Hyperglycaemia, diabetes and risk of fragility fractures: observational and Mendelian randomisation studies.

AIMS/HYPOTHESIS: Fragility fractures may be a complication of diabetes, partly caused by chronic hyperglycaemia. We hypothesised that: (1) individuals with hyperglycaemia and diabetes have increased risk of fragility fracture; (2) hyperglycaemia is causally associated with increased risk of fragility fracture; and (3) diabetes and fragility fracture jointly associate with the highest risk of all-cause mortality. METHODS: In total, 117,054 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study (the Copenhagen studies) and 390,374 individuals from UK Biobank were included for observational and one-sample Mendelian randomisation (MR) analyses. Fragility fractures were defined as fractures at the hip, spine and arm (humerus/wrist), collected from national health registries. Summary data for fasting glucose and HbA1c concentrations from 196,743 individuals in the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) were combined with data on fragility fractures from the Copenhagen studies in two-sample MR analyses. RESULTS: Higher fasting and non-fasting glucose and HbA1c concentrations were associated with higher risk of any fragility fracture (p<0.001). Individuals with vs without diabetes had HRs for fragility fracture of 1.50 (95% CI 1.19, 1.88) in type 1 diabetes and 1.22 (1.13, 1.32) in type 2 diabetes. One-sample MR supported a causal association between high non-fasting glucose concentrations and increased risk of arm fracture in the Copenhagen studies and UK Biobank combined (RR 1.41 [1.11, 1.79], p=0.004), with similar results for fasting glucose and HbA1c in two-sample MR analyses (ORs 1.50 [1.03, 2.18], p=0.03; and 2.79 [1.12, 6.93], p=0.03, respectively). The corresponding MR estimates for any fragility fracture were 1.18 (1.00, 1.41), p=0.06; 1.36 (0.89, 2.09), p=0.15; and 2.47 (0.95, 6.43), p=0.06, respectively. At age 80 years, cumulative death was 27% in individuals with fragility fracture only, 54% in those with diabetes only, 67% in individuals with both conditions and 17% in those with neither. CONCLUSIONS/INTERPRETATION: Hyperglycaemia and diabetes are risk factors for fragility fracture and one- and two-sample MR analyses supported a causal effect of hyperglycaemia on arm fractures. Diabetes and previous fragility fracture jointly conferred the highest risk of death in the general population.

Human P2X7 receptor variants Gly150Arg and Arg276His polymorphisms have differential effects on risk association and cellular functions in pancreatic cancer.

BACKGROUND: The purinergic P2X7 receptor (P2X7R) plays an important role in the crosstalk between pancreatic stellate cells (PSCs) and cancer cells, thus promoting progression of pancreatic ductal adenocarcinoma (PDAC). Single nucleotide polymorphisms (SNPs) in the P2X7R have been reported for several cancers, but have not been explored in PDAC. MATERIALS AND METHODS: Blood samples from PDAC patients and controls were genotyped for 11 non-synonymous SNPs in P2X7R and a risk analysis was performed. Relevant P2X7R-SNP GFP variants were expressed in PSCs and cancer cells and their function was assayed in the following tests. Responses in Ca2+ were studied with Fura-2 and dye uptake with YO-PRO-1. Cell migration was monitored by fluorescence microscopy. Released cytokines were measured with MSD assay. RESULTS: Risk analysis showed that two SNPs 474G>A and 853G>A (rs28360447, rs7958316), that lead to the Gly150Arg and Arg276His variants, had a significant but opposite risk association with PDAC development, protecting against and predisposing to the disease, respectively. In vitro experiments performed on cancer cells and PSCs expressing the Gly150Arg variant showed reduced intracellular Ca2+ response, fluorescent dye uptake, and cell migration, while the Arg276His variant reduced dye uptake but displayed WT-like Ca2+ responses. As predicted, P2X7R was involved in cytokine release (IL-6, IL-1ß, IL-8, TNF-α), but the P2X7R inhibitors displayed varied effects. CONCLUSION: In conclusion, we provide evidence for the P2X7R SNPs association with PDAC and propose that they could be considered as potential biomarkers.

Elevated plasma levels of calcitonin gene-related peptide in individuals with rosacea: A cross-sectional case-control study.

