μm) and compared these with a first-generation patient evaluation (XCTI, 82 μm). A standard structural extraction approach was applied to both XCTII and HR evaluations for assessment of bone volume fraction (BV/TV), and a distance transform was used to assess trabecular number (Tb.N), trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp). For XCTI and XCTIM evaluations we followed the manufacturer's standard procedure and assessed bone mineral density (BMD), Tb.N with a distance transform, and then derived bone volume ratio (BV/TV^d), trabecular thickness (Tb.Th^d) and separation (Tb.Sp^d).The spatial resolution (10% MTF) was 142.2 μm for XCTI, 108.9 μm for XCTIM, 95.2 μm for XCTII, and 55.9 μm for HR. XCTI and XCTIM provided strongly associated measurements of BMD and microarchitectural outcomes (R² > 0.97), however there were systematic differences in all outcomes. The Tb.N was highly associated with HR by both XCTII (R² = 0.93, mean error = − 0.12 mm^− 1) and XCTIM (R² = 0.98, mean error = 0.25 mm^− 1). Also, both XCTII (R² = 0.99, mean error = 0.20 mm) and XCTIM (R² = 0.99, mean error = − 0.18 mm) had Tb.Sp that were strongly related to HR. For Tb.Th, the XCTII was more closely related to HR (R² = 0.94, mean error = 0.04 mm) than the relatively weak XCTIM (R² = 0.16, mean error = − 0.076 mm).We found that trabecular microarchitecture assessment following the XCTII direct morphometric approach accurately represented the HR data. In particular, the measure of Tb.Th was markedly improved for XCTII compared with the derived approach of XCTIM. These data support the application of analysis techniques in HR-pQCT that are analogous to those traditionally used for micro-CT to assess trabecular microarchitecture. The decreased dependence of structural outcomes on density provides a new, important opportunity to monitor human in vivo bone microarchitecture.     

Bone metastasis imaging with SPECT/CT/MRI: A preclinical toolbox for therapy studies

Bone is one of the most common metastatic target sites in breast cancer, with more than 200 thousand new cases of invasive cancer diagnosed in the US alone in 2011. We set out to establish a multimodality imaging platform for bone metastases in small animals as a tool to non-invasively quantify metastasis growth, imaging the ensuing bone lesions and possibly the response to treatment. To this end, a mouse model of osteolytic metastatic bone tumors was characterized with SPECT/CT and MRI over time. A cell line capable of forming bone metastases, MDA-MB-231, was genetically modified to stably express the reporter gene herpes simplex virus-1 thymidine kinase (hsv-1 tk). The intracellular accumulation of the radiolabeled tracer [¹²³I]FIAU promoted by HSV-1 TK specifically pinpoints the location of tumor cells which can be imaged in vivo by SPECT.First, a study using tumors implanted subcutaneously was performed. The SPECT/MRI overlays and the ex vivo γ-counting showed a linear correlation in terms of %ID/cm³ (R² = 0.93) and %ID/g (R² = 0.77), respectively. Then, bone metastasis growth was imaged weekly by SPECT/CT and T₂-weighted MRI over a maximum of 40 days post-intracardiac injection of tumor cells. The first activity spots detectable with SPECT, around day 20 post-cell injection, were smaller than 2 mm³ and not yet visible by MRI and increased in volume and in %ID over the weeks. Osteolytic bone lesions were visible by CT (in vivo) and μCT (ex vivo). The SPECT/MRI overlays also showed a linear correlation in terms of %ID/cm³ (R² = 0.86).In conclusion, a new multimodality imaging platform has been established that non-invasively combines images of active tumor areas (SPECT), tumor volume (MRI) and the corresponding bone lesions (CT and μCT). To our knowledge this is the first report where the combination of soft tissue information from MRI, bone lesions by CT, and reporter gene imaging by SPECT is used to non-invasively follow metastatic bone lesions.     

