High-dose Vitamin D3 Research Articles

A phase II RCT of high-dose vitamin D supplementation and exercise for cancer treatment-induced bone loss in breast cancer patients on aromatase inhibitors.

11500 Background: Cancer-treatment-induced bone loss (CTIBL) is a side effect of aromatase inhibitors (AIs) and can result in osteoporotic fractures. Vitamin D (VITD) protects against postmenopausal bone loss but it is unclear if the recommended daily allowance (RDA: 600 IU/day) of VITD is sufficient to prevent CTIBL. This phase II RCT aimed to assess the feasibility, safety, and preliminary efficacy of high-dose VITD (with and without exercise) on bone mineral density (BMD) compared to the RDA. Methods: Non-metastatic breast cancer patients starting AIs with low VITD (<32 ng/ml) were randomized 1:1:1 into 3 arms: 1) placebo 2) high-dose VITD (50,000 IU/week) or 3) high-dose VITD + Exercise for Cancer Patients (EXCAP): a home-based, personalized walking and resistance band training program for 24 weeks. All subjects received the RDA of VITD 600 IU/day. Serum VITD and calcium levels were assessed at baseline, weeks 6, 12, 18, and 24. BMD was assessed at the hip via DXA at baseline and week 24. Results: Of the 116 subjects randomized (mean age = 60; 94% white; mean baseline VITD = 24.6 ng/mL), 90 provided fully evaluable data. Compliance (≥ 80% of instructed doses) exceeded 95% in all 3 arms with no between-group difference. ANCOVA showed significant differences between groups on final VITD levels (high-dose = 63.6 vs high-dose + EXCAP = 60.3 vs placebo = 32.0 ng/mL; p<0.001) without severe calcium toxicities, as indicated by final calcium level (high-dose = 9.4 vs high-dose + EXCAP = 9.5 vs placebo = 9.4 ng/mL; p = 0.78). The placebo group lost a significant amount of hip BMD (−1.7%; p < 0.01) while hip BMD was maintained in the high-dose (−0.1%; p = 0.77) and high-dose + EXCAP (−0.2%; p = 0.74) resulting in significant between-group differences for high-dose + EXCAP vs placebo (p = 0.04) and high-dose vs placebo (p = 0.05). Conclusions: This is one of the first studies to show our novel high-dose VITD intervention, with and without exercise, significantly reduced hip BMD loss in breast cancer patients on AIs. Moreover, high-dose VITD supplementation is safe and feasible in this population. A phase III RCT is needed to confirm these findings. Funding: K07CA168911. Clinical trial information: NCT01419730.

MON-178 Vitamin D Treatment of Patients with Type 1 Diabetes Reduces RORy, FoxP3 and CD4 Gene Expression in T Helper Cells

Background: Vitamin D (VD) deficiency and the dysregulation of T helper (Th) cells contribute to the pathogenesis of type 1 diabetes (T1D). Based on the modulatory effects of VD on immune cells, we investigated the gene expression of transcription factors (TFs) regulating the Th cell differentiation before and after VD treatment in a pilot trial. Materials and methods: Nineteen patients with T1D (11 females and 8 males) were randomized and treated for three months with 4000 IU/day cholecalciferol. The gene expression of four Th cell specific TFs (Th1/T-bet, Th2/GATA3, Th1/RORy and Treg/FoxP3) as well as the Th cell surface molecule CD4 was measured before (V1) and after three months (V3) of VD treatment. Th cells were isolated by density gradient centrifugation from venous blood samples and subsequently enriched by magnetic sorting with antibodies. Total RNA from the selected cells was extracted, transcribed and analyzed by RT-qPCR. Transcription levels were calculated using the comparative cycle threshold (CT) method (values presented as 2-[CTtarget -CT18S]= 2-[∆CT]). VD-therapy effects on the gene expression were evaluated by the differences between V1 and V3 using the Wilcoxon matched-pairs test. The median differences are given with Hodges-Lehmann estimator (HLS) and 95% confidence interval (CI). Results: The 25(OH)D3 levels increased to 39.1 ng/ml (HLS: 17.22 ng/ml; 95% CI 9.3 to 23.9, p=8 x10-4) after three months cholecalciferol treatment. In response to this the gene expression of the two TFs FoxP3 (HLS: -12.68; 95% CI -21.47 to -3.36, p=0.01) and RORy (HLS: -1.85; 95% CI -4.68 to 0.02,ptrend=0.07) were downregulated. Additionally, a reduced gene expression of CD4 (HLS: -128; 95% CI -452.36 to -15.46, p=0.009) was detected. Notably, all these gene expression changes occurred in women (FoxP3 HLS: -17.30, p=0.02; RORy HLS: -3.96, p=0.01 and CD4 HLS: -146, p=0.007) but not in men. Furthermore, the downregulation of FoxP3 gene expression after VD supplementation was found in patients who had a 25(OH)D3 level below 20 ng/ml (n=9) at study entry (HLS: -17.36;p=0.03). Changes in the gene expressions of T-bet and GATA3 were not significant. Conclusion: Elevated 25(OH)D3 levels after high dose VD therapy result in downregulated genes (FoxP3, RORy and CD4) which are involved in the differentiation of effector Th cells (Treg and Th17). These VD effects occur predominantly in female patients, highlighting a gender specificity of the Th cell response. The downregulation of FoxP3 gene in VD deficiency patients may reflect other Th cell phenotypes. Our results support a targeted approach for anti-inflammatory VD treatment based on the measurement of peripheral 25(OH)D3 levels and Th cell related TFs. To corroborate our observations, further mechanistic studies and larger groups of patients are necessary.

