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1.  L-arginine and Vitamin D Adjunctive Therapies in Pulmonary Tuberculosis: A Randomised, Double-Blind, Placebo-Controlled Trial 
PLoS ONE  2013;8(8):e70032.
Background
Vitamin D (vitD) and L-arginine have important antimycobacterial effects in humans. Adjunctive therapy with these agents has the potential to improve outcomes in active tuberculosis (TB).
Methods
In a 4-arm randomised, double-blind, placebo-controlled factorial trial in adults with smear-positive pulmonary tuberculosis (PTB) in Timika, Indonesia, we tested the effect of oral adjunctive vitD 50,000 IU 4-weekly or matching placebo, and L-arginine 6.0 g daily or matching placebo, for 8 weeks, on proportions of participants with negative 4-week sputum culture, and on an 8-week clinical score (weight, FEV1, cough, sputum, haemoptysis). All participants with available endpoints were included in analyses according to the study arm to which they were originally assigned. Adults with new smear-positive PTB were eligible. The trial was registered at ClinicalTrials.gov NCT00677339.
Results
200 participants were enrolled, less than the intended sample size: 50 received L-arginine + active vitD, 49 received L-arginine + placebo vit D, 51 received placebo L-arginine + active vitD and 50 received placebo L-arginine + placebo vitD. According to the factorial model, 99 people received arginine, 101 placebo arginine, 101 vitamin D, 99 placebo vitamin D. Results for the primary endpoints were available in 155 (4-week culture) and 167 (clinical score) participants. Sputum culture conversion was achieved by week 4 in 48/76 (63%) participants in the active L-arginine versus 48/79 (61%) in placebo L-arginine arms (risk difference −3%, 95% CI −19 to 13%), and in 44/75 (59%) in the active vitD versus 52/80 (65%) in the placebo vitD arms (risk difference 7%, 95% CI −9 to 22%). The mean clinical outcome score also did not differ between study arms. There were no effects of the interventions on adverse event rates including hypercalcaemia, or other secondary outcomes.
Conclusion
Neither vitD nor L-arginine supplementation, at the doses administered and with the power attained, affected TB outcomes.
Registry
ClinicalTrials.gov. Registry number: NCT00677339
doi:10.1371/journal.pone.0070032
PMCID: PMC3743888  PMID: 23967066
2.  Calcium and vitamin D intakes in children: a randomized controlled trial 
BMC Pediatrics  2013;13:86.
Background
Calcium (Ca2+) and vitamin D (VitD) play an important role in child health. We evaluated the daily intake of Ca2+ and VitD in healthy children. Moreover, we demonstrate the efficacy of Ca2+ and VitD supplementation.
Methods
Daily Ca2 + and VitD intake was evaluated in consecutive healthy children through a validated questionnaire. Subjects with <70% of dietary reference intakes (DRIs) of Ca2+ and VitD were invited to participate in a prospective randomized trial with 2 groups of nutritional intervention: Group 1, dietary counseling aiming to optimize daily Ca2+ and VitD intake plus administration of a commercially available Ca2 + and VitD supplementation product; Group 2, dietary counseling alone. At the enrollment (T0) and after 4 months (T1) serum 25(OH) Vitamin D levels were assessed.
Results
We evaluated 150 healthy children (male 50%, mean age 10 years); at baseline a low VitD intake was observed in all subjects (median 0.79 μg/die, IQR 1.78; range 0.01-5.02); this condition was associated with Ca2+ intake <70% of the DRIs in 82 subjects (55%). At baseline serum 25(OH)D levels were low (<30 ng/ml) in all study subjects and after 4 months of nutritional intervention, a normalization of serum 25(OH)D levels (≥30 ng/ml) was observed in all children in Group 1 and in only one subject in Group 2 [Group 1: T1 33.8 ng/ml (IQR 2.5) vs Group 2: T1 24.5 ng/ml (IQR 5.2), p <0.001].
Conclusions
Adequate Ca2+ and VitD intakes are difficult to obtain through dietary counseling alone in pediatric subjects. Oral supplementation with of Ca2+ and VitD is a reliable strategy to prevent this condition.
Trial registration
The study was registered in Clinical Trials Protocol Registration System (ID number: NCT01638494).
doi:10.1186/1471-2431-13-86
PMCID: PMC3665520  PMID: 23702146
25-hydroxyvitamin D; Dietary counseling; Pediatrics; Ca2+ intake; VitD intake; Bone metabolism; Nutritional intervention; Vitamin D supplement; Vitamin D deficiency
3.  Prognostic Role of Vitamin D Status and Efficacy of Vitamin D Supplementation in Cancer Patients: A Systematic Review 
The Oncologist  2011;16(9):1215-1227.
Whether or not hypovitaminosis D can influence the prognosis of cancer patients and whether or not vitamin D supplementation improves outcome were examined through a literature review. It was concluded that the currently available evidence is insufficient to recommend vitamin D supplementation in cancer patients in clinical practice.
Background.
Whether or not hypovitaminosis D can influence the prognosis of cancer patients and whether or not vitamin D (vitD) supplementation improves outcome remain controversial.
Design.
Studies evaluating the prognostic role of vitD and vitD receptor (VDR) in cancer patients and trials evaluating the efficacy of vitD administration on patient outcome were identified by a search of MEDLINE, EMBASE, ISI Web of Knowledge, and the Cochrane Library through June 2010.
Results.
Twenty-five studies were included. A negative prognostic role for low serum vitD level was observed in five cohort studies including patients with breast cancer (one study), colon cancer (two studies), prostate cancer (one study), and melanoma (one study), but not in two studies on non-small cell lung cancer and one study on breast cancer. Three of four studies showed that VDR+ tumors carry a better prognosis than VDR− tumors, whereas VDR polymorphisms were significantly associated with prognosis in five of 10 studies. A significant interaction between serum vitD level and VDR polymorphism was observed in one study. Three randomized trials involving advanced prostate cancer patients explored the prognostic role of vitD supplementation. A meta-analysis of these trials showed no effect on survival (pooled risk ratio, 1.07; 95% confidence interval, CI, 0.93–1.23), with strong heterogeneity among studies.
Conclusion.
Hypovitaminosis D seems to be associated with a worse prognosis in some cancers, but vitD supplementation failed to demonstrate a benefit in prostate cancer patients. The currently available evidence is insufficient to recommend vitD supplementation in cancer patients in clinical practice.
doi:10.1634/theoncologist.2011-0098
PMCID: PMC3228169  PMID: 21835895
Vitamin D; Vitamin D receptor; Neoplasm; Prognosis
4.  Seasonal variation of serum 25-hydroxyvitamin D levels in adult patients with inflammatory bowel disease 
Osteoporosis International  2010;22(11):2857-2867.
