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COVID-19 Mortality Risk Correlates Inversely with Vitamin D3 Status, and a Mortality Rate Close to Zero Could Theoretically Be Achieved at 50 ng/mL 25(OH)D3: Results of a Systematic Review and Meta-Analysis.
Borsche, L, Glauner, B, von Mendel, J
Nutrients. 2021;(10)
Abstract
BACKGROUND Much research shows that blood calcidiol (25(OH)D3) levels correlate strongly with SARS-CoV-2 infection severity. There is open discussion regarding whether low D3 is caused by the infection or if deficiency negatively affects immune defense. The aim of this study was to collect further evidence on this topic. METHODS Systematic literature search was performed to identify retrospective cohort as well as clinical studies on COVID-19 mortality rates versus D3 blood levels. Mortality rates from clinical studies were corrected for age, sex, and diabetes. Data were analyzed using correlation and linear regression. RESULTS One population study and seven clinical studies were identified, which reported D3 blood levels preinfection or on the day of hospital admission. The two independent datasets showed a negative Pearson correlation of D3 levels and mortality risk (r(17) = -0.4154, p = 0.0770/r(13) = -0.4886, p = 0.0646). For the combined data, median (IQR) D3 levels were 23.2 ng/mL (17.4-26.8), and a significant Pearson correlation was observed (r(32) = -0.3989, p = 0.0194). Regression suggested a theoretical point of zero mortality at approximately 50 ng/mL D3. CONCLUSIONS The datasets provide strong evidence that low D3 is a predictor rather than just a side effect of the infection. Despite ongoing vaccinations, we recommend raising serum 25(OH)D levels to above 50 ng/mL to prevent or mitigate new outbreaks due to escape mutations or decreasing antibody activity.
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Relative Efficacy of Vitamin D2 and Vitamin D3 in Improving Vitamin D Status: Systematic Review and Meta-Analysis.
Balachandar, R, Pullakhandam, R, Kulkarni, B, Sachdev, HS
Nutrients. 2021;(10)
Abstract
BACKGROUND Widespread prevalence of vitamin D deficiency has been documented globally. Commonly used interventions to address this deficiency include supplementation and/or fortification with either ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3), but the relative efficacy of these two vitamers is unclear. The current study aimed to evaluate the relative efficacy of ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) for raising the serum levels of vitamin D metabolites and functional indicators including serum parathyroid (PTH) levels, isometric muscle strength, hand grip strength and bone mineral density. METHODS Randomized and non-randomized controlled studies evaluating relative efficacy of ergocalciferol and cholecalciferol were systematically reviewed to synthesize quantitative and qualitative evidence as per the recommendations of according to "Preferred Reporting Items for Systematic reviews and Meta-analysis" guidelines. Search terms were constructed on the basis of the "participants", "intervention", "control", "outcome" and "study type" (PICOS) strategy to systematically search the popular electronic databases. Relevant data from studies meeting inclusion and exclusion criteria were extracted and analyzed. Meta-regression, subgroup and sensitivity analyses were performed to investigate the influence of study-level characteristics including intervention dosage, frequency of dosing, interval between the last dose and test for outcome assessment, participant characteristics and analytical methods. RESULTS Apparently healthy human participants (n = 1277) from 24 studies were included for meta-analysis. The quantitative analysis suggested higher efficacy of cholecalciferol than ergocalciferol in improving total 25(OH)D (mean difference: 15.69, 95%CI: 9.46 to 21.93 nmol/L) and reducing PTH levels, consistently across variable participant demographics, dosage and vehicle of supplementation. Meta-regression suggested smaller differences in the efficacy of cholecalciferol and ergocalciferol at lower doses. Average daily dose was the single significant predictor of effect size, as revealed by multivariate meta-regression analysis. CONCLUSIONS Compared to ergocalciferol, cholecalciferol intervention was more efficacious in improving vitamin D status (serum levels of total 25(OH)D and 25(OH)D3) and regulating PTH levels, irrespective of the participant demographics, dosage and vehicle of supplementation.
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The Health Effects of Vitamin D and Probiotic Co-Supplementation: A Systematic Review of Randomized Controlled Trials.