25(OH)D3 and 1.25(OH)2D3 inhibits TNF-α expression in human monocyte derived macrophages.

PurposeWe wanted to investigate effects of vitamin D3 (25(OH)D3 and 1.25(OH)2D3) on inflammatory cytokine expression in both activated and non-activated Mφ.Materials and methodsMononuclear cells, isolated from healthy donor buffy coats were cultured for a 6-day differentiation-period. Fully differentiated Mφ were pre-treated with either 25(OH)D3 or 1.25(OH)2D3 for (4, 12 or 24 hours) +/-LPS challenge for 4 hours. Gene expression analyses of VDR, Cyp27b1 and pro-inflammatory markers TNF-α, IL-6, NF-κB, MCP-1, was performed using RT-quantitative PCR. TNF-α protein levels from Mφ culture media were analysed by ELISA.ResultsBoth 25(OH)D3 and 1.25(OH)2D3 significantly inhibited TNF-α expression in both LPS-stimulated and unstimulated Mφ. Also, NF-κB, and to a lesser extend IL-6 and MCP-1 were inhibited. LPS up-regulated Cyp27b1 gene expression which was partly reverted by 1.25(OH)2D3.ConclusionThese data show anti-inflammatory effects of vitamin D3 (25(OH)D3 and 1.25(OH)2D3) in human macrophages, and support, that means for targeting high dose vitamin D3 to the immune system may have beneficial clinical effect in inflammatory conditions.

Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer

In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC. Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018). mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level. Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% [95% CI, -20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL [95% CI, -6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]). Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial. ClinicalTrials.gov Identifier: NCT01516216.

A randomized double-blinded placebo controlled trial of ergocalciferol 40,000 versus 100,000IU per week for vitamin D inadequacy in institutionalized postmenopausal women.

Vitamin D inadequacy is common in institutionalized post-menopausal women who are at the highest risk for osteoporotic fracture. To evaluate efficacy and safety of ergocalciferol 40,000 versus 100,000IU per week for 12weeks for vitamin D inadequacy in institutionalized postmenopausal women. A randomized double-blinded placebo-controlled trial was conducted in 94 institutionalized subjects with baseline 25(OH)D levels < 30ng/mL. Subjects were randomized to receive ergocalciferol 40,000 (standard dose) or ergocalciferol 100,000IU (high dose) per week. Serum 25(OH)D levels, calcium, phosphate, handgrip strength, time up and go (TUG) test and quality of life by EQ-5D-5L were measured at baseline and 12weeks after randomization. Of the 94 subjects enrolled, 85 subjects completed the study. Subjects in the high dose group had higher mean 25(OH)D levels than subjects in the standard group (51.73 ± 19.35 and 34.5 ± 9.12, p < 0.001). More subjects in the high dose group (90.9%) achieved optimal 25(OH)D levels (> 30ng/mL) than those in the standard group (65.9%), p = 0.007. In a subgroup analysis of subjects with vitamin D deficiency (< 20ng/mL, n = 44) and severe vitamin D deficiency (< 10ng/mL, n = 9), more subjects in the high dose group achieved optimal 25(OH)D levels than those in the standard group (88% and 100% versus 47.4% and 16.7% with p of 0.007 and 0.018, respectively). There were no differences in handgrip strength, TUG, EQ-5D-5L and adverse events between groups. Subjects who received high dose ergocalciferol achieved more optimal 25(OH)D levels than those who received standard dose. High dose ergocalciferol is preferred to optimize 25(OH)D levels in subjects with severe vitamin D deficiency.