Summary
Patients with inflammatory bowel disease (IBD) are at risk of osteoporosis. Vitamin D (vitD) deficiency is known as a risk factor of osteoporosis. We observed low vitD blood levels in adult IBD patients both at the end of summer and winter. Furthermore, effects of oral vitD supplementation in (generally low) daily dosages were poor.
Introduction
Patients with IBD are at risk of osteoporosis. This study evaluates seasonal vitD status, determinants of vitD deficiency and effects of vitD supplementation in adult IBD patients.
Methods
Patients were screened for vitD deficiency at the end of summer and winter using serum 25OHD3 (cut-off point, <50 nmol/L) combined with routine laboratory tests. A standardized questionnaire was used for demographic/lifestyle data i.e. IBD activity, health behaviour and vitD intake through diet and ultraviolet light.
Results
Late-summer, 39% of the included 316 patients were vitD deficient. Late-winter, 57% of the follow-up patients (n = 281) were deficient. Independent protective determinants of vitD deficiency were oral vitD supplementation (summer/winter: odds ratio [OR], 0.52 [95% confidence interval [CI], 0.29–0.94]/OR, 0.44 [95% CI, 0.26–0.75]), recent sun holiday (summer: OR, 0.42 [95% CI, 0.24–0.74]) and regular solarium visits (summer/winter: OR, 0.28 [95% CI, 0.13–0.63]/OR, 0.17 [0.06–0.50]). IBD activity (p = 0.031), red blood cell distribution width (RDW; p = 0.04) and erythrocyte sedimentation rate (p = 0.03) were associated with low vitD levels using univariate analyses of the extreme 25OHD quartiles. In a subgroup with vitD supplementation, still 30% (late-summer) and 44% (late-winter) were vitD deficient.
Conclusion
VitD deficiency is common in IBD patients, but prevalence might be comparable with the general population. Ultraviolet light is essential for adequate vitD levels. Effects of oral vitD supplementation in (generally low) daily dosages are poor. Determinants for low vitD levels were IBD activity and elevated inflammatory markers, suggesting that increased risk of osteoporosis in IBD might be more related to the inflammation than to vitD deficiency.
doi:10.1007/s00198-010-1484-y
PMCID: PMC3186887  PMID: 21113577
Inflammatory bowel disease; Osteoporosis; Pathophysiology; Prevalence; Seasonal variation; Serum 25-hydroxyvitamin D
5.  Decreased Serum Vitamin D Levels in Children with Asthma are Associated with Increased Corticosteroid Usage 
Background
There is little knowledge about clinical variables associated with vitamin D (vitD) insufficiency in asthmatic children.
Objective
To investigate disease variables associated with vitD insufficiency in childhood asthma and interaction of vitD with corticosteroid-mediated anti-inflammatory responses.
Methods
We analyzed 25-hydroxyvitamin D serum levels in 100 asthmatic children to investigate relationships between 25-hydroxyvitamin D levels and patient characteristics. We determined vitD effects on dexamethasone (DEX) induction of mitogen-activated protein kinase phosphatase-1 (MKP-1) and IL-10 in peripheral blood mononuclear cells (PBMC).
Results
The median 25-hydroxyvitamin D serum level was 31 ng/mL. 47% of subjects had vitD levels in the insufficient range (<30 ng/mL), while 17% were vitD deficient (<20 ng/mL). Log10 IgE (p=0.01, ρ=−0.25) and the number of positive aeroallergen skin prick tests (p=0.02, ρ=−0.23) showed a significant inverse correlation with vitD, whereas FEV1% predicted (p =0.004, ρ=0.34) and FEV1/FVC ratio (p=0.01, ρ=0.30) showed a significant positive correlation with vitD. The use of inhaled steroids (p=0.0475), oral steroids (p=0.02), and total steroid dose (p=0.001), all showed significant inverse correlations with vitD. The amount of MKP-1 and IL-10 mRNA induced by vitD plus DEX was significantly greater than that induced by DEX alone (p<0.01). In an experimental model of steroid resistance where DEX alone did not inhibit T cell proliferation, addition of vitD to DEX resulted in significant dose dependent suppression of cell proliferation.
Conclusions
Corticosteroid use and worsening airflow limitation is associated with lower vitD serum levels in asthmatics. VitD enhances glucocorticoid action in asthmatic PBMC and enhances the immunosuppressive function of DEX in vitro.
Clinical Implications
Our study suggests that vitD supplementation may potentiate anti-inflammatory function of corticosteroids in asthmatics and thereby improve asthma control.
doi:10.1016/j.jaci.2010.03.008
PMCID: PMC2866800  PMID: 20381849
vitamin D; children; asthma
6.  Vitamin D3 Decreases Parathyroid Hormone in HIV-Infected Youth Being Treated With Tenofovir: A Randomized, Placebo-Controlled Trial 
In this randomized, double-blind, placebo-controlled trial of human immunodeficiency virus–infected youths aged 18–25, vitamin D3, 50000 IU once monthly for 3 months decreased parathyroid hormone in participants treated with tenofovir-containing antiretroviral regimens but not in those participants whose regimens did not contain tenofovir.
Background. The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF).
Methods. This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18–25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo.
Results. At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, −7.9 and −6.2 pg/mL; P = .031 and .053, respectively).
Conclusions. In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration.
Clinical Trials Registration. NCT00490412.
doi:10.1093/cid/cir968
PMCID: PMC3297650  PMID: 22267714
7.  The Association of Concurrent Vitamin D and Sex Hormone Deficiency with Bone Loss and Fracture Risk in Older Men: The MrOS Study 
Low 25-hydroxyvitamin D (VitD), low sex hormones (SH), and high sex hormone binding globulin (SHBG) levels are common in older men. We tested the hypothesis that combinations of low VitD, low SH, and high SHBG would have a synergistic effect on bone mineral density (BMD), bone loss, and fracture risk in older men. Participants were a random subsample of 1468 men (mean age 74) from the Osteoporotic Fractures in Men Study (MrOS) plus 278 MrOS men with incident non-spine fractures studied in a case-cohort design. “Abnormal” was defined as lowest quartile for VitD (<20 ng/ml), bioavailable testosterone (BioT, <163 ng/dl), and bioavailable estradiol (BioE, <11 pg/ml); and highest quartile for SHBG (>59 nM).
Overall, 10% had isolated VitD deficiency; 40% had only low SH or high SHBG; 15% had both SH/SHBG and VitD abnormality, and 35% had no abnormality. Compared to men with all normal levels, those with both SH/SHBG and VitD abnormality tended to be older, more obese, and to report less physical activity. Isolated VitD deficiency, and low BioT with or without low VitD, was not significantly related to skeletal measures. The combination of VitD deficiency with low BioE and/or high SHBG was associated with significantly lower baseline BMD and higher annualized rates of hip bone loss than SH abnormalities alone or no abnormality. Compared to men with all normal levels, the multivariate-adjusted hazard ratio (95% CI) for incident non-spine fracture during 4.6 yr median follow-up was 1.2 (0.8–1.8) for low VitD alone; 1.3 (0.9–1.9) for low BioE and/or high SHBG alone; and 1.6 (1.1–2.5) for low BioE/high SHBG plus low VitD.