Abboud, M, Rizk, R, AlAnouti, F, Papandreou, D, Haidar, S, Mahboub, N
Nutrients. 2020;(1)
Abstract
Evidence of synergic health effects of co-supplementation with vitamin D and probiotics is emerging. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA statement, scientific databases and the grey literature were searched, and a narrative review and risk of bias assessment were conducted. Seven randomized controlled trials were included, which had low risk of bias. Six studies were double-blind, and once single-blind, extended over 6-12 weeks, and included 50-105 participants. Conditions explored included schizophrenia, gestational diabetes, type 2 diabetes and coronary heart disease, polycystic ovarian syndrome, osteopenia, irritable bowel syndrome (IBS), and infantile colic. Supplementation frequency was daily or bi-monthly, with mainly vitamin D3, and Lactobacillus, Bifidobacterium, and Streptococcus. Comparators were placebo, vitamin D, lower vitamin D dose, and probiotics and lower vitamin D dose. The co-supplementation yielded greater health benefits than its comparators did in all studies except in one assessing IBS. Beneficial effects included decreased disease severity, improved mental health, metabolic parameters, mainly insulin sensitivity, dyslipidemia, inflammation, and antioxidative capacity, and lower use of healthcare. Co-supplementation of vitamin D and probiotics generated greater health benefits than its comparators did. More studies in other diseases and various populations are needed to confirm these findings and to elucidate the optimal form, composition, and frequency of this co-supplementation.
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Efficacy of Vitamin D3 Buccal Spray Supplementation Compared to Other Delivery Methods: A Systematic Review of Superiority Randomized Controlled Trials.
Grammatikopoulou, MG, Gkiouras, K, Nigdelis, MP, Bogdanos, DP, Goulis, DG
Nutrients. 2020;(3)
Abstract
(1) Background: Vitamin D deficiency is an important public health concern and supplementation is common for this deficiency. Many different modes of delivering supplementation have been proposed in order to enhance absorption and utilization. The present review compared the efficacy of vitamin D3 buccal spray against other forms of supplementation delivery. (2) Methods: The protocol was registered at PROSPERO (CRD42019136146). Medline/PubMed, CENTRAL and clinicaltrials.gov were searched from their inception until September 2019, for randomized controlled trials (RCTs) that compare vitamin D3 delivery via sublingual spray against other delivery methods. Eligible RCTs involved humans, of any age and health status, published in any language that evaluated changes in plasma 25(OH)D concentrations. Three reviewers independently extracted data, assessed risk of bias (RoB) and the quality of the trials. (3) Results: Out of 9759 RCTs, four matched the predefined criteria. Intervention duration ranged from 30 days to 3 months whereas vitamin D3 dosage ranged between 800 and 3000 IU/day. One RCT advocated for the superiority of buccal spray in increasing plasma 25(OH)D concentrations, although several limitations were recorded in that trial. The rest failed to report differences in post-intervention 25(OH)D concentrations between delivery methods. Considerable clinical heterogeneity was observed due to study design, intervention duration and dosage, assays and labs used to perform the assays, population age and health status, not allowing for synthesis of the results. (4) Conclusions: Based on the available evidence, delivery of vitamin D3 via buccal spray does not appear superior to the other modes of delivery. Future RCTs avoiding the existing methodological shortcomings are warranted.
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Oral vitamin D3 supplementation increases serum fibroblast growth factor 23 concentration in vitamin D-deficient patients: a systematic review and meta-analysis.
Charoenngam, N, Rujirachun, P, Holick, MF, Ungprasert, P
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2019;(11):2183-2193
Abstract
Studies have suggested that vitamin D supplementation may increase serum fibroblast growth factor 23 (FGF23) among vitamin D-deficient patients although the results were inconsistent across the studies. This systematic review and meta-analysis was conducted to summarize all available data. A systematic review was conducted using MEDLINE and EMBASE database from inception to February 2019 to identify studies that provided oral vitamin D3 supplement to vitamin D-deficient participants (25-hydroxyvitamin D < 20 ng/mL). Mean serum FGF23 concentration and standard deviation of participants at baseline and after vitamin D3 supplementation were extracted to calculate standard mean difference (SMD). Pooled SMD was calculated by combining SMDs of each study using random effects model. Nine studies were eligible for the meta-analyses. Seven studies measured serum intact FGF23, and two studies measured serum C-terminal FGF23. The meta-analyses found that serum intact FGF23 increased significantly after oral vitamin D3 supplementation in vitamin D-deficient participants with the pooled SMD of 0.36 (95%CI, 0.14, 0.57; p = 0.001; I2 of 36%). Serum C-terminal FGF23 also increased after vitamin D3 supplementation in vitamin D-deficient participants with the pooled SMD of 0.28 although without reaching statistical significance (95%CI, - 0.08, 0.65; p = 0.13; I2 of 0%). Funnel plot of the meta-analysis of serum intact FGF23 did not provide a suggestive evidence for publication bias. Vitamin D supplementation leads to a significant increase in serum intact FGF23 among vitamin D-deficient patients. An increase in serum C-terminal FGF23 was also observed although the number of included studies was too small to demonstrate statistical significance. The present systematic review and meta-analysis revealed that serum intact FGF23 concentration increased significantly after oral vitamin D3 supplementation in vitamin D-deficient participants. An increase in serum C-terminal FGF23 concentration was also observed although the number of included studies was too small to demonstrate statistical significance.