Impact of two oral doses of 100,000\u2009IU of vitamin D3 in preschoolers with viral-induced asthma: a pilot randomised controlled trial

BackgroundNew evidence supports the use of supplemental vitamin D in the prevention of exacerbation of asthma; however, the optimal posology to sufficiently raise serum levels while maximising adherence is unclear. The objective was to ascertain the efficacy of high-dose vitamin D3 in increasing serum vitamin D in preschoolers with asthma and provide preliminary data on safety and efficacy outcomes.MethodsWe conducted a 7-month, triple-blind, randomised, placebo-controlled, pilot trial of children aged 1–5 years with viral-induced asthma. Participants were allocated to receive two oral doses of 100,000 IU vitamin D3 (intervention) or identical placebo (control) 3.5 months apart, once in the fall and once in the winter. Serum 25-hydroxyvitamin D (25OHD) was measured by tandem mass spectrometry at baseline, 10 days, 3.5 months, 3.5 months + 10 days, and 7 months. The main outcome was the change in serum 25OHD from baseline (Δ25OHD) over time and at 3.5 and 7 months; other outcomes included the proportion of children with 25OHD ≥ 75 nmol/L, safety, and adverse event rates.ResultsChildren (N = 47) were randomised (intervention, 23; control, 24) in the fall. There was a significant adjusted group difference in the Δ25OHD (95% confidence interval) of 57.8 (47.3, 68.4) nmol/L, p < 0.0001), with a time (p < 0.0001) and group*time interaction effect (p < 0.0001), in favour of the intervention. A significant group difference in the Δ25OHD was observed 10 days after the first (119.3 [105.8, 132.9] nmol/L) and second (100.1 [85.7, 114.6] nmol/L) bolus; it did not reach statistical significance at 3.5 and 7 months. At 3.5 and 7 months, respectively, 63% and 56% of the intervention group were vitamin D sufficient (≥ 75 nmol/L) compared to 39% and 36% of the control group. Hypercalciuria, all without hypercalcaemia, was observed in 8.7% of intervention and 10.3% of control samples at any time point. Exacerbations requiring rescue oral corticosteroids, which appear as a promising primary outcome, occurred at a rate of 0.87/child.ConclusionTwo oral boluses of 100,000 IU vitamin D3,once in the fall and once in the winter, rapidly, safely, and significantly raises overall serum vitamin D metabolites. However, it is sufficient to maintain 25OHD ≥ 75 nmol/L throughout 7 months in only slightly more than half of participants.Trial registrationClinicalTrials.gov, NCT02197702 (23 072014). Registered on 23 July 2014.

Abstract PD6-02: A randomized, controlled trial of high dose vs. standard dose vitamin D for aromatase inhibitor-induced arthralgia in breast cancer survivors

Abstract Background: Approximately half of women on aromatase inihbitor (AI) therapy develop AI-induced arthralgia (AIA), and many discontinue the medication because of this common side effect. While Vitamin D has been studied as a treatment for AIA, trial results have been conflicting thus far. Patients and Methods: All subjects were post menopausal women who were beginning adjuvant AI therapy for stage I-III hormone receptor positive breast cancer. Patients were randomized 1:1 to receive standard dose vitamin D3 (800 IU daily for 52 weeks) or high dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). All patients also took oral calcium 600 mg daily. The primary endpoint was development of AIA, as defined by pre-specified changes in the Health Assessment Questionnaire II (HAQ-II). Secondary endpoints include compliance with AI therapy, and correlation between grip strength and development of AIA. Exploratory endpoint was measurement of inflammatory cytokine reduction in each arm. The trial was designed to enroll 184 patients, but this futility analysis was performed after 93 patients were enrolled. The futility boundary for stopping the trial early was calculated as p = 0.47. Results: All 93 patients (46 in the high dose arm, and 47 in the standard dose arm) enrolled in the study at the time of the interim analysis were evaluable. The HAQ-II was completed at 12 weeks in 76% on the high dose arm, and 68% in the standard dose arm. Subjects who did not complete the questionnaire were deemed as study failures (i.e. development of AIA was assumed). In the high dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard dose arm. The one-tailed p value is 0.3818, and the Z-score is 0.3, yielding only a 38% conditional power that that study would find a significant difference between the two arms. Thus, the study was terminated early for futility. There was no significant difference between the two arms in adherence to AI therapy. The grip strength and inflammatory cytokine data are pending at this time. They will be ready by the time of the conference. Conclusions: There was no significant signal for benefit of high dose vitamin D supplementation, as compared to standard dose vitamin D, for AIA prevention in post menopausal women taking adjuvant AI therapy. These results further characterize the role of Vitamin D in AIA, and they inform future clinical trials in this arena. Further research is necessary, as this remains an important cause of non-adherence to this highly effective therapy. Citation Format: Niravath P, Wang T, Hilsenbeck SG, Lipscomb K, Pavlick A, Jiralerspong S, Nangia J, Ellis M, Ademuyiwa F, Cherian M, Frith A, Ma C, Park H, Rigden C, Suresh R, Osborne CK, Rimawi MF. A randomized, controlled trial of high dose vs. standard dose vitamin D for aromatase inhibitor-induced arthralgia in breast cancer survivors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-02.