In summary, adverse skeletal effects of low sex steroid levels were most pronounced in older men with low VitD levels. The presence of low VitD in the presence of low BioE/high SHBG may contribute substantially to poor skeletal health.
doi:10.1002/jbmr.1697
PMCID: PMC3474871  PMID: 22777902
bone loss; fracture; older men; sex hormones; vitamin
8.  Vitamin D Status and Related Factors in Newborns in Shanghai, China 
Nutrients  2014;6(12):5600-5610.
With the increasing recognition of the importance of the non-skeletal effects of vitamin D (VitD), more and more attention has been drawn to VitD status in early life. However, the VitD status of newborns and factors that influence VitD levels in Shanghai, China, remain unclear. A total of 1030 pregnant women were selected from two hospitals in Shanghai, one of the largest cities in China located at 31 degrees north latitude. Umbilical cord serum concentrations of 25-hydroxy vitamin D [25(OH)D] were measured by LC-MS-MS, and questionnaires were used to collect information. The median cord serum 25(OH)D concentration was 22.4 ng/mL; the concentration lower than 20 ng/mL accounted for 36.3% of the participants, and the concentration lower than 30 ng/mL for 84.1%. A multivariable logistic regression model showed that the determinants of low 25(OH)D status were being born during autumn or winter months and a lack of VitD-related multivitamin supplementation. The relative risk was 1.7 for both autumn (95% CI, 1.1–2.6) and winter (95% CI, 1.1–2.5) births (p < 0.05). VitD-related multivitamin supplementation more than once a day during pregnancy reduced the risk of VitD deficiency [adjusted OR (aOR) = 0.6, 95% CI (0.45–1.0) for VitD supplementation] (p < 0.05). VitD deficiency and insufficiency are common in newborns in Shanghai, China, and are independently associated with season and VitD supplementation. Our findings may assist future efforts to correct low levels of 25(OH)D in Shanghai mothers and their newborn children.
doi:10.3390/nu6125600
PMCID: PMC4276986  PMID: 25486368
vitamin D; related factors; newborn
9.  Vitamin D supplementation during exercise training does not alter inflammatory biomarkers in overweight and obese subjects 
European journal of applied physiology  2011;112(8):3045-3052.
The purpose of this study was to examine the effects of vitamin D supplementation on inflammatory biomarkers in overweight and obese adults participating in a progressive resistance exercise training program. Twenty-three (26.1±4.7 y) overweight and obese (BMI: 31.3±3.2 kg·m−2) adults were randomized into a double-blind vitamin D supplementation (VitD, 4000 IU/d, female=5; male=5) or placebo (PL, female=7; male=6) intervention trial. Both groups performed 12 wk (three d/wk) of progressive resistance exercise training (three sets of eight exercises) at 70 – 80% of one repetition maximum. Whole blood lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) α production as well as circulating C-reactive protein (CRP), TNFα, interleukin 6 (IL-6), and alanine aminotransferase (ALT) were assessed at baseline and after the 12 wk intervention. No main effects of group or time were detected for circulating CRP, TNFα, IL-6 and ALT. As expected, when PL and VitD groups were combined, there was a significant correlation between percent body fat and CRP at baseline (r=0.45, P=0.04), and between serum 25OHD and CRP at 12 weeks (r=0.49, P=0.03). The PL group had a significant increase in 25 μg/ml LPS+polymixin B-stimulated TNFα production (P=0.04), and both groups had a significant reduction in unstimulated TNFα production (P<0.05) after the 12 week intervention. Vitamin D supplementation in healthy, overweight and obese adults participating in a resistance training intervention did not augment exercise-induced changes in inflammatory biomarkers.
doi:10.1007/s00421-011-2279-3
PMCID: PMC3417103  PMID: 22183086
25-hydroxyvitamin D; resistance training; inflammation; tumor necrosis factor α; C-reactive protein; cytokine
10.  Cardiovascular effects of cholecalciferol treatment in dialysis patients – a randomized controlled trial 
BMC Nephrology  2014;15:50.
Background
Patients on chronic dialysis are at increased risk of vitamin D deficiency. In observational studies plasma 25-hydroxyvitamin D (p-25(OH) D) levels are inversely correlated with plasma BNP and adverse cardiovascular outcomes. Whether a causal relation exists has yet to be established. The aim of this study was to test the hypothesis that cholecalciferol supplementation improves cardiac function and reduces blood pressure (BP) and pulse wave velocity (PWV) in patients on chronic dialysis.
Methods
In a randomized, placebo-controlled, double-blind study, we investigated the effect of 75 μg (3000 IU) cholecalciferol daily for 6 months, in patients on chronic dialysis. We performed two-dimensional echocardiography, with doppler and tissue-doppler imaging, 24-h ambulatory BP (24-h BP), PWV, augmentation index (AIx), central BP (cBP) and brain natriuretic peptide (BNP) measurements at baseline and after 6 months.
Results
Sixty-four patients were allocated to the study. Fifty dialysis patients with a mean age of 68 years (range: 46–88) and baseline p-25(OH) D of 28 (20;53) nmol/l completed the trial. Cholecalciferol increased left ventricular (LV) volume, but had no impact on other parameters regarding LV structure or left atrial structure. LV systolic function, LV diastolic function, PWV, cBP, AIx and BNP were not changed in placebo or cholecalciferol group at follow-up. 24-h BP decreased significantly in placebo group and tended to decrease in cholecalciferol group without any difference between treatments.
Conclusion
Six months of cholecalciferol treatment in patients on chronic dialysis did not improve 24-h BP, arterial stiffness or cardiac function.
Trial registration
NCT01312714, Registration Date: March 9, 2011.
doi:10.1186/1471-2369-15-50
PMCID: PMC3994388  PMID: 24661355
Cholecalciferol; Chronic kidney disease; Cardiac function; Brain natriuretic peptide; Blood pressure
11.  Association of vitamin D and vitamin D receptor gene polymorphisms with chronic inflammation, insulin resistance and metabolic syndrome components in type 2 diabetic Egyptian patients 
Meta Gene  2014;2:540-556.
Background
To date the published data concerning the possible interplay between vitamin D (VitD) and Vit D receptor (VDR) gene polymorphism with the immune/inflammatory mediators in type 2 diabetes mellitus (DM) is insufficient. Some of the immune non-classical actions of vitamin D may point to its role in the pathogenesis of type 2 DM through down-regulation of cytokines (IL-6). Although there is evidence to support a relationship among vitamin D status, chronic inflammation and insulin resistance, the underlying mechanism requires further exploration. We aimed to investigate the role of vitamin D in chronic inflammation and insulin resistance in type 2 DM. Moreover, to examine the association of VDR gene polymorphisms [VDR 2228570 C > T (FokI); VDR 1544410 A > G (BsmI)] with the components of metabolic syndrome (MetSyn) in type 2 diabetic Egyptian patients .