Outcomes of partial and total calcanectomies for the treatment of diabetic heel ulcers complicated with osteomyelitis. A systematic review and meta-analysis

BackgroundInfected diabetic foot ulcers (DFU) complicated with calcaneal osteomyelitis are a real challenge for limb preservation. Very few alternatives to amputation are available, mainly the resection of a part or the totality of the calcaneal bone. Calcanectomies were advanced as limb-sparing procedures in patients with heel osteomyelitis. However, there is a lack of pooled quantitative evidence on their efficacy and complications.ObjectivesThe present systematic review and meta-analysis was conducted to determine the primary outcome of healing rates following partial (PC) and total calcanectomies (TC) in treating calcaneal osteomyelitis due to diabetic heel ulcers. Additionally, secondary outcomes such as secondary TC following PC, secondary below knee amputation (BKA), mortality and the change in the ambulation status were analyzed.MethodsMedline, Scopus, Web of science, Cochrane Library and Google Scholar were searched since inception. All types of study design were included. Single case report studies and studies reporting osteomyelitis due to other etiologies than DFU were excluded.ResultsTwenty studies met the inclusion criteria comprising 295 patients with 300 calcanectomies (270 PC and 30 TC). With a mean follow-up period of 29.3 ± 17.7 months, the weighted results were as follows: a) the osteomyelitis healing rate was of 80% (95% CI = 0.728 to 0.861, I² = 48.3%), b) the rate of secondary total calcanectomy was of 5.4% (95% CI = 0.022 to 0.097, I² = 7.5%), c) the rate of secondary BKA was of 17.1% (95% CI = 0.111 to 0.241, I² = 50.6%) with no difference between subgroups of TC and PC, and d) the combined mortality rate of both calcanectomies was of 13.4% (95% CI = 0.064 to 0.224, I² = 73.6%); however, significant higher mortality was found following TC compared to PC (p < 0.0001).ConclusionPartial and total calcanectomies were found to yield very good healing rates with acceptable complication frequencies. When compared to the reported outcomes of below and above-knee amputations in the literature, calcanectomies could be fairly considered as good alternatives to above ankle amputations.     

Cortical measurements of the tibia from high resolution peripheral quantitative computed tomography images: A comparison with synchrotron radiation micro-computed tomography

High resolution-peripheral quantitative computed tomography (HR-pQCT) measurements are carried out in clinical research protocols to analyze cortical bone. Micro-computed tomography (micro-CT) is a standard tool for ex vivo examination of bone in 3D. The aim of this work was to evaluate cortical measurements derived from HR-pQCT images compared to those from synchrotron radiation (SR) micro-CT in a distal position (4.2 cm from the distal pilon).Twenty-nine tibia specimens were scanned with HR-pQCT using protocols provided by the manufacturer. The standard measured outcomes included volumetric bone density (g HA/cm³) of the cortical region (Dcomp), and the cortical thickness (Ct.Th, mm). New features, such as cortical porosity (Ct.Po) and mean pore diameter (Ct.Po.Dm), were measured by an auto-contouring process. All tibias were harvested from the posterior region and imaged with SR micro-CT (voxel size = 7.5μm). The cortical thickness, (Ct.Th_micro-CT), porosity (PoV/TV), pore diameter, pore spacing, pore number, and degree of mineralization of bone (DMB) were obtained for SR micro-CT images. For standard measurements on HR-pQCT images, site matched analyses with micro-CT were completed to obtain Dcomp_local and Ct.Th_local.Dcomp was highly correlated to PoV/TV (r = − 0.84,p < 10^− 4) but not to DMB. Dcomp_local was correlated to PoV/TV (r = − 0.72, p < 10^− 4) and to DMB (r = 0.40, p > 0.05). Ct.Th_local and Ct.Th_micro-CT were moderately correlated (r = 0.53,p < 0.01). Ct.Th and Ct.Po results from the autocontouring process are influenced by the level of trabecularization of the cortical bone and need manual correction of the endosteal contour.Distal tibia is a reliable region to study cortical bone with Dcomp as the best parameter because it reflects both the micro-porosity (Havers canals) and macro-porosity (resorption lacunae) of the cortical bone.     

Microdamage induced calcium efflux from bone matrix activates intracellular calcium signaling in osteoblasts via L-type and T-type voltage-gated calcium channels