Single high-dose oral vitamin D3 treatment in New Zealand children with inflammatory bowel disease.

High-dose oral vitamin D (stoss) is a novel treatment in children with inflammatory bowel disease (IBD). Vitamin D supplementation may have benefits in IBD beyond bone health including reduced disease activity and improvements in inflammatory markers. The aim of this study was to retrospectively assess the efficacy, safety and impact on disease activity of single oral high-dose vitamin D3 therapy in New Zealand (NZ) children with IBD and vitamin D deficiency. In this retrospective chart review, children with IBD and vitamin D deficiency [serum 25-OH vitamin D level (25-OHD) <50 nmol/L] in Christchurch, NZ, who were managed with single high-dose vitamin D3 therapy were identified. Measurements of serum 25-OHD, calcium and standard serum inflammatory markers prior to and up to 6 months following stoss therapy were extracted from patient records. Disease activity was also defined using the Pediatric Crohn's Disease (CD) Activity Index (PCDAI) at time points before and 3 months following stoss. Twenty-eight doses of stoss were given to 23 children, aged 3-16 years. Mean 25-OHD levels increased after stoss therapy from 39 nmol/L (95% CI: 37-42 nmol/L) at baseline to 189 nmol/L (148-231 nmol/L) at 1-2 months (P<0.001). All children with 1 month levels measured achieved 25-OHD >75 nmol/L. One child had a serum calcium of 2.7 (normal range, 2.2 to 2.6 mmol/L) 2 weeks after treatment, which normalized on repeat testing 10 days later. PCDAI scores, mean platelet count, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) all reduced significantly from baseline to 3 months following stoss therapy. Single high-dose oral vitamin D therapy was used successfully and safely to manage vitamin D deficiency in these children with IBD. An improvement in inflammatory markers and disease activity scores also occurred following stoss therapy.

High-dose preoperative cholecalciferol to prevent post-thyroidectomy hypocalcaemia: A randomized, double-blinded placebo-controlled trial.

Post-thyroidectomy hypocalcaemia is a significant cause of morbidity and prolonged hospitalization, usually due to transient parathyroid gland damage, treated with calcium and vitamin D supplementation. We present a randomized, double-blinded placebo-controlled trial of preoperative loading with high-dose cholecalciferol (300000 IU) to reduce post-thyroidectomy hypocalcaemia. Patients (n=160) presenting for thyroidectomy at tertiary hospitals were randomized 1:1 to cholecalciferol (300000IU) or placebo 7days prior to thyroidectomy. Ten patients withdrew prior to surgery. The primary outcome was post-operative hypocalcaemia (corrected calcium <2.1mmol/L in first 180days). The study included 150 patients undergoing thyroidectomy for Graves' disease (31%), malignancy (20%) and goitre (49%). Mean pre-enrolment vitamin D was 72±26nmol/L. Postoperative hypocalcaemia occurred in 21/72 (29%) assigned to cholecalciferol and 30/78 (38%) participants assigned to placebo (P=0.23). There were no differences in secondary end-points between groups. In pre-specified stratification, baseline vitamin D status did not predict hypocalcaemia, although most individuals were vitamin D replete at baseline. Post-hoc stratification by day 1 parathyroid hormone (PTH) (<10pg/mL, low vs ≥10pg/mL, normal) was explored due to highly divergent rates of hypocalcaemia in these groups. Using a Cox regression model, the hazard ratio for hypocalcaemia in the cholecalciferol group was 0.56 (95%CI 0.32-0.98, P=0.04) after stratification for Day 1 PTH. Further clinical benefits were observed in these subgroups. Pre-thyroidectomy treatment with high-dose cholecalciferol did not reduce the overall rate of hypocalcaemia following thyroidectomy. In subgroups stratified by day 1 PTH status, improved clinical outcomes were noted.