Subjects and methods
A total of 190 subjects were enrolled in this study, 60 controls and 130 type 2 diabetic patients (Group II). Group II was subdivided into 63 patients without MetSyn (subgroup IIa) and 67 patients with MetSyn (subgroup IIb). Genetic analysis for VDR gene polymorphisms was done in all subjects. VitD and IL-6 plasma levels were estimated.
Results
The TT genotype for the VDR FokI was significantly more frequent in subgroup IIb than in subgroup IIa and controls (X2 = 6.83, P = 0.03 and X2 = 16.592, P = 0.000) respectively. The T allele was more frequent in the MetSyn group as compared to diabetics without MetSyn (p = 0.001), odds ratio (OR) and 95% CI for the T allele of C > T (FokI) = 2.30 (1.37–3.86). We did not detect any significant difference in VDR BsmI genotypes between patients and control groups (P = 0.947). FokI VDR was significantly associated with the lipid profile parameters, VitD and IL-6 plasma levels in subgroup IIa and associated with HOMA-IR, insulin, VitD, IL-6 levels, waist circumference (WC) and body mass index (BMI) in subgroup IIb while BsmI VDR variant was associated only with VitD values in both subgroups.
Conclusion
The present study suggests an interaction between VDR polymorphisms and important components of MetSyn, VitD and pro-inflammatory cytokines (IL-6). FokI VDR polymorphisms may be linked to mild inflammation and insulin resistance and might represent a genetic determinant for developing MetSyn in type 2 diabetic Egyptian patients. The challenge is determining the mechanisms of VitD action for recommendation of VitD supplementation that reduces the risks of MetSyn, insulin resistance and progression to type 2 diabetes.
doi:10.1016/j.mgene.2014.07.002
PMCID: PMC4287888  PMID: 25606437
VitD, Vitamin D; DM, diabetes mellitus; VDR, Vit D receptor; MetSyn, metabolic syndrome; HOMA, Homeostasis of Metabolic Assessment; WC, waist circumference; OR, odds ratio; BMI, body mass index; IL-6, interleukin -6; SOCS, suppressors of cytokine signaling; IRS, insulin receptor substrates; CRP, C-reactive protein; FBG, fasting blood glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; FPI, fasting plasma insulin; TC, total cholesterol; TG, triglyceride; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; HPLC, High performance liquid chromatography; SD, standard deviation; X2, Chi-square; CI, confidence intervals; PGs, pro-inflammatory prostaglandins; NHANES III, National Health and Examination Survey; PTH, parathyroid hormone; Insulin resistance; Type 2 diabetes mellitus (DM); Metabolic syndrome; Vitamin D; Vitamin D Receptor gene; Polymorphisms; Pro-inflammatory cytokines; Interleukin-6 (IL-6)
12.  Vitamin D status of early preterm infants and the effects of vitamin D intake during hospital stay 
Objectives
To evaluate vitamin D (vitD) status in early preterm infants (EPTIs) at birth and during birth hospitalisation on current vitD intake.
Design/methods
Serum 25-hydroxyvitamin-D [25(OH)D] concentrations, vitD intake and risk factors for low vitD status were assessed in 120 infants born at ≤32 weeks gestation.
Results
Mean (SD) serum 25(OH)D at birth was 46.2 (14.0) nmol/L with lower concentrations in infants born <28 weeks than at 28–32 weeks gestation, p=0.02. Serum 25(OH)D was <50 nmol/L in 63% of mothers, 64% of infants at birth and 35% of infants at discharge. Mean daily vitD intake was 289±96 IU at 4 weeks of age and 60% achieved 400 IU/day intake at discharge.
Conclusions
Serum 25(OH)D <50 nmol/L was widespread in parturient women and in EPTIs at birth and at discharge. Optimising maternal vitD status during pregnancy and improving postnatal vitD intake may enhance infant vitD status during hospitalisation.
doi:10.1136/archdischild-2013-303999
PMCID: PMC3933171  PMID: 23852093
Neonatology; Nutrition
13.  Vitamin D2 Supplementation Amplifies Eccentric Exercise-Induced Muscle Damage in NASCAR Pit Crew Athletes 
Nutrients  2013;6(1):63-75.
This study determined if 6-weeks vitamin D2 supplementation (vitD2, 3800 IU/day) had an influence on muscle function, eccentric exercise-induced muscle damage (EIMD), and delayed onset of muscle soreness (DOMS) in National Association for Stock Car Auto Racing (NASCAR) NASCAR pit crew athletes. Subjects were randomized to vitD2 (n = 13) and placebo (n = 15), and ingested supplements (double-blind) for six weeks. Blood samples were collected and muscle function tests conducted pre- and post-study (leg-back and hand grip dynamometer strength tests, body weight bench press to exhaustion, vertical jump, 30-s Wingate test). Post-study, subjects engaged in 90 min eccentric-based exercise, with blood samples and DOMS ratings obtained immediately after and 1- and 2-days post-exercise. Six weeks vitD2 increased serum 25(OH)D2 456% and decreased 25(OH)D3 21% versus placebo (p < 0.001, p = 0.036, respectively), with no influence on muscle function test scores. The post-study eccentric exercise bout induced EIMD and DOMS, with higher muscle damage biomarkers measured in vitD2 compared to placebo (myoglobin 252%, 122% increase, respectively, p = 0.001; creatine phosphokinase 24 h post-exercise, 169%, 32%, p < 0.001), with no differences for DOMS. In summary, 6-weeks vitD2 (3800 IU/day) significantly increased 25(OH)D2 and decreased 25(OH)D3, had no effect on muscle function tests, and amplified muscle damage markers in NASCAR pit crew athletes following eccentric exercise.
doi:10.3390/nu6010063
PMCID: PMC3916849  PMID: 24362707
delayed onset of muscle soreness (DOMS); myoglobin; creatine phosphokinase; muscle function testing; eccentric exercise; LC-MS/MS
14.  Polymorphisms in GC and NADSYN1 Genes are associated with vitamin D status and metabolic profile in Non-diabetic adults 
Background
Our aim was to assess the associations between vitamin D (vitD) status, metabolic profile and polymorphisms in genes involved in the transport (Group-Component: GC) and the hydroxylation (NAD synthetase 1: NADSYN1) of 25 hydroxyvitamin D (25(OH)D) in non-diabetic individuals.
Methods
We conducted a cross-sectional study with 323 individuals recruited from the Health Center of Guadeloupe, France. The rs2282679 T > G and rs2298849 T > C in GC and rs12785878 G > T in NADSYN1 were genotyped.