BACKGROUND: Understanding the role of calcitonin gene-related peptide (CGRP) in the pathogenesis of rosacea might provide new therapeutic avenues for individuals with this disease. OBJECTIVE: To compare plasma levels of CGRP between individuals with rosacea and healthy controls. METHODS: In this cross-sectional case-control study conducted in Copenhagen, Denmark, we collected blood samples from the antecubital vein from adults with rosacea and from healthy controls. RESULTS: We enrolled 123 individuals with rosacea and 68 healthy controls. After adjusting for age and sex, plasma levels of CGRP were significantly higher in individuals with rosacea (mean, 95% confidence interval: 140.21 pmol/L, 128.50-151.92 pmol/L), compared with controls (110.77 pmol/L, 99.91-120.14 pmol/L, p = 0.002). Plasma levels of CGRP were not affected by age, sex, BMI, concomitant migraine, rosacea sub- or phenotype, concomitant disease or current treatment. LIMITATIONS: Participants were not age-, sex- and BMI-matched. CONCLUSIONS AND RELEVANCE: Elevated plasma levels of CGRP in individuals with rosacea suggest a role of CGRP in the pathogenesis of rosacea. Targeting CGRP signalling might hold therapeutic promise in people affected by this disease. GOV LISTING: NCT03872050.

Vitamin K supplementation and bone mineral density in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

BACKGROUND: Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis. METHODS: In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1-L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status. RESULTS: After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo -0.023 g/cm2 [95% confidence interval (CI) -0.039 to -0.008]}, whereas the decrease in lumbar spine BMD seen in the placebo group was prevented [mean difference of changes between groups 0.050 g/cm2 (95% CI 0.015-0.085)]. No significant effects were observed at the remaining skeletal sites. Vitamin K status strongly improved in MK-7-supplemented participants. CONCLUSION: Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.

Fibroblast growth factor-23 is associated with imaging markers of diabetic cardiomyopathy and anti-diabetic therapeutics.

BACKGROUND: The biomarker fibroblast growth factor-23 (FGF-23) has been associated with increased cardiovascular morbidity and mortality in both patients with and without type 2 diabetes. The aim of this study was to evaluate the relationship between FGF-23 and cardiac structure, function and perfusion in patients with type 2 diabetes and normal or mildly impaired kidney function. Furthermore, to investigate the association between FGF-23, anti-diabetes therapy and the classic complications and risk factors associated with type 2 diabetes. METHODS: In this cross-sectional study, 246 patients with type 2 diabetes underwent echocardiography and advanced cardiac magnetic resonance imaging to assess left ventricular (LV) structure and function. In addition, myocardial blood flow (MBF) during rest and pharmacological stress (adenosine 140 µg/kg/min) were evaluated in 183 of the patients. Patients with eGFR < 60 ml/min/1.73 m2 were excluded. RESULTS: Median (Q1-Q3) FGF-23 was 74 (58-91) ng/L. Patients with FGF-23 above the median had lower MBF during stress (2.3 ± 0.9 vs. 2.7 ± 0.9 ml/min/g, P = 0.001) and lower overall myocardial perfusion reserve (MPR) (2.7 ± 0.8 vs. 3.3 ± 1.1, P < 0.001). LV mass (143 ± 40 vs. 138 ± 36 g, P = 0.04) and E/e* (8.5 ± 3.2 vs. 7.6 ± 2.7, P = 0.04) were higher in patients with FGF-23 above the median. In a linear model adjusted for age, sex, eGFR and hypertension, increasing FGF-23 was associated with decreased MPR (P < 0.01, R2 = 0.11) and increased E/e* (P < 0.01, R2 = 0.07). FGF-23 was lower in patients receiving glucagon like peptide-1 (GLP-1) analogues (71 (57-86) vs. 80 (60-98) ng/L, P = 0.01) than in those who did not receive GLP-1 analogues. CONCLUSIONS: In patients with type 2 diabetes and normal or mildly impaired kidney function, increased levels of FGF-23 are associated with impaired cardiac diastolic function and decreased MPR, caused by a decrease in maximal MBF during stress. Use of GLP-1 analogues is associated with decreased levels of FGF-23. Clinical trial registration https://www.clinicaltrials.gov . Unique identifier: NCT02684331. Date of registration: February 18, 2016.

Bone turnover biomarkers in COPD patients randomized to either a regular or shortened course of corticosteroids: a substudy of the randomized controlled CORTICO-COP trial.