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Effects of vitamin D3 supplementation on serum 25(OH)D concentration and strength in athletes: a systematic review and meta-analysis of randomized controlled trials.
Han, Q, Li, X, Tan, Q, Shao, J, Yi, M
Journal of the International Society of Sports Nutrition. 2019;(1):55
Abstract
BACKGROUND The purpose of this systematic review and meta-analysis is to investigate the effects of vitamin D3 supplementation on skeletal muscle strength in athletes. Vitamin D3 supplements or vitamin D3 fortified foods always have claims for bringing people health benefits including bone and muscle health. An up-to-date rigorous systematic review and meta-analysis is important to better understand the effect of vitamin D3 supplementation on muscle strength. METHODS English written randomized controlled trials (RCTs) that looked at effects of vitamin D3 supplementation on muscle strength in healthy athletes were searched using three databases (PubMed, Embase and Cochrane Library). Serum 25(OH)D above 30 ng/mL is considered to be sufficient in this systematic review and meta-analysis. RESULTS Five RCTs with 163 athletes (vitamin D3 n = 86, placebo n = 77) met inclusion criteria. Fourteen athletes were lost to follow-up and 149 athletes (vitamin D3 n = 80, placebo n = 69) were documented with complete result. Among athletes with baseline serum 25(OH)D values suggesting insufficiency, vitamin D3 daily dosage at 5000 IU for over 4 weeks led to a serum 25(OH)D concentration of 31.7 ng/mL. Athletes with sufficient serum 25(OH)D level at baseline were recruited in only one study, and the participants of which were assigned to either vitamin D3 at a daily dosage of 3570 IU or placebo for 12 weeks, their serum 25(OH)D sufficiency (VD: 37.2 ± 7.6 vs. 45.6 ± 7.6; PL: 38 ± 6.8 vs. 32 ± 8.4) was well maintained above the cut-off boundary. One repetition maximum Bench Press (1-RM BP) was not improved significantly (SMD 0.07, 95% CI: - 0.32 to 0.47, P = 0.72) and there was no significant increase in maximal quadriceps contraction (SMD -2.14, 95% CI: - 4.87 to 0.59, P = 0.12). Furthermore, there was no significant overall effect of vitamin D3 intervention on muscle strength in this meta-analysis (SMD -0.75, 95% CI: - 1.82 to 0.32, P = 0.17). CONCLUSION Although, serum 25(OH)D concentrations after supplementation reached sufficiency was observed, muscle strength did not significantly improve at this point of current meta-analysis. Additional well-designed RCTs with large number of participants examined for the effect of vitamin D3 supplementation on serum 25(OH)D concentrations, muscle strength in a variety of sports, latitudes and diverse multicultural populations are needed.
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The effect of vitamin D3 on blood pressure in people with vitamin D deficiency: A system review and meta-analysis.
He, S, Hao, X
Medicine. 2019;(19):e15284
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Abstract
OBJECTIVE To evaluate the effect of vitamin D3 on blood pressure in people with vitamin D deficiency. METHODS Randomized controlled trials (RCTs) were electronically searched databases including CNKI, VIP, WanFang Data, the Cochrane Library, PubMed, and EMbase which were about oral vitamin D3 among people with vitamin D deficiency from inception to December 2017. Two reviewers independently screened literature according to the inclusion and extracted data; meta-analysis was performed using RevMan5.3. RESULTS A total of 17 RCTs with 22 arms involving 1687 participants were included. The results of meta-analysis showed that, there were no significant differences between the vitamin D deficiency group and the control group on the level of change in systolic pressure (ΔSBP) [weighted mean difference (WMD) = -1.94, 95% confidence interval (CI) (-3.93,0.04) P = .06] and on the level of change in diastolic pressure (ΔDBP) [WMD = -0.50, 95% CI (-1.17, 0.17) P = .14]. The results of subgroups showed that, there were statistically significant differences in the age of >50 years subgroup on ΔSBP [WMD = -2.32, 95% CI (-4.39, -0.25) P = .03]; there were statistically significant differences in the hypertension subgroup on ΔSBP [WMD = -6.58, 95% CI (-8.72, -4.44) P <.00001]; there were statistically significant differences in the hypertension subgroup on ΔDBP [WMD = -3.07, 95% CI (-4.66, -1.48) P = .0002]; there were statistically significant differences in the body mass index (BMI) >30 subgroup on ΔSBP [WMD = -3.51, 95% CI (-5.96, -1.07) P = .005]. CONCLUSION Oral vitamin D3 has no significant effect on blood pressure in people with vitamin D deficiency. It reduces systolic blood pressure in people with vitamin D deficiency that was older than 50 years old or obese. It reduces systolic blood pressure and diastolic pressure in people with both vitamin D deficiency and hypertension.