Vitamin D in the ICU: More sun for critically ill adult patients?

Critical illness in patients is characterized by systemic inflammation and oxidative stress. Vitamin D has a myriad of biological functions relevant to this population, including immunomodulation by the alteration of cytokine production and nuclear factor loop amplification. Low serum levels have consistently been found in observational studies conducted on critically ill patients, but the causality with mortality and worse outcomes has not been confirmed. The current focus is on interventional trials, whereas the pharmacokinetic profile of vitamin D administration remains sparse and the optimal strategy has not been confirmed. So far, high-dose oral or enteral supplementation is the most studied strategy. The largest randomized controlled trial published so far, the VITdAL-ICU (Effect of High-dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients with Vitamin D Deficiency) trial, showed no benefits on mortality in its primary analysis. However, secondary analysis suggested improvement in those patients with severe deficiency (i.e., 25-dihydroxyvitaminD <12 ng/mL). Smaller trials investigated intramuscular and intravenous administration and found interesting intermediate biochemical findings, including increased cathelicidins, but were not powered to investigate relevant clinical outcomes in the critically ill. The latest meta-analysis, which was recently published, does not support benefits of vitamin D supplementation in the heterogeneous population of critically ill patients. The European guidelines, published in the last year, suggest supplementing severely deficient patients with levels <12.5 ng/mL within the first week after ICU admission. However, other societies do not support such supplementation in their older recommendations. Large trials are currently recruiting ICU patients and could elucidate potential clinical benefits of vitamin D therapy in the critically ill.

Vitamin D to Prevent Lung Injury Following Esophagectomy-A Randomized, Placebo-Controlled Trial.

Observational studies suggest an association between vitamin D deficiency and adverse outcomes of critical illness and identify it as a potential risk factor for the development of lung injury. To determine whether preoperative administration of oral high-dose cholecalciferol ameliorates early acute lung injury postoperatively in adults undergoing elective esophagectomy. A double-blind, randomized, placebo-controlled trial. Three large U.K. university hospitals. Seventy-nine adult patients undergoing elective esophagectomy were randomized. A single oral preoperative (3-14 d) dose of 7.5 mg (300,000 IU; 15 mL) cholecalciferol or matched placebo. Primary outcome was change in extravascular lung water index at the end of esophagectomy. Secondary outcomes included PaO2:FIO2 ratio, development of lung injury, ventilator and organ-failure free days, 28 and 90 day survival, safety of cholecalciferol supplementation, plasma vitamin D status (25(OH)D, 1,25(OH)2D, and vitamin D-binding protein), pulmonary vascular permeability index, and extravascular lung water index day 1 postoperatively. An exploratory study measured biomarkers of alveolar-capillary inflammation and injury. Forty patients were randomized to cholecalciferol and 39 to placebo. There was no significant change in extravascular lung water index at the end of the operation between treatment groups (placebo median 1.0 [interquartile range, 0.4-1.8] vs cholecalciferol median 0.4 mL/kg [interquartile range, 0.4-1.2 mL/kg]; p = 0.059). Median pulmonary vascular permeability index values were significantly lower in the cholecalciferol treatment group (placebo 0.4 [interquartile range, 0-0.7] vs cholecalciferol 0.1 [interquartile range, -0.15 to -0.35]; p = 0.027). Cholecalciferol treatment effectively increased 25(OH)D concentrations, but surgery resulted in a decrease in 25(OH)D concentrations at day 3 in both arms. There was no difference in clinical outcomes. High-dose preoperative treatment with oral cholecalciferol was effective at increasing 25(OH)D concentrations and reduced changes in postoperative pulmonary vascular permeability index, but not extravascular lung water index.