Mechanisms by which bone microdamage triggers repair response are not completely understood. It has been shown that calcium efflux ([Ca^2 +]_E) occurs from regions of bone undergoing microdamage. Such efflux has also been shown to trigger intracellular calcium signaling ([Ca^2 +]_I) in MC3T3-E1 cells local to damaged regions. Voltage-gated calcium channels (VGCCs) are implicated in the entry of [Ca^2 +]_E to the cytoplasm. We investigated the involvement of VGCC in the extracellular calcium induced intracellular calcium response (ECIICR). MC3T3-E1 cells were subjected to one dimensional calcium efflux from their basal aspect which results in an increase in [Ca^2 +]_I. This increase was concomitant with membrane depolarization and it was significantly reduced in the presence of Bepridil, a non-selective VGCC inhibitor. To identify specific type(s) of VGCC in ECIICR, the cells were treated with selective inhibitors for different types of VGCC. Significant changes in the peak intensity and the number of [Ca^2 +]_I oscillations were observed when L-type and T-type specific VGCC inhibitors (Verapamil and NNC55-0396, respectively) were used. So as to confirm the involvement of L- and T-type VGCC in the context of microdamage, cells were seeded on devitalized notched bone specimen, which were loaded to induce microdamage in the presence and absence of Verapamil and NNC55-0396. The results showed significant decrease in [Ca^2 +]_I activity of cells in the microdamaged regions of bone when L- and T-type blockers were applied. This study demonstrated that extracellular calcium increase in association with damage depolarizes the cell membrane and the calcium ions enter the cell cytoplasm by L- and T-type VGCCs.     

Inverse association between bone microarchitecture assessed by HR-pQCT and coronary artery calcification in patients with end-stage renal disease

It is a matter of debate whether vascular calcification and bone loss are simultaneously occurring but largely independent processes or whether poor bone health predisposes to vascular calcification, especially in patients with kidney disease. Here we investigated the association between the changes of microarchitecture in weight bearing bone and the extent of coronary artery calcification in patients with chronic renal failure.The bone microarchitecture of the tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT), bone mineral density using dual X-ray absorptiometry (DXA) of the lumbar spine, femoral neck and distal radius as well as coronary artery calcification using multi-slice CT and reported as Agatston score were measured in 66 patients with end-stage renal disease on chronic hemodialysis. Markers of bone turnover, vitamin D status and intact parathyroid hormone (iPTH) were assessed.CAC score was found to be < 100 in 39% and ≥ 100 in 61% of patients. The median [95% CI] total CAC score was 282 [315–2587]. By univariate analysis, significant correlations between CAC and age (R = 0.52, p < 0.001), weight (R = 0.3, p < 0.01) and serum cross laps (CTX, R = − 0.39, p < 0.01) were found, and parameters of bone microarchitecture were numerically but not significantly lower in patients with CAC scores ≥ 100. In multivariate analysis stratifying for gender and correcting for age, tibial density (D_tot) and bone volume/total volume (BV/TV) were significantly lower in patients with CAC scores ≥ 100 (p < 0.05 for both).Low trabecular bone volume and decreased cortical bone density are associated with coronary artery calcification in dialysis patients.     

Evaluating the relationship between muscle and bone modeling response in older adults

Bone modeling, the process that continually adjusts bone strength in response to prevalent muscle-loading forces throughout an individual's lifespan, may play an important role in bone fragility with age. Femoral stress, an index of bone modeling response, can be estimated using measurements of DXA derived bone geometry and loading information incorporated into an engineering model. Assuming that individuals have adapted to habitual muscle loading forces, greater stresses indicate a diminished response and a weaker bone. The purpose of this paper was to evaluate the associations of lean mass and muscle strength with the femoral stress measure generated from the engineering model and to examine the extent to which lean mass and muscle strength account for variation in femoral stress among 2539 healthy older adults participating in the Health ABC study using linear regression. Mean femoral stress was higher in women (9.51, SD = 1.85 Mpa) than in men (8.02, SD = 1.43 Mpa). Percent lean mass explained more of the variation in femoral stress than did knee strength adjusted for body size (R² = 0.187 vs. 0.055 in men; R² = 0.237 vs. 0.095 in women). In models adjusted for potential confounders, for every percent increase in lean mass, mean femoral stress was 0.121 Mpa lower (95% CI: − 0.138, − 0.104; p < 0.001) in men and 0.139 Mpa lower (95% CI: − 0.158, − 0.121; p < 0.001) in women. The inverse association of femoral stress with lean mass and with knee strength did not differ by category of BMI. Results from this study provide insight into bone modeling differences as measured by femoral stress among older men and women and indicate that lean mass may capture elements of bone's response to load.     