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Vitamin D for the management of multiple sclerosis.
Jagannath, VA, Filippini, G, Di Pietrantonj, C, Asokan, GV, Robak, EW, Whamond, L, Robinson, SA
The Cochrane database of systematic reviews. 2018;(9):CD008422
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Abstract
BACKGROUND This review is an update of a previously published review, "Vitamin D for the management of multiple sclerosis" (published in the Cochrane Library; 2010, Issue 12). Multiple sclerosis (MS) is characterised by inflammation, demyelination, axonal or neuronal loss, and astrocytic gliosis in the central nervous system (CNS), which can result in varying levels of disability. Some studies have provided evidence showing an association of MS with low levels of vitamin D and benefit derived from its supplementation. OBJECTIVES To evaluate the benefit and safety of vitamin D supplementation for reducing disease activity in people with MS. SEARCH METHODS We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Specialized Register up to 2 October 2017 through contact with the Information Specialist with search terms relevant to this review. We included references identified from comprehensive electronic database searches and from handsearches of relevant journals and abstract books from conferences. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs that compared vitamin D versus placebo, routine care, or low doses of vitamin D in patients with MS. Vitamin D was administered as monotherapy or in combination with calcium. Concomitant interventions were allowed if they were used equally in all trial intervention groups. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and assessed the methodological quality of studies, while another review author sorted any disagreements. We expressed treatment effects as mean differences (MDs) for continuous outcomes (Expanded Disability Status Scale and number of magnetic resonance imaging (MRI) gadolinium-enhancing T1 lesions), as standardised MDs for health-related quality of life, as rate differences for annualised relapse rates, and as risk differences (RDs) for serious adverse events and minor adverse events, together with 95% confidence intervals (CIs). MAIN RESULTS We identified 12 RCTs enrolling 933 participants with MS; 464 were randomised to the vitamin D group, and 469 to the comparator group. Eleven trials tested vitamin D₃, and one trial tested vitamin D₂. Vitamin D₃ had no effect on the annualised relapse rate at 52 weeks' follow-up (rate difference -0.05, 95% CI -0.17 to 0.07; I² = 38%; five trials; 417 participants; very low-quality evidence according to the GRADE instrument); on the Expanded Disability Status Scale at 52 weeks' follow-up (MD -0.25, 95% CI -0.61 to 0.10; I² = 35%; five trials; 221 participants; very low-quality evidence according to GRADE); and on MRI gadolinium-enhancing T1 lesions at 52 weeks' follow-up (MD 0.02, 95% CI -0.45 to 0.48; I² = 12%; two trials; 256 participants; very low-quality evidence according to GRADE). Vitamin D₃ did not increase the risk of serious adverse effects within a range of 26 to 52 weeks' follow-up (RD 0.01, 95% CI -0.03 to 0.04; I² = 35%; eight trials; 621 participants; low-quality evidence according to GRADE) or minor adverse effects within a range of 26 to 96 weeks' follow-up (RD 0.02, 95% CI -0.02 to 0.06; I² = 20%; eight trials; 701 participants; low-quality evidence according to GRADE). Three studies reported health-related quality of life (HRQOL) using different HRQOL scales. One study reported that vitamin D improved ratings on the psychological and social components of the HRQOL scale but had no effects on the physical components. The other two studies found no effect of vitamin D on HRQOL. Two studies reported fatigue using different scales. One study (158 participants) reported that vitamin D₃ reduced fatigue compared with placebo at 26 weeks' follow-up. The other study (71 participants) found no effect on fatigue at 96 weeks' follow-up. Seven studies reported on cytokine levels, four on T-lymphocyte proliferation, and one on matrix metalloproteinase levels, with no consistent pattern of change in these immunological outcomes. The randomised trials included in this review provided no data on time to first treated relapse, number of participants requiring hospitalisation owing to progression of the disease, proportion of participants who remained relapse-free, cognitive function, or psychological symptoms. AUTHORS' CONCLUSIONS To date, very low-quality evidence suggests no benefit of vitamin D for patient-important outcomes among people with MS. Vitamin D appears to have no effect on recurrence of relapse, worsening of disability measured by the Expanded Disability Status Scale (EDSS), and MRI lesions. Effects on health-related quality of life and fatigue are unclear. Vitamin D₃ at the doses and treatment durations used in the included trials appears to be safe, although available data are limited. Seven ongoing studies will likely provide further evidence that can be included in a future update of this review.