BACKGROUND: Long-term treatment with corticosteroids causes loss of bone density, but the effects of using short-term high-dose systemic-corticosteroid therapy to treat acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are unclear. Our aim was to determine whether high-dose corticosteroid therapy affected bone turnover markers (BTMs) to a greater extent compared to low-dose corticosteroid therapy. METHODS: The CORTICO-COP trial (NCT02857842) showed that an eosinophil-guided corticosteroid intervention led to approximately 60% lower accumulated corticosteroid dose for hospitalized patients with AECOPD (low-dose group) compared with 5-day standard corticosteroid treatment (high-dose group). We compared the levels of BTMs C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) in 318 participants during AECOPD and at 1- and 3-month follow-up visits. RESULTS: CTX decreased and P1NP increased significantly over time in both treatment groups. There were no significant differences between the groups at 1- or 3-months follow-up for P1NP. A significant drop in CTX was seen at 3 months (down Δ24% from the baseline, p = 0.017) for the high dose group. CONCLUSION: Short-term, high-dose systemic corticosteroid treatment caused a rapid suppression of biomarkers of bone resorption. Corticosteroids did not suppress biomarkers of bone formation, regardless of patients receiving low or high doses of corticosteroids. This therapy was, therefore, harmless in terms of bone safety, in our prospective series of COPD patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02857842 . Submitted August 2nd, 2016.

Adults with pathogenic MC4R mutations have increased final height and thereby increased bone mass.

Pathogenic mutations in the melanocortin-4 receptor (MC4R) are associated with obesity, increased linear growth, and higher bone mass in children, and rodent studies have indicated an effect of the MC4R on bone turnover. Furthermore, GLP-1 receptor agonists (GLP-1 RAs) may influence bone metabolism. However, these associations have not been assessed in adults with pathogenic MC4R mutations. Thus, we wished to assess the impact of the MC4R on bone mass and metabolism. Secondly, we wished to investigate the impact of the GLP-1 RA liraglutide on bone mass in adults with pathogenic MC4R mutations. 17 patients with obesity-causing MC4R mutations (BMI: 35.5 ± 7.6) and 35 matched control participants with common obesity (BMI: 34.3 ± 7.1) underwent a DEXA scan for assessment of bone mineral density (BMD), bone mineral apparent density [BMAD = (BMD/√(bone area)], and bone turnover markers (BTMs). Individuals with a BMI above 28 (14 MC4R mutation carriers and 28 matched control participants) underwent 16 weeks treatment with liraglutide 3.0 mg. The MC4R group had higher BMD [mean difference: 0.065 g/m2 (- 0.008 to 0.138), p = 0.03], but BMAD and BTMS were not different compared to the control group. In response to liraglutide, BMAD increased in the control group, compared to no change in the MC4R group [mean group difference: 0.0007 (0.0001-0.001), p = 0.04]. In conclusion, BMD is increased in MC4R causal obesity compared to common obesity, but when corrected for body size (BMAD), bone mass was not increased, and no evidence of an influence of the MC4R on bone metabolism in adults was found. Liraglutide treatment did not change bone metabolism in MC4R causal obesity, but increased bone mass as measured by BMAD in common obesity.

Bone turnover markers during the remission phase in children and adolescents with type 1 diabetes.

BACKGROUND AND AIM: In rodents, osteocalcin (OCN) stimulates insulin production and insulin sensitivity, both important factors during partial remission in humans with type 1 diabetes (T1D). However, decreased OCN has been reported in both adult and pediatric T1D. This study aims at investigating bone turnover and partial remission in children and adolescents with recent onset T1D. SUBJECTS AND METHODS: Ninety-nine individuals (33% girls) were recruited within 3 months of T1D onset and examined three times, 6 months apart. Outcome variables were bone formation markers OCN and procollagen type 1 amino-terminal propeptide (P1NP) and the bone resorption marker C-terminal crosslinked telopeptide of type 1 collagen (CTX). Dependent variables included IDAA1c (surrogate marker of partial remission), total body bone mineral density (BMD) and stimulated C-peptide as representative of endogenous insulin production. RESULTS: OCN- and P1NP Z-scores were significantly decreased throughout the study, whereas CTX Z-scores were increased. None of the bone turnover markers changed significantly between visits. Total body BMD Z-score did not change during the study but was significantly higher than the reference population at visit 2 (P = .035). There were no differences in the bone turnover markers for those in partial remission as defined by either C-peptide or IDAA1c at any visit. The individual change in CTX Z-score was negatively associated with the increase of IDAA1c (P = .030) independent of C-peptide decline (P = .034). CONCLUSION: Bone turnover markers indicate increased bone resorption and decreased bone formation during the first year of T1D. The negative association between bone resorption and IDAA1c might represent compensatory mechanisms affecting insulin sensitivity.