Results
Mean age was 46(range 18–86) years. 57% of participants had vitD insufficiency, 8% had vitD deficiency, 61% were overweight and 58% had dyslipidemia. A higher frequency of overweight was noted in women carrying rs2298849T allele v CC carriers (71% v 50%; P = 0.035). The rs2282679G allele was associated with increased risks of vitD deficiency and vitD insufficiency (OR =3.53, P = 0.008, OR = 2.34, P = 0.02 respectively). The rs2298849 TT genotype was associated with vitD deficiency and overweight (OR =3.4, P = 0.004 and OR = 1.76, P = 0.04 respectively) and the rs12785878 GG genotype with vitD insufficiency and dyslipidemia (OR = 1.80, P = 0.01 and OR = 1.72, P = 0.03 respectively). Based on the number of risk alleles for rs2282679 and rs12785878 combined, a genotype score of 3 (vs. 0–1) was associated with a 5.5 ng/mL average reduction in serum 25(OH)D levels (P = 0.001).
Conclusions
The GC and NADSYN1 genes are associated with the vitamin D status and might contribute to dyslipidemia and overweight independently of 25(OH)D levels.
doi:10.1186/1472-6823-13-36
PMCID: PMC3849583  PMID: 24073860
Dyslipidemia; Overweight; Vitamin D; NAD synthetase 1; NADSYN; Group specific component; GC
15.  Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youth treated with tenofovir disoproxil fumarate 
Antiviral therapy  2014;19(6):613-618.
Background
Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biologic activity, and is elevated in persons with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youth treated with combination antiretroviral therapy (cART) containing or not containing TDF.
Methods
A randomized controlled trial in HIV+ youth ages 18–25 years enrolled participants based on cART treatment with TDF (TDF, N=118) or without TDF (no-TDF, N=85) and randomized within those groups to VITD (50,000 IU every four weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group.
Results
At baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was +7.7 pg/mL in the TDF/VITD group, compared to −1.7 (no-TDF/VITD, p=0.010); −1.3 (TDF/PL, p=0.006); and +1.1 (no-TDF/PL, p=0.035).
Conclusions
These results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youth.
doi:10.3851/IMP2755
PMCID: PMC4135028  PMID: 24535626
16.  Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats 
Neurobiology of aging  2009;32(5):864-874.
Administration of the neurosteroid progesterone (PROG) has been shown to be beneficial in a number of brain injury models and in two recent clinical trials. Given widespread vitamin D deficiency and increasing traumatic brain injuries (TBIs) in the elderly, we investigated the interaction of vitamin D deficiency and PROG with cortical contusion injury in aged rats. Vitamin D deficient (VitD-deficient) animals showed elevated inflammatory proteins (TNFα, IL-1β, IL-6, NFκB p65) in the brain even without injury. VitD-deficient rats with TBI, whether given PROG or vehicle, showed increased inflammation and greater open-field behavioral deficits compared to VitD-normal animals. Although PROG was beneficial in injured VitD-normal animals, in VitD-deficient subjects neurosteroid treatment conferred no improvement over vehicle. A supplemental dose of 1,25-dihydroxyvitamin D3 (VDH) given with the first PROG treatment dramatically improved results in VitD-deficient rats, but treatment with VDH alone did not. Our results suggest that VitD-deficiency can increase baseline brain inflammation, exacerbate the effects of TBI, and attenuate the benefits of PROG treatment; these effects may be reversed if the deficiency is corrected.
doi:10.1016/j.neurobiolaging.2009.04.017
PMCID: PMC3586224  PMID: 19482377
Aging; Inflammation; Progesterone; 1,25-Dihydroxyvitamin D3; Traumatic brain injury; Vitamin D deficiency
17.  Effect of Folic Acid and Betaine Supplementation on Flow-Mediated Dilation: A Randomized, Controlled Study in Healthy Volunteers 
PLoS Clinical Trials  2006;1(2):e10.
Objectives:
We investigated whether lowering of fasting homocysteine concentrations, either with folic acid or with betaine supplementation, differentially affects vascular function, a surrogate marker for risk of cardiovascular disease, in healthy volunteers. As yet, it remains uncertain whether a high concentration of homocysteine itself or whether a low folate status—its main determinant—is involved in the pathogenesis of cardiovascular disease. To shed light on this issue, we performed this study.
Design:
This was a randomized, placebo-controlled, double-blind, crossover study.
Setting:
The study was performed at Wageningen University in Wageningen, the Netherlands.
Participants:
Participants were 39 apparently healthy men and women, aged 50–70 y.
Interventions:
Participants ingested 0.8 mg/d of folic acid, 6 g/d of betaine, and placebo for 6 wk each, with 6-wk washout in between.
Outcome Measures:
At the end of each supplementation period, plasma homocysteine concentrations and flow-mediated dilation (FMD) of the brachial artery were measured in duplicate.
Results:
Folic acid supplementation lowered fasting homocysteine by 20% (−2.0 μmol/l, 95% confidence interval [CI]: −2.3; −1.6), and betaine supplementation lowered fasting plasma homocysteine by 12% (−1.2 μmol/l; −1.6; −0.8) relative to placebo. Mean (± SD) FMD after placebo supplementation was 2.8 (± 1.8) FMD%. Supplementation with betaine or folic acid did not affect FMD relative to placebo; differences relative to placebo were −0.4 FMD% (95%CI, −1.2; 0.4) and −0.1 FMD% (−0.9; 0.7), respectively.
Conclusions:
Folic acid and betaine supplementation both did not improve vascular function in healthy volunteers, despite evident homocysteine lowering. This is in agreement with other studies in healthy participants, the majority of which also fail to find improved vascular function upon folic acid treatment. However, homocysteine or folate might of course affect cardiovascular disease risk through other mechanisms.
Editorial Commentary
Background: Evidence from observational studies indicates a link between high concentrations of homocysteine (an amino acid) in the blood and increased risk of cardiovascular disease. However, the basis for the link between homocysteine concentrations and cardiovascular disease risk is not clear. Supplementing the diet with B-vitamins lowers homocysteine levels, and large-scale trials are underway that will determine whether B-vitamin supplementation has an effect on cardiovascular outcomes, such as heart attacks and strokes. These trials also involve administration of folic acid as well as other B-vitamins. It is not obvious, however, whether the effects of B-vitamin supplementation arise as a result of homocysteine lowering or via some other biochemical pathway.
What this trial shows: Olthof and colleagues aimed to further understand the effects of homocysteine lowering by randomizing 40 healthy volunteer participants to receive either folic acid supplementation; placebo; or betaine, a nutrient that lowers homocysteine levels via a different biochemical pathway than folic acid. Each participant in the trial received each supplement for 6 wk, with a 6-wk washout period before the next supplement was given. The researchers then used a technique called flow-mediated dilation (FMD) to measure functioning of the main artery of the upper arm, as a surrogate for cardiovascular disease risk. In this trial, both folic acid and betaine supplementation significantly lowered homocysteine levels over the 6-wk supplementation period. However, both forms of supplementation failed to result in any significant change in functioning of the artery, as measured using FMD.