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The effect of combined resistance exercise training and vitamin D3 supplementation on musculoskeletal health and function in older adults: a systematic review and meta-analysis.
Antoniak, AE, Greig, CA
BMJ open. 2017;(7):e014619
Abstract
OBJECTIVES In older adults, there is a blunted responsiveness to resistance training and reduced muscle hypertrophy compared with younger adults. There is evidence that both exercise training and vitamin D supplementation may benefit musculoskeletal health in older adults, and it is plausible that in combination their effects may be additive. The aim of this systematic review was to evaluate the effectiveness of combined resistance exercise training and vitamin D3 supplementation on musculoskeletal health in older adults. DATA SOURCES A comprehensive search of electronic databases, including Science Direct, Medline, PubMed, Google Scholar and Cochrane Central Register of Controlled Trials (Cochrane CENTRAL accessed by Wiley Science) was conducted. Eligible studies were randomised controlled trials including men and women (aged ≥65 years or mean age ≥65 years); enlisting resistance exercise training and vitamin D3 supplementation; including outcomes of muscle strength, function, muscle power, body composition, serum vitamin D/calcium status or quality of life comparing results with a control group. The review was informed by a preregistered protocol (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015020157). RESULTS Seven studies including a total of 792 participants were identified. Studies were categorised into two groups; group 1 compared vitamin D3 supplementation and exercise training versus exercise alone (describing the additive effect of vitamin D3 supplementation when combined with resistance exercise training) and group 2 compared vitamin D3 supplementation and exercise training versus vitamin D3 supplementation alone (describing the additive effect of resistance exercise training when combined with vitamin D3 supplementation).Meta-analyses for group 1 found muscle strength of the lower limb to be significantly improved within the intervention group (0.98, 95% CI 0.73 to 1.24, p<0.001); all other outcomes showed small but non-significant positive effects for the intervention group. The short physical performance battery (SPPB), timed up and go (TUG), muscle strength of the lower limb and femoral neck bone mineral density showed significantly greater improvements in the intervention group for group 2 comparisons. CONCLUSIONS This review provides tentative support for the additive effect of resistance exercise and vitamin D3 supplementation for the improvement of muscle strength in older adults. For other functional variables, such as SPPB and TUG, no additional benefit beyond exercise was shown. Further evidence is required to draw firm conclusions or make explicit recommendations regarding combined exercise and vitamin D3 supplementation.
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Effect of cholecalciferol supplementation on arterial stiffness: a systematic review and meta-analysis.
Upala, S, Sanguankeo, A, Congrete, S, Jaruvongvanich, V
Scandinavian cardiovascular journal : SCJ. 2016;(4):230-5
Abstract
BACKGROUND Vitamin D deficiency increases risk of cardiovascular diseases, arterial stiffness, and endothelial dysfunction. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the impact of vitamin D supplementation on arterial stiffness. METHODS A comprehensive search of the databases of the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE was performed from inception through November 2015. The inclusion criterion was RCTs that assessed the impact of cholecalciferol supplementation in adults on the surrogate markers of arterial stiffness (aortic pulse wave velocity (PWV) and augmentation index (AIx)). Outcome was the pooled mean difference (MD) of PWV and AIx between the vitamin D supplementation (intervention) group and placebo. RESULTS The initial search yielded 1164 articles. Twenty-eight articles underwent full-length review and data were extracted from seven RCTs involving totally 547 participants. Dose of cholecalciferol supplementation varied from 1000 IU/day to 120,000 IU/month of cholecalciferol. Duration of treatment ranged from 2 to 12 months. There was no significant difference in the change of PWV (pooled MD = 0.18, 95% CI: -0.17 to 0.52 or AIx (pooled MD = 2.39, 95% CI: -4.43 to 4.92) between the intervention group and placebo. CONCLUSIONS There was no improvement of markers of arterial stiffness after vitamin D supplementation.