Serum FGF-21 levels are associated with worsened radial trabecular bone microarchitecture and decreased radial bone strength in women with anorexia nervosa

BackgroundAnorexia nervosa (AN) is a psychiatric disorder characterized by self-induced starvation and low body weight. Women with AN have impaired bone formation, low bone mass and an increased risk of fracture. FGF-21 is a hormone secreted by the liver in starvation and FGF-21 transgenic mice have significant bone loss due to an uncoupling of bone resorption and bone formation. We hypothesized that FGF-21 may contribute to the low bone mass state of AN.Subjects and methodsWe studied 46 women: 20 with AN (median age [interquartile range]: 27.5 [25, 30.75] years) and 26 normal-weight controls (NWC) of similar age (25 [24, 28.5] years). We investigated associations between serum FGF-21 and 1) aBMD measured by dual energy X-ray absorptiometry, 2) parameters of bone microarchitecture in the distal radius and tibia measured by high-resolution peripheral quantitative CT and 3) bone strength, estimated by microfinite element analysis.ResultsFGF-21 levels were similar in AN and NWC (AN: 33.1 [18.1, 117.0] pg/ml vs. NWC: 57.4 [23.8, 107.1] pg/ml; p = 0.54). There was a significant inverse association between log FGF-21 and trabecular number in the radius in both AN (R = − 0.57, p < 0.01) and NWC (R = − 0.53, p < 0.01) and a significant positive association between log FGF-21 and trabecular separation in the radius in AN (R = 0.50, p < 0.03) and NWC (R = 0.52, p < 0.01). Estimates of radial bone strength were inversely associated with log FGF-21 in AN (R = − 0.50, p < 0.03 for both stiffness and failure load). There were no associations between FGF-21 and aBMD, cortical parameters or tibial parameters in the AN or NWC groups.ConclusionsFGF-21 may be an important determinant of trabecular skeletal homeostasis in AN.     

Vitamin D metabolites and bone mineral density: The multi-ethnic study of atherosclerosis

Previous studies demonstrate associations of low 25-hydroxyvitamin D (25(OH)D) concentrations with low bone mineral density (BMD) and fractures, motivating widespread use of vitamin D supplements for bone health. However, previous studies have been limited to predominantly White populations despite differences in the distribution and metabolism of 25(OH)D by race/ethnicity. We determined associations of serum 25(OH)D, 24,25-dihydroxyvitamin D (24,25(OH₂)D₃), and parathyroid hormone (PTH) with BMD among 1773 adult participants in the Multi-Ethnic Study of Atherosclerosis (MESA) in a staggered cross-sectional study design. Vitamin D metabolites were measured using liquid chromatography-mass spectroscopy and PTH using a 2-site immunoassay from serum collected in 2000–2002. Volumetric trabecular lumbar BMD was measured from computed tomography scans performed in 2002–2005 expressed as g/cm³. We used linear regression and graphical methods to compare associations of vitamin D metabolite and PTH concentrations with BMD as the outcomes measure among White (n = 714), Black (n = 353), Chinese (n = 249), and Hispanic (n = 457) participants. Serum 25(OH)D and 24,25(OH₂)D₃ concentrations were highest among Whites and lowest among Blacks. BMD was greatest among Black participants. Higher serum 25(OH)D was only associated with higher BMD among Whites and Chinese participants (P-for-interaction = 0.054). Comparing the lowest category of 25(OH)D (< 20 ng/ml) to the highest (≥ 30 ng/ml), the adjusted mean difference in BMD was –8.1 g/cm³ (95% CI − 14.8, − 1.4) for Whites; − 10.2 g/cm³ (− 20.4, 0.0) for Chinese vs. 8.8 g/cm³ (− 2.8, 20.5) for Black and − 1.1 g/cm³ (− 8.3, 6.2) for Hispanic. Similar results were observed for serum 24,25(OH₂)D_3. Serum PTH was not associated with BMD. In a multi-ethnic population, associations of 25(OH)D with BMD were strongest among White and Chinese participants and null among Black and Hispanic participants. Further studies are needed to determine optimal biomarkers for bone health for multiple ethnic groups.     