Strengths and limitations: In this trial 40 participants were recruited, and 39 were followed up to trial completion. A crossover design was used, with each participant receiving each supplement and a placebo in sequence. This method enabled a smaller number of participants to be used to answer the question of interest, as compared to parallel-group designs. The majority of participants in the trial were followed up. However, the trial's outcomes are surrogates for cardiovascular disease risk, measured over fairly short time periods, and no clinical outcomes were examined.
Contribution to the evidence: This trial adds to the evidence on the effects of nutrient supplementation on surrogate outcomes for cardiovascular disease risk. The results show that over a 6-wk study period, these surrogate outcomes are not affected by either folic acid or betaine supplementation.
doi:10.1371/journal.pctr.0010010
PMCID: PMC1488898  PMID: 16871332
18.  Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study 
Critical Care  2011;15(2):R104.
Introduction
Vitamin D deficiency is encountered frequently in critically ill patients and might be harmful. Current nutrition guidelines recommend very low vitamin D doses. The objective of this trial was to evaluate the safety and efficacy of a single oral high-dose vitamin D3 supplementation in an intensive care setting over a one-week observation period.
Methods
This was a randomized, double-blind, placebo-controlled pilot study in a medical ICU at a tertiary care university center in Graz, Austria. Twenty-five patients (mean age 62 ± 16yrs) with vitamin D deficiency [25-hydroxyvitamin D (25(OH)D) ≤20 ng/ml] and an expected stay in the ICU >48 hours were included and randomly received either 540,000 IU (corresponding to 13.5 mg) of cholecalciferol (VITD) dissolved in 45 ml herbal oil or matched placebo (PBO) orally or via feeding tube.
Results
The mean serum 25(OH)D increase in the intervention group was 25 ng/ml (range 1-47 ng/ml). The highest 25(OH)D level reached was 64 ng/ml, while two patients showed a small (7 ng/ml) or no response (1 ng/ml). Hypercalcemia or hypercalciuria did not occur in any patient. From day 0 to day 7, total serum calcium levels increased by 0.10 (PBO) and 0.15 mmol/L (VITD; P < 0.05 for both), while ionized calcium levels increased by 0.11 (PBO) and 0.05 mmol/L (VITD; P < 0.05 for both). Parathyroid hormone levels decreased by 19 and 28 pg/ml (PBO and VITD, ns) over the seven days, while 1,25(OH)D showed a transient significant increase in the VITD group only.
Conclusions
This pilot study shows that a single oral ultra-high dose of cholecalciferol corrects vitamin D deficiency within 2 days in most patients without causing adverse effects like hypercalcemia or hypercalciuria. Further research is needed to confirm our results and establish whether vitamin D supplementation can affect the clinical outcome of vitamin D deficient critically ill patients.
EudraCT Number
2009-012080-34
German Clinical Trials Register (DRKS)
DRKS00000750
doi:10.1186/cc10120
PMCID: PMC3219377  PMID: 21443793
19.  Ribavirin induced anaemia: the effect of vitamin D supplementation on erythropoietin and erythrocyte indices in normal Wistar rat 
Objectives: To measure the effect of vitamin D3 (VitD) supplementation on erythrocyte indices, serum and kidney erythropoietin (EPO) in normal rats treated with Pegylated interferon-α (Peg-INF-α) and ribavirin (RBV). Materials and methods: Eighty male Wistar rats were divided equally into 8 groups. ‘Control’; ‘P’: only received Peg-INF-α; ‘PD’: Peg-INF-α/VitD; ‘PR’: Peg-INF-α/RBV; ‘PRD’: Peg-INF-α/RBV/VitD; ‘R’: only received RBV; ‘RD’: RBV/VitD and ‘VitD’: only received vitamin D3. Peg-INF-α-2a was injected subcutaneously (6 µg/rat/week) for 4 weeks. RBV (4 mg/rat/day) and VitD (500 IU/rat/day) were given orally for 5 weeks. Blood samples were collected to measure erythrocyte indices and serum 25(OH) vitamin D. EPO was measured in serum samples and kidney specimens by ELISA. Results: Peg-INF-α alone did not affect the RBCs count, haemoglobin, serum and kidney EPO compared to control (P > 0.05). RBV significantly decreased (P < 0.05) the erythrocyte count, haemoglobin and EPO levels in kidney and serum, either individually (R group) or combined with Peg-INF-α (PR group), compared to ‘Control’ and ‘P’ groups. VitD prevented the development of anaemia and significantly increased the concentrations of EPO at serum and kidney levels in the ‘RD’ and ‘PRD’ groups compared to ‘R’ and ‘PR’ groups. There was a significant positive correlation between blood levels of VitD with serum and kidney EPO, Red cell count and haemoglobin concentrations. Conclusion: VitD could have a potential beneficial role in the prevention of ribavirin-induced anaemia by promoting endogenous EPO. Further studies are needed to explore the role of vitamin D in the prevention of ribavirin associated anaemia.
PMCID: PMC4211774  PMID: 25356124
Anaemia; erythropoietin hormone; pegylated interferon-α; ribavirin and vitamin D
20.  A randomized control trial to assess the impact of vitamin D supplementation compared to placebo on vascular stiffness in chronic kidney disease patients 
Background
Vitamin D deficiency is associated with cardiovascular (CV) risk in multiple populations, including those with chronic kidney disease (CKD). The active form of the hormone (1,25 OH2D3) binds to receptors in multiple organs. CKD patients are deficient in both 25 Vitamin D and 1,25 OH2D3. Clinical trial data demonstrating the benefits of vitamin D formulations are limited, and fail to show significant benefits on CV outcomes, and have compared different compounds, in various populations, and focused on a variety of outcomes. A understanding of the mechanism by which different vitamin D compounds confer CV protection in CKD is important for the design of future studies.
Methods/Design
This 3 arm randomized prospective double-blinded placebo-controlled study examining the impact of calcitriol (1,25 OH2D3) and 25-hydroxyvitamin D3 supplementation compared to placebo on vascular stiffness, as measured by pulse wave velocity (PWV). Patients are enrolled from 2 tertiary care institutions if they meet inclusion criteria (stable estimated glomerular filtration rate (eGFR) between 15-45ml/min, <±5ml/min change in previous 6 months), on stable doses of renin-angiotensin aldosterone system blockade. For those already receiving vitamin D therapies, a 3 month washout period before randomization is mandatory. Treatment duration is 6 months; medications are given thrice weekly in fixed doses. The primary outcome measure is Vascular stiffness, measured non-invasively by pulse wave velocity (PWV). Other measurements include BP, kidney function and serial blood levels of biomarkers. The primary analysis will compare any vitamin D therapy versus placebo for the primary outcome defined as the change of PWV from baseline to 6 months. Analysis of covariance will be used to detect differences between vitamin D preparations in the magnitude of reduction in PWV.
