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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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Comparison of Paricalcitol and Calcitriol in Dialysis Patients With Secondary Hyperparathyroidism: A Meta-Analysis of Randomized Controlled Studies.
Zhang, T, Ju, H, Chen, H, Wen, W
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2019;(1):73-79
Abstract
Paricalcitol and calcitriol are widely used for the treatment of secondary hyperparathyroidism in dialysis patients. We conducted a systematic review and meta-analysis to compare the efficacy and safety of paricalcitol and calcitriol for secondary hyperparathyroidism in dialysis patients. PubMed, EMbase, Web of Science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCT) assessing the efficacy of paricalcitol and calcitriol for secondary hyperparathyroidism in dialysis patients are included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. Meta-analysis was carried out using the random-effect model. Six randomized controlled trials are included in the meta-analysis. Overall, compared with calcitriol treatment for secondary hyperparathyroidism in dialysis patients, paricalcitol treatment has comparable ≥50% reduction of parathyroid hormone (risk ratio [RR] = 1.33; 95% CI = 0.93-1.91; P = 0.12), calcium concentration (standard mean difference [Std. MD] = -0.21; 95% CI = -0.94 to 0.52; P = 0.58), phosphate concentration (Std. MD = -0.17; 95% CI = -0.58 to 0.24; P = 0.42), calcium phosphate (Std. MD = -0.08; 95% CI = -0.49-0.34; P = 0.71), alkaline phosphatase (Std. MD = -0.21; 95% CI = -0.73-0.31; P = 0.43), hypercalcemia (RR = 1.43; 95% CI = 0.51 to 3.98; P = 0.49), adverse events (RR = 0.79; 95% CI = 0.42-1.49; P = 0.47), and serious adverse events (RR = 0.78; 95% CI = 0.47-1.30; P = 0.33). Paricalcitol and calcitriol result in similar ≥50% reduction of parathyroid hormone, calcium concentration, phosphate concentration, calcium phosphate, alkaline phosphatase, hypercalcemia, adverse events, and serious adverse events for secondary hyperparathyroidism in dialysis patients.
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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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Comparison between paricalcitol and active non-selective vitamin D receptor activator for secondary hyperparathyroidism in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.
Cai, P, Tang, X, Qin, W, Ji, L, Li, Z
International urology and nephrology. 2016;(4):571-84
Abstract
PURPOSE The goal of this systematic review is to evaluate the efficacy and safety of paricalcitol versus active non-selective vitamin D receptor activators (VDRAs) for secondary hyperparathyroidism (SHPT) management in chronic kidney disease (CKD) patients. METHODS PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), clinicaltrials.gov (inception to September 2015), and ASN Web site were searched for relevant studies. A meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs that assessed the effects and adverse events of paricalcitol and active non-selective VDRA in adult CKD patients with SHPT was performed using Review Manager 5.2. RESULTS A total of 10 trials involving 734 patients were identified for this review. The quality of included trials was limited, and very few trials reported all-cause mortality or cardiovascular calcification without any differences between two groups. Compared with active non-selective VDRAs, paricalcitol showed no significant difference in both PTH reduction (MD -7.78, 95% CI -28.59-13.03, P = 0.46) and the proportion of patients who achieved the target reduction of PTH (OR 1.27, 95% CI 0.87-1.85, P = 0.22). In addition, no statistical differences were found in terms of serum calcium, episodes of hypercalcemia, serum phosphorus, calcium × phosphorus products, and bone metabolism index. CONCLUSIONS Current evidence is insufficient, showing paricalcitol is superior to active non-selective VDRAs in lowering PTH or reducing the burden of mineral loading. Further trials are required to prove the tissue-selective effect of paricalcitol and to overcome the limitation of current research.
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Nutritional vitamin D supplementation and health-related outcomes in hemodialysis patients: a protocol for a systematic review and meta-analysis.
Mehrotra, A, Leung, WY, Joson, T
Systematic reviews. 2015;:13
Abstract
BACKGROUND The prevalence of vitamin D deficiency in hemodialysis patients is high. While most hemodialysis patients are treated with activated vitamin D (1,25[OH]2D) to prevent renal osteodystrophy, clinical practices of the screening and treatment of 25(OH)2D deficiency are highly variable. It is unclear if nutritional vitamin D supplementation with D2 or D3 provides an additional clinical benefit beyond that provided by activated vitamin D treatment in this population. METHODS/DESIGN We will conduct a systematic review of nutritional vitamin D (D2/D3) supplementation and health-related outcomes in hemodialysis patients according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary objective is to assess the impact of nutritional vitamin D supplementation on clinical outcomes relevant in hemodialysis patients, such as mortality, cardiovascular events, infections, and fractures. Secondary outcomes will include anemia, hyperparathyroidism, medication use (erythrocyte-stimulating agents, activated vitamin D), and quality of life. We will search MEDLINE, Scopus, Web of Science, and ClinicalTrials.gov for randomized, controlled trials of nutritional vitamin D supplementation (ergocalciferol/D2 or cholecalciferol/D3) in chronic hemodialysis patients. The Cochrane Risk Assessment Tool will be used to assess the quality of eligible studies. We will perform meta-analyses using standard techniques for the outcomes listed above if pooling is deemed appropriate/sufficient. The results of this systematic review may highlight gaps in our knowledge of the relevance of nutritional vitamin D in end-stage renal disease, allowing for the informed design of clinical trials assessing the impact of nutritional vitamin D therapy in the hemodialysis population in the future. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42014013931.