Effect of Monthly Vitamin D on Chronic Pain Among Community-Dwelling Seniors: A Randomized, Double-Blind Controlled Trial

ObjectiveWith advancing age, the prevalence of vitamin D deficiency and musculoskeletal pain increases. However, published data on the effectiveness of vitamin D supplementation in reducing chronic pain are inconclusive. The purpose of this study was to test the effect of 3 different monthly doses of vitamin D on chronic pain in seniors 70 years and older with a prior fall event. Design1-year, double-blind randomized clinical trial. SettingThe trial was conducted in Zurich, Switzerland. Participants were 200 community-dwelling men and women 70 years and older with a prior fall. InterventionThree study groups with monthly treatments were randomized to either a low-dose control group of vitamin D (24,000 IU vitamin D3/mo), a high dose of vitamin D3 (60,000 IU vitamin D3/mo), or a combination of calcifediol and vitamin D3 (24,000 IU vitamin D3 plus 300 μg calcifediol/mo). MeasurementsThe primary endpoint was the change in the mean number of painful areas using the McGill Pain map over 12 months of follow-up. All analyses were adjusted for age, sex, body mass index, 25-hydroxyvitamin (OH)D3 levels, and pain scores at baseline. A predefined subgroup analysis was performed by baseline 25(OH)D status (<20 vs ≥ 20 ng/mL). ResultsThe mean age of the participants was 78 years, 67.0% (134 of 200) were female, and 58.0% (116 of 200) were vitamin D deficient (<20 ng/mL) at baseline. Over 12 months of follow-up, the changes in the mean number of painful areas did not differ significantly among treatment groups (P = .46). However, there was a significant interaction effect between baseline vitamin levels (<20 vs ≥ 20 ng/mL) and treatment (P = .02). Among those who were vitamin D replete at baseline (n = 84), there was a significant difference between treatment groups over time (P = .04), and only seniors in the 24,000-IU vitamin D3 group had a marginally significant decrease in their total mean pain score (−0.77; 95% CI, −1.56 to 0.01, P = .05), whereas there were no changes in the high-dose groups. Among seniors who were vitamin D deficient at baseline (n = 116), chronic pain did not differ by treatment groups over time (P = .33). ConclusionOur results suggest that both starting level of 25(OH)D3 and monthly treatment dose of vitamin D may be important with respect to chronic pain reduction—with the only benefit seen among vitamin D–replete seniors treated with a monthly dose of 24,000 IU vitamin D3.

Vitamin D3 as adjunctive therapy in the treatment of depression in tuberculosis patients: a short-term pilot randomized double-blind controlled study.

ObjectiveWe aimed to evaluate whether high-dose cholecalciferol has beneficial effects on depression in pulmonary tuberculosis (PTB) patients.MethodsThis pilot, randomized, and double-blind trial enrolled 123 recurrent PTB patients (aged ≥18 years) meeting Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria of major depressive disorder from four hospitals in Southeast China. Patients were randomly assigned to 8-week oral treatment with 100,000 IU/week cholecalciferol (Vit D group) or a matching placebo (control group). The primary outcome was treatment response, defined as a 50% reduction in symptoms and change in scores of the Chinese version of Beck Depression Inventory (BDI) from baseline to 8 weeks. Relative risks of depression were estimated using multivariable logistic regression.ResultsFinally, 120 patients were enrolled, including 56 test patients and 64 controls. After 8 weeks, the treatment response or BDI scores did not differ significantly between groups. Multivariate logistic regression showed that BDI scores were not significantly improved in the Vit D group after adjustment for age, time to first negative smear, or 25-hydroxyvitamin D level.ConclusionThe use of high-dose Vit D3 supplementation may not be warranted for reducing depressive symptoms in the PTB population. Nevertheless, this finding should be validated by further large-scale studies according to different kinds of depression or Vit D receptor polymorphism genotype.

Vitamin D levels in children and adolescents with attention-deficit hyperactivity disorder (ADHD): a meta-analysis.