Inhalation versus intravenous anaesthesia for adults undergoing on-pump or off-pump coronary artery bypass grafting: A systematic review and meta-analysis of randomized controlled trials

Study objectiveTo compare the use of inhalation versus intravenous anaesthesia for adults undergoing on-pump or off-pump coronary artery bypass grafting.DesignA systematic review.SettingA hospital-affiliated university.MeasurementsThe following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 10), MEDLINE, EMBASE, and LILACS (from inception to October 2016). We used the GRADE approach to rate overall certainty of the evidence.ResultsIn total we included 58 studies with a total of 6105 participants. The methodological quality was difficult to assess as it was poorly reported in 35 included studies (three or more domains were rated as unclear risk of bias). Two trials of sevoflurane showed a statistically significant reduction in death within 180 to 365 days of surgery (on-pump) (RR 4.10, 95% CI 1.42 to 11.79; p = 0.009; I² = not applicable; high quality of evidence). There was also a statistically significant difference favouring sevoflurane compared to propofol on both inotropic (RR 2.11, 95% CI 1.53 to 2.90; p < 0.00001; I² = 0%) and vasoconstrictor support needed (RR 1.51, 95% CI 1.04 to 2.22; p = 0.03; I² = 0%) after coronary artery bypass grafting on-pump. Two trials of sevoflurane (MD − 0.22, 95% CI − 0.41 to − 0.03; p = 0.02; I² = 0%) and two further trials of desflurane (MD − 0.33, 95% CI − 0.45 to − 0.20; p < 0.00001; I² = 82%) showed a statistically significant difference on cardiac index during and after coronary artery bypass grafting on-pump, respectively.ConclusionsThere is high quality evidence that sevoflurane reduces death within 180 to 365 days of surgery and, inotropic and vasoconstrictor support compared to propofol for patients undergoing coronary artery bypass grafting. There is also some evidence showing that the cardiac index is minimally influenced by administration of sevoflurane and desflurane compared to propofol.     

Vertebral bone marrow glucose uptake is inversely associated with bone marrow fat in diabetic and healthy pigs: [18F]FDG-PET and MRI study

ObjectivesDiabetes induces osteoporosis and during osteoporosis, vertebral bone marrow (VBM) adipose tissue amount increases. The association between this adiposity and bone marrow metabolism is unclear. Here, we compared VBM glucose metabolism and fat content in healthy and diabetic pigs, in vivo, using positron emission tomography (PET), in-phase and out-of-phase magnetic resonance imaging and magnetic resonance proton spectroscopy (¹H MR spectroscopy).Materials/methodsEleven pigs (n = 11) were used. The intervention group had five diabetic and the control group had six healthy pigs. To measure metabolism, PET-imaging with [¹⁸F]fluoro-deoxy-glucose ([¹⁸F]FDG) intravenous tracer was used. 1.5-T MRI with ¹H spectroscopy, in-phase and out-of-phase imaging and chemical TAG analysis of the VBM were performed.ResultsWe found a significant inverse correlation between VBM glucose uptake (GU) and VBM fat content (R = − 0.800, p < 0.01) and TAG concentration assay (R = − 0.846, p < 0.05). There was a trend, although non-significant, of a linear correlation between VBM ¹H MR spectroscopy and TAG concentration (R = 0.661) and ¹H MR spectroscopy and in-phase and out-of-phase MR imaging (R = 0.635).ConclusionsVBM glucose metabolism coupled with VBM fat content may impact diabetic induced osteoporosis.     

Longitudinal elastic properties and porosity of cortical bone tissue vary with age in human proximal femur

Tissue level structural and mechanical properties are important determinants of bone strength. As an individual ages, microstructural changes occur in bone, e.g., trabeculae and cortex become thinner and porosity increases. However, it is not known how the elastic properties of bone change during aging. Bone tissue may lose its elasticity and become more brittle and prone to fractures as it ages. In the present study the age-dependent variation in the spatial distributions of microstructural and microelastic properties of the human femoral neck and shaft were evaluated by using acoustic microscopy. Although these properties may not be directly measured in vivo, there is a major interest to investigate their relationships with the linear elastic measurements obtained by diagnostic ultrasound at the most severe fracture sites, e.g., the femoral neck. However, before the validity of novel in vivo techniques can be established, it is essential to understand the age-dependent variation in tissue elastic properties and porosity at different skeletal sites. A total of 42 transverse cross-sectional bone samples were obtained from the femoral neck (Fn) and proximal femoral shaft (Ps) of 21 men (mean ± SD age 47.1 ± 17.8, range 17–82 years). Samples were quantitatively imaged using a scanning acoustic microscope (SAM) equipped with a 50 MHz ultrasound transducer. Distributions of the elastic coefficient (c₃₃) of cortical (Ct) and trabecular (Tr) tissues and microstructure of cortex (cortical thickness Ct.Th and porosity Ct.Po) were determined. Variations in c₃₃ were observed with respect to tissue type (c_33Tr < c_33Ct), location (c₃₃(Ct.Ps) = 37.7 GPa > c₃₃(Ct.Fn) = 35.3 GPa > c₃₃(Tr.Ps) = 33.8 GPa > c₃₃(Tr.Fn) = 31.9 GPa), and cadaver age (R² = 0.28–0.46, p < 0.05). Regional variations in porosity were found in the neck (superior 13.1%; inferior 6.1%; anterior 10.1%; posterior 8.6%) and in the shaft (medial 9.5%; lateral 7.7%; anterior 8.6%; posterior 12.0%). In conclusion, significant variations in elastic coefficients were detected between femoral neck and shaft as well as between the quadrants of the cross-sections of neck and shaft. Moreover, an age-related increase in cortical porosity and a stiffening of the bone tissue were observed. These findings may explain in part the increase in susceptibility to suffer low energy fractures during aging and highlight the potential of ultrasound in clinical osteoporosis diagnostics.     