S100B and NSE in Cluster Headache - Evidence for Glial Cell Activation?

OBJECTIVE: Neuronal-specific enolase (NSE) and protein S100B have gained considerable interest as the markers of CNS injury, glial cell activation, and/or blood-brain barrier (BBB) disruption. No studies have investigated NSE and S100B in cluster headache (CH), but these biomarkers could contribute to the understanding of CH. METHODS: Patients with episodic CH in bout (eCHa), in remission (eCHr), and chronic CH (cCH) were included in this randomized, double-blind, placebo-controlled, 2-way cross-over provocation study carried out at the Danish Headache Center. The primary endpoints included (1) differences of NSE and S100B in between groups (eCHa, eCHr, and cCH) at baseline; (2) differences over time in plasma concentrations of NSE and S100B between patient developing an attack and those who did not; (3) differences in plasma concentrations over time of NSE and S100B between active day and placebo day. Baseline findings were compared to the historical data on migraine patients and healthy controls and presented with means ± SD. RESULTS: Nine eCHa, 9 eCHr, and 13 cCH patients completed the study and blood samples from 11 CGRP-induced CH attacks were obtained. There were no differences in NSE levels between CH groups at baseline, but CH patients in active disease phase had higher levels compared with 32 migraine patients (9.1 ± 2.2 µg/L vs 6.0 ± 2.2 µg/L, P < .0001) and 6 healthy controls (9.1 ± 2.2 µg/L vs 7.3 ± 2.0 µg/L, P = .007). CGRP-infusion caused no NSE changes and, but a slight, non-significant, increase in NSE was seen in patients who reported a CGRP-induced CH attack (2.39 µg/L, 95% Cl [-0.26, 3.85], P = .061). At baseline S100B levels in eCHa patients were higher compared to cCH patients (0.06 ± 0.02 µg/L vs 0.04 ± 0.02 µg/L, P = .018). Infusion of CGRP and CGRP-induced attacks did not change S100B levels. Apart from induced CH-attacks no other adverse events were noted. CONCLUSIONS: At baseline eCHa patients had higher S100B plasma levels than cCH patients and there was a slight, however not significant, NSE increase in response to CGRP-induced CH attack. Our findings suggest a possible role of an ictal activation of glial cells in CH pathophysiology, but further studies are warranted.

Acute response of biochemical bone turnover markers and the associated ground reaction forces to high-impact exercise in postmenopausal women.

The aim of the study was to examine the acute response of biochemical bone turnover markers (BTM) to high-impact jumping exercise, and to quantify the ground reaction forces (GRF) achieved during each jumping exercise, in postmenopausal women. In a randomized controlled cross-over study over three days, 29 postmenopausal women (age (mean±SD): 60.0±5.6 years) were randomly assigned to 6 x 10 repetitions of three different jumps: countermovement jump (CMJ), drop jump (DJ), diagonal drop jump (DDJ). A fourth day without jumping served as a control (CON). Blood samples were collected before (PRE), after (POST), and 2 hours after (2Hr) exercise. Bone turnover was evaluated by bone formation markers (procollagen type-1 amino-terminal propeptide (P1NP) and osteocalcin (OC)) and the bone resorption marker C-terminal telopeptide of type-1 collagen (CTX). Peak anteroposterior (Fx), mediolateral (Fy), and vertical (Fz) GRF were measured using a force platform. From PRE to POST, P1NP increased (p<0.01) by 7.7±1.8%, 9.4±1.3%, and 10.6±1.6% for CMJ, DJ, and DDJ, which were higher (p<0.01) than CON. OC increased (p<0.05) by 5.5±1.8% for DJ, which was higher (p<0.05) than CON. CTX was not significantly changed at POST. There were no significant differences in BTM Δ-values between the jumps at any time point. For the CMJ, the combined three-axis peak GRF was positively associated with the PRE to POST Δ-change in P1NP (r=0.71, p<0.05). The acute, jumping-induced increase in P1NP and OC without any rise in CTX may indicate increased bone formation. Moreover, the study shows a dose-response relationship between GRF and the acute P1NP response after countermovement jumps.

Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study.

AIMS/HYPOTHESIS: Individuals with type 2 diabetes have an altered bacterial composition of their gut microbiota compared with non-diabetic individuals. However, these alterations may be confounded by medication, notably the blood-glucose-lowering biguanide, metformin. We undertook a clinical trial in healthy and previously drug-free men with the primary aim of investigating metformin-induced compositional changes in the non-diabetic state. A secondary aim was to examine whether the pre-treatment gut microbiota was related to gastrointestinal adverse effects during metformin treatment. METHODS: Twenty-seven healthy young Danish men were included in an 18-week one-armed crossover trial consisting of a pre-intervention period, an intervention period and a post-intervention period, each period lasting 6 weeks. Inclusion criteria were men of age 18-35 years, BMI between 18.5 kg/m2 and 27.5 kg/m2, HbA1c < 39 mmol/mol (5.7%) and plasma creatinine within the normal range. No prescribed medication, including antibiotics, for 2 months prior to recruitment were allowed and no previous gastrointestinal surgery, discounting appendectomy or chronic illness requiring medical treatment. During the intervention the participants were given metformin up to 1 g twice daily. Participants were examined five times in the fasting state with blood sampling and recording of gastrointestinal symptoms. Examinations took place at Frederiksberg Hospital, Denmark before and after the pre-intervention period, halfway through and immediately after the end of intervention and after the wash-out period. Faecal samples were collected at nine evenly distributed time points, and bacterial DNA was extracted and subjected to 16S rRNA gene amplicon sequencing in order to evaluate gut microbiota composition. Subjective gastrointestinal symptoms were reported at each visit. RESULTS: Data from participants who completed visit 1 (n=23) are included in analyses. For the primary outcome the relative abundance of 11 bacterial genera significantly changed during the intervention but returned to baseline levels after treatment cessation. In line with previous reports, we observed a reduced abundance of Intestinibacter spp. and Clostridium spp., as well as an increased abundance of Escherichia/Shigella spp. and Bilophila wadsworthia. The relative abundance at baseline of 12 bacterial genera predicted self-reported gastrointestinal adverse effects. CONCLUSIONS/INTERPRETATION: Intake of metformin changes the gut microbiota composition in normoglycaemic young men. The microbiota changes induced by metformin extend and validate previous reports in individuals with type 2 diabetes. Secondary analyses suggest that pre-treatment gut microbiota composition may be a determinant for development of gastrointestinal adverse effects following metformin intake. These results require further investigation and replication in larger prospective studies. TRIAL REGISTRATION: Clinicaltrialsregister.eu 2015-000199-86 and ClinicalTrials.gov NCT02546050 FUNDING: This project was funded by Danish Diabetes Association and The Novo Nordisk Foundation.

Assessment of acute bone loading in humans using [18F]NaF PET/MRI.

PURPOSE: The acute effect of loading on bone tissue and physiology can offer important information with regard to joint function in diseases such as osteoarthritis. Imaging studies using [18F]-sodium fluoride ([18F]NaF) have found changes in tracer kinetics in animals after subjecting bones to strain, indicating an acute physiological response. The aim of this study is to measure acute changes in NaF uptake in human bone due to exercise-induced loading. METHODS: Twelve healthy subjects underwent two consecutive 50-min [18F]NaF PET/MRI examinations of the knees, one baseline followed by one post-exercise scan. Quantification of tracer kinetics was performed using an image-derived input function from the popliteal artery. For both scans, kinetic parameters of KiNLR, K1, k2, k3, and blood volume were mapped parametrically using nonlinear regression with the Hawkins model. The kinetic parameters along with mean SUV and SUVmax were compared between the pre- and post-exercise examinations. Differences in response to exercise were analysed between bone tissue types (subchondral, cortical, and trabecular bone) and between regional subsections of knee subchondral bone. RESULTS: Exercise induced a significant (p < <0.001) increase in [18F]NaF uptake in all bone tissues in both knees, with mean SUV increases ranging from 47% in trabecular bone tissue to 131% in subchondral bone tissue. Kinetic parameters involving vascularization (K1 and blood volume) increased, whereas the NaF extraction fraction [k3/(k2 + k3)] was reduced. CONCLUSIONS: Bone loading induces an acute response in bone physiology as quantified by [18F]NaF PET kinetics. Dynamic imaging after bone loading using [18F]NaF PET is a promising diagnostic tool in bone physiology and imaging of biomechanics.