The aim of this article was to assess the differences in serum 25(OH)D levels between children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and healthy controls. We used the PubMed (1966-2017), Scopus (2004-2017), ClinicalTrials.gov (2008-2017), Cochrane Central Register of Controlled Trials CENTRAL (2000-2017), and Google Scholar (2004-2017) databases. Statistical meta-analysis was performed with RevMan 5.3. Εight studies were finally included in the present meta-analysis with a total number of 11,324 children. Among them, 2655 were diagnosed with ADHD, while the remaining 8669 were recruited as healthy controls. All eight trials reported significantly lower serum concentrations of 25(OH)D in patients diagnosed with ADHD compared to healthy controls. The pooled data showed that there was a significant difference between the ADHD group and the control group (SMD = - 0.73, 95% CI [- 1.00, - 0.46]). The systematic review and meta-analysis of observational studies demonstrated an inverse association between serum 25(OH)D and young patients with ADHD. Large cohort studies are required to investigate whether vitamin D-deficient infants are more likely to develop ADHD in the future. Also, whether children with ADHD should be supplemented with higher doses of vitamin D3 remains to be confirmed through long-term controlled clinical trials.

GW29-e0700 Ligustilide protects against the pathological intimal hyperplasia in spontaneously hypertensive rats

This experment reports for the first time that investigated the effect of ligustilide on the pathological intimal hyperplasia and its related mechanisms. 10-week-old spontaneously hypertensive rats were injected intraperitoneally with a high doses of vitamin D3, and then the rats fed with a high-

Effect of adjunctive single high-dose vitamin D3 on outcome of community-acquired pneumonia in hospitalised adults: The VIDCAPS randomised controlled trial

Low vitamin D status is associated with increased risk of pneumonia, greater disease severity and poorer outcome. However, no trials have examined the effect of adjunctive vitamin D therapy on outcomes in adults with community-acquired pneumonia (CAP). We conducted a randomised, double-blind, placebo-controlled trial examining the effects of adjunctive vitamin D in adults hospitalised with CAP. Participants were randomised to either a single oral dose of 200,000 IU vitamin D3 or placebo. The primary outcome was the complete resolution of chest radiograph infiltrate at 6 weeks post-study treatment. Secondary outcomes included length of hospital stay, intensive care admission and return to normal activity. Only participants who completed the study or died within the 6 week period were included in the analysis (n = 60 vitamin D, n = 57 placebo). Adjunctive vitamin D did not have any effect on the primary outcome (OR 0.78, 95% CI 0.31 to 1.86, p = 0.548). However, there was evidence it increased the complete resolution of pneumonia in participants with baseline vitamin D levels <25 nmol/L (OR 17.0, 95% CI 1.40–549.45, P = 0.043), but this did not reach statistical significance using exact methods (OR 13.0, 95%CI 0.7–960.4, P = 0.083). There were no significant effects for any secondary outcome.

Bone mass preservation with high-dose cholecalciferol and dietary calcium in HIV patients following antiretroviral therapy. Is it possible?

Objective: To evaluate whether treatment with 100,000 IU/month (equivalent to 3200 IU/day) of cholecalciferol and 1 g/day of dietary calcium supplementation in HIV patients following different cART regimens yields normal levels of vitamin D3 and PTH as well as whether changes in bone mineral density are clinically significant.Methods: Consecutive HIV patients following different cART regimens received 100,000 IU/month (equivalent to 3200 IU/day) of cholecalciferol and 1 g/day of dietary calcium supplementation. The participants underwent BMD assessment via dual energy X-ray absorptiometry of the spine and hip at baseline (T0) and after 24 months (T1). Levels of 25(OH) vitamin D3 and parathyroid hormone (PTH) were assessed at T0 and T1. Quantitative variables were assessed with a paired t-test, independent t-test or analysis of variance, as appropriate. A chi-squared analysis was used to assess the association between qualitative variables. A p-value <0.05 was considered significant. Patients were divided into three groups depending on the cART regimen.Results: A total of 79 patients were included (40 males, 51% and 39 females, 49%), with a mean age of 46.6 (SD ±11.2) years, a baseline CD4 count of 649 cells/µl and a mean 25 hydroxycholecalciferol (25(OH) D3) value of 25 + 10 ng/ml. After 24 months, the 25(OH) D3 increased to 40 + 11 ng/ml. The initial BMDs at T0 were estimated as 0.919 (±0.27) and 0.867 (±0.14) g/cm2 at the spine and hip, respectively. After 24 months, the BMD was 0.933 (±0.15) g/cm2 at the spine and 0.857 (±0.14) g/cm2 at the hip. Based on a BMD change exceeding 3%, a worsening was observed in 23% of patients at the spine and 27% at the hip, whereas stability or improvement was demonstrated in 77% of patients at the spine and 73% at the hip.Subgrouping patients based on antiretroviral therapy indicated that, at T1, there was a statistically significant increase in vitamin D3 concentration in all patients, while PTH concentration was not significantly reduced in patients taking tenofovir or efavirenz. BMD stability or improvement was demonstrated in 77% of patients at the spine and 73% at the hip after 24 months.The multivariate analysis confirms a decrease in vitamin D3 and an increase in PTH levels in smokers, as well higher vitamin D3 concentrations in males and lower spine BMDs in menopausal females.Conclusion: The proposed protocol of cholecalciferol and dietary calcium supplementation is safe and valid for correcting vitamin D abnormalities in almost all patients as well as reducing PTH levels in a high percentage of patients; however, it is not sufficient for normalization, particularly in patients exposed to tenofovir or efavirenz. At the spine, no significant BMD change was found in any of the therapy groups. At the hip, our data confirm a modest negative effect on bone mass caused by tenofovir and efavirenz.