Discussion
This study is novel in that we are using a robust study design in CKD patients (not on dialysis) comparing placebo to different forms of vitamin D supplementation in fixed doses, irrespective of baseline values. We hope to demonstrate the biological mechanistic effect of vitamin D supplementation on vascular function in order for this information to be used in designing larger randomized controlled trials.
Trial registration
Current Controlled Trials NCT01247311. Date of Registration: November 12, 2010.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2261-14-156) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2261-14-156
PMCID: PMC4230794  PMID: 25381032
Chronic kidney disease; Vitamin D; Vascular stiffness; PWV; Randomized protocol study
21.  Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial 
PLoS Medicine  2008;5(10):1-12.
Background
Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.
Methods and Findings
This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.
Conclusions
Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.
Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)
Angela Cheung and colleagues investigate whether vitamin K1 can prevent bone loss among postmenopausal women with osteopenia.
Editors' Summary
Background.
Osteoporosis is a bone disease in which the bones gradually become less dense and more likely to break. In the US, 10 million people have osteoporosis and 18 million have osteopenia, a milder condition that precedes osteoporosis. In both conditions, insufficient new bone is made and/or too much old bone is absorbed. Although bone appears solid and unchanging, very little bone in the human body is more than 10 y old. Old bone is continually absorbed and new bone built using calcium, phosphorous, and proteins. Because the sex hormones control calcium and phosphorous deposition in the bones and thus bone strength, the leading cause of osteoporosis in women is reduced estrogen levels after menopause. In men, an age-related decline in testosterone levels can cause osteoporosis. Most people discover they have osteoporosis only when they break a bone, but the condition can be diagnosed and monitored using bone mineral density (BMD) scans. Treatments can slow down or reverse bone loss (antiresorptive therapies) and some (bone formation therapies) can even make bone and build bone tissue.
Why Was This Study Done?
Although regular exercise and a healthy diet can help to keep bones strong, other ways of preventing osteoporosis are badly needed. Recently, the lay media has promoted vitamin K supplements as a way to reduce bone loss in postmenopausal women. Vitamin K (which is found mainly in leafy green vegetables) is required for a chemical modification of proteins called carboxylation. This modification is essential for the activity of three bone-building proteins. In addition, there is some evidence that low bone density and fractures are associated with a low vitamin K intake. However, little is known about the long-term benefits or harms of vitamin K supplements. In this study, the researchers investigate whether a high-dose daily vitamin K supplement can safely reduce bone loss, bone turnover, and fractures in postmenopausal women with osteopenia in a randomized controlled trial called the “Evaluation of the Clinical Use of Vitamin K Supplementation in Post-Menopausal Women With Osteopenia” (ECKO) trial.
What Did the Researchers Do and Find?
In the study, 440 postmenopausal women with osteopenia were randomized to receive 5mg of vitamin K1 (the type of vitamin K in North American food; the recommended daily adult intake of vitamin K1 is about 0.1 mg) or an inactive tablet (placebo) daily for 2 y; 261 of the women continued their treatment for 2 y to gather information about the long-term effects of vitamin K1 supplementation. All the women had regular bone density scans of their lower back and hips and were examined for fractures and for changes in bone turnover. After 2 y and after 4 y, lower back and hip bone density measurements had decreased by similar amounts in both treatment groups. The women who took vitamin K1 had 10-fold higher amounts of vitamin K1 in their blood than the women who took placebo and lower amounts of a bone formation marker; the levels of a bone resorption marker were similar in both groups. Over the 4-y period, fewer women in the vitamin K group had fractures (nine versus 20 women in the placebo group), and fewer had cancer (three versus 12). Finally, vitamin K supplementation was well tolerated over the 4-y period and adverse health effects were similar in the two treatment groups.
What Do These Findings Mean?
These findings indicate that a high daily dose of vitamin K1 provides no protection against the age-related decline in bone density in postmenopausal women with osteopenia, but that vitamin K1 supplementation may protect against fractures and cancers in these women. The apparent contradiction between the effects of vitamin K1 on bone density and on fractures could mean that vitamin K1 supplements strengthen bone by changing factors other than bone density, e.g., by changing its fine structure rather than making it denser. However, because so few study participants had fractures, the difference in the fracture rate between the two treatment groups might have occurred by chance. Larger studies are therefore needed to examine the effect of vitamin K1 on fractures (and on cancer) and, until these are done, high-dose vitamin K1 supplementation should not be recommended for the prevention of osteoporosis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050196.
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides detailed information about osteoporosis (in English and Spanish) and links to other resources, including an interactive web tool called Check Up On Your Bones
MedlinePlus provides links to additional information about osteoporosis (in English and Spanish)
The MedlinePlus Encyclopedia has a page about vitamin K
The UK Food Standards Agency provides information about vitamin K
Full details about the ECKO trial are available on the ClinicalTrials.gov Web site
The Canadian Task Force for Preventive Health Care provides recommendations on the prevention of osteoporosis and osteoporotic fractures in postmenopausal women
Osteoporosis Canada provides information on current topics related to osteoporosis
doi:10.1371/journal.pmed.0050196
PMCID: PMC2566998  PMID: 18922041
22.  Pretreatment vitamin D level and response to neoadjuvant chemotherapy in women with breast cancer on the I-SPY trial (CALGB 150007/150015/ACRIN6657) 
Cancer Medicine  2014;3(3):693-701.
Laboratory studies suggest that vitamin D (vitD) enhances chemotherapy-induced cell death. The objective of this study was to determine whether pretreatment vitD levels were associated with response to neoadjuvant chemotherapy (NACT) in women with breast cancer. Study patients (n = 82) were enrolled on the I-SPY TRIAL, had HER2-negative tumors, and available pretreatment serum. VitD levels were measured via DiaSorin radioimmunoassay. The primary outcome was pathologic residual cancer burden (RCB; dichotomized 0/1 vs. 2/3). Secondary outcomes included biomarkers of proliferation, differentiation, and apoptosis (Ki67, grade, Bcl2, respectively) and 3-year relapse-free survival (RFS). Mean and median vitD values were 22.7 ng/mL (SD 11.9) and 23.1 ng/mL, respectively; 72% of patients had levels deemed “insufficient” (<30 ng/mL) by the Institute of Medicine (IOM). VitD level was not associated with attaining RCB 0/1 after NACT (univariate odds ratio [OR], 1.01; 95% CI, 0.96–1.05) even after adjustment for hormone receptor status (HR), grade, Ki67, or body mass index (BMI). Lower vitD levels were associated with higher tumor Ki67 adjusting for race (OR, 0.95; 95% CI, 0.90–0.99). VitD level was not associated with 3-year RFS, either alone (hazard ratio [HzR], 0.98; 95% CI, 0.95–1.02) or after adjustment for HR, grade, Ki-67, BMI, or response. VitD insufficiency was common at the time of breast cancer diagnosis among women who were candidates for NACT and was associated with a more proliferative phenotype. However, vitD levels had no impact on tumor response to NACT or short-term prognosis.
doi:10.1002/cam4.235
PMCID: PMC4101761  PMID: 24719175
Breast cancer; neoadjuvant chemotherapy; response; vitamin D
23.  Impact of Vitamin D Supplementation on Arterial Vasomotion, Stiffness and Endothelial Biomarkers in Chronic Kidney Disease Patients 
PLoS ONE  2014;9(3):e91363.