Bone turnover markers in children and adolescents with type 1 diabetes-A systematic review.

Type 1 diabetes (T1D) is associated with impaired bone health and both osteocalcin (OCN) and procollagen type 1 amino terminal propetide (P1NP) (markers of bone formation) and C-terminal cross-linked telopeptide (CTX) (marker of bone resorption) are decreased in adult patients with T1D. We review the existing literature characterizing these bone turnover markers in children and adolescents with T1D and by meta-analysis examine whether alterations in OCN, P1NP, and CTX are evident and if potential changes correlate to the metabolic control (hemoglobin A1c, HbA1c). Systematic searches at MEDLINE and EMBASE were conducted in January 2018 identifying all studies describing OCN, P1NP, or CTX in children and adolescents with T1D. A total of 26 studies were included, representing data from more than 1000 patients with T1D. Pooled analyses of standard mean difference and summary effects analysis were performed when sufficient data were available. Pooled analysis revealed mean OCN to be significantly lower in children and adolescents with T1D compared to healthy controls (standard mean difference: -1.87, 95% confidence interval, CI: -2.83; -0.91) whereas both P1NP and CTX did not differ from the controls. Only data on OCN was sufficient to make pooled correlation analysis revealing a negative correlation between OCN and HbA1c (-0.31 95% CI: -0.45; -0.16). In conclusion, OCN is decreased in children and adolescents with T1D, whether CTX and P1NP are affected as well is unclear, due to very limited data available. New and large studies including OCN, P1NP, and CTX (preferably as z-scores adjusting for age variability) is needed to further elucidate the status of bone turnover in children and adolescents with T1D.

Biochemical markers of inflammation are associated with increased mortality in hip fracture patients: the Bispebjerg Hip Fracture Biobank.

PURPOSE: The purpose of this study was to examine the possible association between mortality following a hip fracture and known biochemical markers of inflammation. METHODS: The study population was identified using two local databases from Bispebjerg Hospital (Copenhagen, Denmark): the Hip Fracture Database containing all patients admitted to the hospital with a fractured hip from 1996 to 2012 and the Hip Fracture Biobank, containing whole blood, serum and plasma taken in relation to admission on a subgroup of patients from the Hip Fracture Database, consecutively collected over a period of 2.5 years from 2008 to 2011. The following biochemical markers of inflammation were included: C-reactive protein (CRP), the soluble urokinase plasminogen activating receptor (suPAR), ferritin and transferrin. The association between the blood markers and mortality was examined using Cox proportional hazards models. Hazard ratios (HR) were expressed per quartile increase in the biochemical markers. RESULTS: A total of 698 patients were included, 69 (9.9%) died within 30 days after sustaining a hip fracture. The HR for 30-day mortality was significantly increased with increasing quartiles of suPAR, CRP and ferritin and with decreasing quartiles of transferrin. CONCLUSION: This study shows that 30-day mortality after a hip fracture is associated with elevated levels of suPAR, CRP and ferritin as well as with lower levels of transferrin. This excess inflammatory response is likely caused by muscle damage associated with the hip fracture. However, this needs to be further clarified.

Effects of high-dose, intravenous lipid emulsion on laboratory tests in humans: a randomized, placebo-controlled, double-blind, clinical crossover trial.