Cholecalciferol attenuates induced Parkinson’s like-disease variation and cellular morphology of striatum and substantial Nigra

Parkinson’s disease is the commonest motor neurodegenerative disorder which affects the dopaminergic neurons and causes significant loss of dopamine. 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective neurotoxin in the nigrostriatal pathway leading to this motor disorder. Cholecalciferol (Vitamin D3) has been described as an active neurosteriod with antioxidant properties ubiquitously present in the brain. The study hypothesized that stimulation of vitamin D receptor by cholecalciferol could reduce autophagic cell death and degeneration following a state of drug induced parkinsonism in mice. The aim of the research was to observe the cytoarchitectural, histochemical, neurobehavioural and immunohistochemical effects of cholecalciferol on striatum and substantia nigra in mice model of MPTP-induced Parkinson’s disease. Fifty adult male C57BL/6J mice weighing about 25-35g were randomly selected and assigned into 5 groups for this study. The mice were then subjected to neurobehavioural, neurochemical and neuropathological evaluations. The results obtained showed a significant reduction (*p&lt;0.05) in the estimated markers of oxidative stress with high dose of vitamin D3 following MPTP induction. There was also statistical significant reduction (**p&lt;0.01, ***p&lt;0.001) in the expression of GFAP-immuno-positive cells in the substantia nigra of the experimental mice when compared with the control group. It can be inferred that the administration of Vitamin D3 was associated with significant attenuation of focal effects linked with MPTP in mice model of Parkinson’s Disease.Keywords: Aging, Neurodegeneration, Dopaminergic neuron, Vitamin D3, Environmental toxins

Monthly high-dose vitamin D3 supplementation and self-reported adverse events in a 4-year randomized controlled trial

The use of high-dose vitamin D supplementation has increased in recent years. However, relatively little is known about the safety of long-term high doses. To investigate the safety of a monthly high-dose of vitamin D3 supplementation taken for up to 4 years. Data were collected in a randomized, double blind, placebo-controlled trial of 5108 adults aged 50-84 years old from Auckland, New Zealand. Participants were given monthly doses of 100,000 IU vitamin D3 or placebo, for a median of 3.3 years (range 2.5-4.2 years). They answered an open-ended question in a monthly questionnaire about any adverse events they attributed to the study capsules, which were coded blindly. Incidence rates per person months were calculated for categories of adverse events. Cox regression model used to calculate hazard ratio of time to first adverse-event. In total, 419 (16.5%) participants taking vitamin D and 399 (15.8%) taking placebo reported ≥1 adverse event. Compared to placebo, the hazard ratio (HR) of reporting first adverse event in the vitamin D group was 1.03 (95% CI: 0.90, 1.18; p=0.63). Despite a slightly higher incidence of recurrent adverse events in vitamin D arm, the incidence rate ratio (1.17) was not significantly higher in vitamin D (95% CI: 0.97, 1.41; p=0.10). All regression results were adjusted for age, sex, and ethnicity. There was no difference between study arms in terms of participants' allocation perception (p=0.52). Monthly supplementation of 100,000 IU vitamin D3 for a median of 3.3 years did not affect participant-reported adverse events. clinicaltrials.gov Identifier: ACTRN12611000402943; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12611000402943.

Recovery after unilateral knee replacement due to severe osteoarthritis and progression in the contralateral knee: a randomised clinical trial comparing daily 2000 IU versus 800 IU vitamin D

ObjectiveTo test whether daily high-dose vitamin D improves recovery after unilateral total knee replacement.MethodsData come from a 24-month randomised, double-blind clinical trial. Adults aged 60 and older undergoing unilateral joint...