Structural analysis of the human tibia in men with spinal cord injury by tomographic (pQCT) serial scans

Spinal cord injury (SCI), as a primarily neurological disorder that causes muscular atrophy, is well known to be associated with sub-lesional bone losses. These losses are more pronounced from epiphyseal than from diaphyseal regions. We hypothesized that this discrepancy may be explained by anatomical variation in endocortical circumference.Nine men who had attracted SCI 9 to 32 (mean 21.4) years prior to study inclusion were matched to able bodied control (Ctrl) people by age, height and weight. Serial scans by peripheral quantitative computed tomography were obtained from the tibia at steps corresponding to 5%-steps of the tibias length (s05 to s95, from distal to the proximal end of the tibia).As expected, SCI people had lower total bone mineral content (vBMC.tot) than able bodied control people (P < 0.001 at all sites). This group difference (ΔvBMC.tot) was more pronounced at the distal and proximal tibia than in the shaft (P < 0.001), and it amounted to 51% at s05, to 22% at s40, and to 47% at s95. Both endocortical and periosteal circumference were better predictors of ΔvBMC.tot (R² = 0.98 and R² = 0.97, respectively; P < 0.001 in both cases) than vBMC.tot (R² = 0.58, P < 0.001), suggesting that anatomical variation in geometry, rather than in bone mass can explain differential rates of bone loss after SCI. Moreover, the s04:s38 ratio in vBMC.tot was found to be 1.00 (95% confidence interval: 0.95–1.05) in the Ctrl group, and 0.63 in the SCI group (P < 0.001, 95% confidence interval: 0.54–0.68).These findings offer a rationale to account for the discrepancy between epiphyseal and diaphyseal bone losses following SCI. The suggestion is that the bone adaptive responses involved are limited in time, and that the reduced surface:volume ratio constitutes a limit within the available time window, in particular in the diaphysis. Finally, the drastically reduced s04:s38 vBMC.tot ratio observed in the SCI group in this study provides a rationale to scrutinize this Capozza index also in other studies as a general indicator of immobilisation-induced bone loss.     

Total and Regional Body Volumes Derived From Dual-Energy X-Ray Absorptiometry Output

Total body volume is an important health metric used to measure body density, shape, and multicompartmental body composition but is currently only available through underwater weighing or air displacement plethysmography (ADP). The objective of this investigation was to derive an accurate body volume from dual-energy X-ray absorptiometry (DXA)–reported measures for advanced body composition models. Volunteers received a whole body DXA scan and an ADP measure at baseline (N = 25) and 6 mo (N = 22). Baseline measures were used to calibrate body volume from the reported DXA masses of fat, lean, and bone mineral content. A second population (N = 385) from the National Health and Nutrition Examination Survey was used to estimate the test-retest precision of regional (arms, legs, head, and trunk) and total body volumes. Overall, we found that DXA-volume was highly correlated to ADP-volume (R² = 0.99). The 6-mo change in total DXA-volume was highly correlated to change in ADP-volume (R² = 0.98). The root mean square percent coefficient of variation precision of DXA-volume measures ranged from 1.1% (total) to 3.2% (head). We conclude that the DXA-volume method can measure body volume accurately and precisely, can be used in body composition models, could be an independent health indicator, and is useful as a prospective or retrospective biomarker of body composition.