Background
Cardiovascular events are frequent and vascular endothelial function is abnormal in patients with chronic kidney disease (CKD). We demonstrated endothelial dysfunction with vitamin D deficiency in CKD patients; however the impact of cholecalciferol supplementation on vascular stiffness and vasomotor function, endothelial and bone biomarkers in CKD patients with low 25-hydroxy vitamin D [25(OH)D] is unknown, which this study investigated.
Methods
We assessed non-diabetic patients with CKD stage 3/4, age 17–80 years and serum 25(OH)D <75 nmol/L. Brachial artery Flow Mediated Dilation (FMD), Pulse Wave Velocity (PWV), Augmentation Index (AI) and circulating blood biomarkers were evaluated at baseline and at 16 weeks. Oral 300,000 units cholecalciferol was administered at baseline and 8-weeks.
Results
Clinical characteristics of 26 patients were: age 50±14 (mean±1SD) years, eGFR 41±11 ml/min/1.73 m2, males 73%, dyslipidaemia 36%, smokers 23% and hypertensives 87%.
At 16-week serum 25(OH)D and calcium increased (43±16 to 84±29 nmol/L, p<0.001 and 2.37±0.09 to 2.42±0.09 mmol/L; p = 0.004, respectively) and parathyroid hormone decreased (10.8±8.6 to 7.4±4.4; p = 0.001). FMD improved from 3.1±3.3% to 6.1±3.7%, p = 0.001.
Endothelial biomarker concentrations decreased: E-Selectin from 5666±2123 to 5256±2058 pg/mL; p = 0.032, ICAM-1, 3.45±0.01 to 3.10±1.04 ng/mL; p = 0.038 and VCAM-1, 54±33 to 42±33 ng/mL; p = 0.006. eGFR, BP, PWV, AI, hsCRP, von Willebrand factor and Fibroblast Growth Factor-23, remained unchanged.
Conclusion
This study demonstrates for the first time improvement of endothelial vasomotor and secretory functions with vitamin D in CKD patients without significant adverse effects on arterial stiffness, serum calcium or FGF-23.
Trial Registration
ClinicalTrials.gov NCT02005718
doi:10.1371/journal.pone.0091363
PMCID: PMC3960127  PMID: 24646518
24.  Vitamin D supplementation and endothelial function in vitamin D deficient HIV-infected patients: a randomized placebo-controlled trial 
Antiviral therapy  2011;17(4):613-621.
Background
Studies suggest that vitamin D deficiency is a risk factor for cardiovascular disease and diabetes. Vitamin D deficiency is prevalent in HIV patients but the effect of vitamin D supplementation on cardiovascular risk in this population is unknown.
Methods
We conducted a randomized, double-blind, placebo-controlled trial among 45 HIV-infected adults in Cleveland (OH, USA) on stable antiretroviral therapy with durable virological suppression and a baseline serum 25-hydroxyvitamin D level of ≤20 ng/ml. Participants were randomized 2:1 to vitamin D3 4,000 IU daily or placebo for 12 weeks. The primary outcome was a change in flow-mediated brachial artery dilation (FMD).
Results
Baseline demographics were similar except for age (vitamin D versus placebo, mean ±SD 47 ±8 versus 40 ±10 years; P=0.009). Both groups had reduced FMD at baseline (median values 2.9% [IQR 1.6–4.8] for vitamin D versus 2.5% [IQR 1.7–6.4] for placebo; P=0.819). Despite an increase in the concentration of serum 25-hydroxyvitamin D from baseline to 12 weeks (5.0 ng/ml [IQR −0.9–7.4] versus −1.9 ng/ml [IQR −4.0–0.1] for vitamin D versus placebo, respectively; P=0.003), there was no difference in FMD change (0.55% [IQR −1.05–2.13] versus 0.29% [IQR −1.61–1.77]; P=0.748). Vitamin D supplementation was associated with a decrease in total and non-high-density lipoprotein cholesterol, and an increase in indices of insulin resistance.
Conclusions
Among HIV-infected individuals with vitamin D deficiency, supplementation with 4,000 IU vitamin D3 daily for 12 weeks modestly improved vitamin D status and cholesterol but worsened insulin resistance without change in endothelial function. The mechanisms of resistance to standard doses of vitamin D and the complex role of vitamin D in glucose metabolism in this population require further investigation.
doi:10.3851/IMP1983
PMCID: PMC3898848  PMID: 22293363
25.  The Peroxisome Proliferator Activated Receptor‐γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis 
Background
Rheumatoid arthritis (RA) is associated with heightened mortality due to atherosclerotic cardiovascular disease (CVD). Inflammatory pathways in RA negatively affect vascular physiology and promote metabolic disturbances that contribute to CVD. We hypothesized that the peroxisome proliferator activated receptor‐γ (PPAR‐γ) pioglitazone could promote potent vasculoprotective and anti‐inflammatory effects in RA.
Methods and Results
One hundred forty‐three non‐diabetic adult RA patients (76.2% female, age 55.2±12.1 [mean±SD]) on stable RA standard of care treatment were enrolled in a randomized, double‐blind placebo controlled crossover trial of 45 mg daily pioglitazone versus placebo, with a 3‐month duration/arm and a 2‐month washout period. Pulse wave velocity of the aorta (PWV), brachial artery flow mediated dilatation (FMD), nitroglycerin mediated dilatation (NMD), microvascular endothelial function (reactive hyperemia index [RHI]), and circulating biomarkers of inflammation, insulin resistance, and atherosclerosis risk all were quantified. RA disease activity was assessed with the 28‐Joint Count Disease Activity Score (DAS‐28) C‐reactive protein (CRP) and the Short Form (36) Health Survey quality of life questionnaire. When added to standard of care RA treatment, pioglitazone significantly decreased pulse wave velocity (ie, aortic stiffness) (P=0.01), while FMD and RHI remained unchanged when compared to treatment with placebo. Further, pioglitazone significantly reduced RA disease activity (P=0.02) and CRP levels (P=0.001), while improving lipid profiles. The drug was well tolerated.
Conclusions
Addition of pioglitazone to RA standard of care significantly improves aortic elasticity and decreases inflammation and disease activity with minimal safety issues. The clinical implications of these findings remain to be established.
Clinical Trial Registration
URL: ClinicalTrials.gov Unique Identifier: NCT00554853.
doi:10.1161/JAHA.113.000441
PMCID: PMC3886758  PMID: 24252844
drugs; inflammation; rheumatoid arthritis; vasodilation

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