Background Intravenous lipid emulsion (ILE) is used to treat drug poisonings. The resultant hyperlipemia may affect laboratory tests but the consequences are poorly characterized. In a clinical trial we therefore investigated the effects of ILE on laboratory tests analyzed on common analytical platforms (Roche® cobas 8000 and SYSMEX® flow-cytometry). Methods Ten healthy participants each completed 4 trial days (two with ILE and two with placebo). ILE (5.25 mL/kg) was administered from 12.5 to 30 min from baseline. At 0, 30 and 60 min, blood samples were drawn for measurement of 20 analytes. We investigated the effects of ILE on analyte levels and frequencies of exceedance of predefined analyzer hemolysis (H) or lipemia (L)-index cut-offs and test-specific reference change values (RCVs) on ILE-days. If the results were blocked due to exceedance of index values, we manually extracted the results. Results Sixteen out of 20 tests were blocked because H- or L-index cut-offs were exceeded on ILE-days. Differences in analyte levels between ILE- and placebo-days above the RCV were observed for aspartate aminotransferase, total calcium, lactate dehydrogenase (LDH), sodium and neutrophils. Mean values outside the normal range after ILE were observed for LDH (219 U/L), sodium (135.3 mmol/L) and total calcium (2.1 mmol/L). Conclusions ILE-infusion caused report failure of nearly all laboratory tests performed on a cobas 8000-platform, but it was possible to manually retrieve the results. For most test results - particularly alkaline phosphatase, bilirubin, phosphate and carbamide - the consequences of ILE were marginal, and the effects of ILE were reduced at the 60-min timepoint.

Osteogenic impact of football training in 55- to 70-year-old women and men with prediabetes.

The effects of football training on bone health were examined in 55- to 70-year-old sedentary women and men with prediabetes. Patients (n = 50) with prediabetes (age; 61 ± 9 years, BMI 29.7 ± 0.6 kg/m2 , body fat content; 37 ± 1%, VO2max ; 22.7 ± 0.8 mL/min/kg and mean arterial pressure; 104 ± 3 mm Hg) were randomized into a football training group (FTG; n = 27, 14 women) and a control group (CON; n = 23, 11 women). At baseline, 73% and 24% were diagnosed with femur osteopenia and osteoporosis, respectively. FTG performed football training twice weekly 30-60-minute sessions in 16 weeks, and both FTG and CON received professional dietary advice. Pre- and post-intervention whole-body and regional bone mineral content (BMC) and density (BMD) were determined with DXA-scans, and venous blood samples were drawn and analyzed for plasma bone turnover markers. Change scores were greater (P < 0.05) in FTG compared to CON in leg BMD (0.023 ± 0.005 vs -0.004 ± 0.001 g/cm2 ) and in leg BMC (32 ± 8 vs -4 ± 6 g). Between-group changes in favor of FTG (P < 0.05) also occurred in the femur neck BMD (3.2%) and femur shaft BMD (2.5%). Whole-body BMC and BMD were unchanged in both groups during the intervention. In FTG, resting plasma osteocalcin, P1NP, and CTX-1 rose (P < 0.05) by 23 ± 8, 52 ± 9 and 38 ± 7%, with greater change scores (P < 0.05) than in CON. Finally, P1NP (formation)/CTX-1 (resorption) ratio increased (P < 0.05) in FTG (127 ± 15 vs 150 ± 11) from pre- to post-intervention, with no change in CON (124 ± 12 and 123 ± 12). In conclusion, football training provides a powerful osteogenic stimulus and improves bone health in 55- to 70-year-old women and men diagnosed with prediabetes.

Effect of GLP-1 receptor agonist treatment on body weight in obese antipsychotic-treated patients with schizophrenia: a randomized, placebo-controlled trial.

AIMS: Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D2 receptor antagonists and are the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects such as obesity and diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP-1RA, exenatide once-weekly, in non-diabetic, antipsychotic-treated, obese patients with schizophrenia. MATERIAL AND METHODS: Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis. RESULTS: Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment. CONCLUSIONS: Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia.

Vitamin D Status and Muscle Function Among Adolescent and Young Swimmers.

Impaired muscle function has been coupled to vitamin D insufficiency in young women and in elderly men and women. Those living at Northern latitudes are at risk for vitamin D insufficiency due to low sun exposure which may be more pronounced among elite swimmers because of their indoor training schedules. We aimed to examine vitamin D status among young elite swimmers and evaluate the association between vitamin D status and muscle strength. Twenty-nine swimmers, 12 female and 17 male (16-24 years) residing at latitude 55-56°N were studied in March and April. Blood samples were analyzed for serum 25-hydroxyvitamin D (s-25(OH)D) and hand-grip strength was measured as marker of muscle strength. Subjects´ vitamin D and calcium intake were assessed by food frequency questionnaire and sun exposure and training status by questionnaires. Mean (± SD) s-25(OH)D was 52.6 ± 18.3nmol/L among all swimmers. In 45% of the swimmers s-25(OH)D was below 50 nmol/L. Female swimmers had higher s-25(OH)D concentration than male swimmers (61.7 ± 17,5 nmol/L vs. 46.2 ± 16,5 nmol/L, p = .026). Among male swimmers, those with sufficient vitamin D status had higher hand grip strength than those with insufficient vitamin D status (50.6 ± 6.4 kg vs. 41.1 ± 7.8 kg, p = .02). Among Danish elite swimmers 45% had an insufficient vitamin D status during the spring; the prevalence being higher among male swimmers. Muscle strength was significantly higher in male swimmers with sufficient vitamin D status.

Football training in men with prostate cancer undergoing androgen deprivation therapy: activity profile and short-term skeletal and postural balance adaptations.

PURPOSE: To investigate the activity profile of football training and its short-term effects on bone mass, bone turnover markers (BTMs) and postural balance in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). METHODS: This was a randomised 12-week study in which men with PCa undergoing ADT were assigned to a football intervention group [FTG, n = 29, 67 ± 7 (±SD) years] training 2‒3 times per week for 45‒60 min or to a control group (n = 28, 66 ± 5 years). The activity profile was measured using a 5-Hz GPS. The outcomes were total body and leg bone mineral content (BMC) and density, BTMs and postural balance. RESULTS: In the last part of the 12 weeks, FTG performed 194 ± 41 accelerations and 296 ± 65 decelerations at >0.6 m/s/s and covered a distance of 905 ± 297 m at speeds >6 km/h and 2646 ± 705 m per training session. Analysis of baseline-to-12-week change scores showed between-group differences in favour of FTG in total body BMC [26.4 g, 95 % confidence interval (CI): 5.8-46.9 g, p = 0.013], leg BMC (13.8 g, 95 % CI: 7.0‒20.5 g, p < 0.001) and markers of bone formation: P1NP (36.6 µg/L, 95 % CI: 10.4‒62.8 µg/L, p = 0.008) and osteocalcin (8.6 µg/L, 95 % CI: 3.3‒13.8 µg/L, p < 0.01). The number of decelerations correlated to the increase in leg BMC (r = 0.65, p = 0.012). No between-group differences were observed for the remaining outcomes. CONCLUSION: Football training involves numerous runs, accelerations and decelerations, which may be linked to marked increases in bone formation markers and preserved bone mass in middle-aged and elderly men with PCa undergoing ADT. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01711892.

Effects of soccer vs swim training on bone formation in sedentary middle-aged women.

PURPOSE: The present study examined the effects of 15 weeks of soccer training and two different swimming training protocols on bone turnover in sedentary middle-aged women. METHODS: Eighty-three premenopausal mildly hypertensive women [age: 45 ± 6 (± SD) years, height: 165 ± 6 cm, weight: 80.0 ± 14.1 kg, body fat: 42.6 ± 5.7 %, systolic blood pressure/diastolic blood pressure: 138 ± 6/85 ± 3 mmHg] were randomized into soccer training (SOC, n = 21), high-intensity intermittent swimming (HS, n = 21), moderate-intensity swimming (MS, n = 21) intervention groups, and a control group (C, n = 20). The training groups completed three sessions per week for 15 weeks. DXA scans were performed and resting blood samples were drawn pre- and post-intervention. RESULTS: In SOC, plasma osteocalcin, procollagen type I N propeptide and C-terminal telopeptide increased (P < 0.05) by 37 ± 15, 52 ± 23 and 42 ± 18 %, respectively, with no changes in MS, HS and C. The intervention-induced increase in SOC was larger (P < 0.05) than in MS, HS and C. In SOC, leg BMC increased (P < 0.05) by 3.1 ± 4.5 %, with a larger increase in SOC than in C. Femoral shaft and trochanter bone mineral density (BMD) increased (P < 0.05) by 1.7 ± 1.9 and 2.4 ± 2.9 %, respectively, in SOC, with a greater (P < 0.05) change in SOC than in MS and C, whereas total body and total leg BMD did not change in any of the groups. CONCLUSION: In conclusion, 15 weeks of soccer training with sedentary middle-aged women caused marked increases in bone turnover markers, with concomitant increases in leg bone mass. No changes in bone formation and resorption markers were seen after prolonged submaximal or high-intensity intermittent swimming training. Thus, soccer training appears to provide a powerful osteogenic stimulus in middle-aged women.