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Vitamin D supplementation for prevention of mortality in adults.
Bjelakovic, G, Gluud, LL, Nikolova, D, Whitfield, K, Wetterslev, J, Simonetti, RG, Bjelakovic, M, Gluud, C
The Cochrane database of systematic reviews. 2014;(1):CD007470
Abstract
BACKGROUND Available evidence on the effects of vitamin D on mortality has been inconclusive. In a recent systematic review, we found evidence that vitamin D3 may decrease mortality in mostly elderly women. The present systematic review updates and reassesses the benefits and harms of vitamin D supplementation used in primary and secondary prophylaxis of mortality. OBJECTIVES To assess the beneficial and harmful effects of vitamin D supplementation for prevention of mortality in healthy adults and adults in a stable phase of disease. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index-Expanded and Conference Proceedings Citation Index-Science (all up to February 2012). We checked references of included trials and pharmaceutical companies for unidentified relevant trials. SELECTION CRITERIA Randomised trials that compared any type of vitamin D in any dose with any duration and route of administration versus placebo or no intervention in adult participants. Participants could have been recruited from the general population or from patients diagnosed with a disease in a stable phase. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)) or as an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS Six review authors extracted data independently. Random-effects and fixed-effect meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RRs). To account for trials with zero events, we performed meta-analyses of dichotomous data using risk differences (RDs) and empirical continuity corrections. We used published data and data obtained by contacting trial authors.To minimise the risk of systematic error, we assessed the risk of bias of the included trials. Trial sequential analyses controlled the risk of random errors possibly caused by cumulative meta-analyses. MAIN RESULTS We identified 159 randomised clinical trials. Ninety-four trials reported no mortality, and nine trials reported mortality but did not report in which intervention group the mortality occurred. Accordingly, 56 randomised trials with 95,286 participants provided usable data on mortality. The age of participants ranged from 18 to 107 years. Most trials included women older than 70 years. The mean proportion of women was 77%. Forty-eight of the trials randomly assigned 94,491 healthy participants. Of these, four trials included healthy volunteers, nine trials included postmenopausal women and 35 trials included older people living on their own or in institutional care. The remaining eight trials randomly assigned 795 participants with neurological, cardiovascular, respiratory or rheumatoid diseases. Vitamin D was administered for a weighted mean of 4.4 years. More than half of the trials had a low risk of bias. All trials were conducted in high-income countries. Forty-five trials (80%) reported the baseline vitamin D status of participants based on serum 25-hydroxyvitamin D levels. Participants in 19 trials had vitamin D adequacy (at or above 20 ng/mL). Participants in the remaining 26 trials had vitamin D insufficiency (less than 20 ng/mL).Vitamin D decreased mortality in all 56 trials analysed together (5,920/47,472 (12.5%) vs 6,077/47,814 (12.7%); RR 0.97 (95% confidence interval (CI) 0.94 to 0.99); P = 0.02; I(2) = 0%). More than 8% of participants dropped out. 'Worst-best case' and 'best-worst case' scenario analyses demonstrated that vitamin D could be associated with a dramatic increase or decrease in mortality. When different forms of vitamin D were assessed in separate analyses, only vitamin D3 decreased mortality (4,153/37,817 (11.0%) vs 4,340/38,110 (11.4%); RR 0.94 (95% CI 0.91 to 0.98); P = 0.002; I(2) = 0%; 75,927 participants; 38 trials). Vitamin D2, alfacalcidol and calcitriol did not significantly affect mortality. A subgroup analysis of trials at high risk of bias suggested that vitamin D2 may even increase mortality, but this finding could be due to random errors. Trial sequential analysis supported our finding regarding vitamin D3, with the cumulative Z-score breaking the trial sequential monitoring boundary for benefit, corresponding to 150 people treated over five years to prevent one additional death. We did not observe any statistically significant differences in the effect of vitamin D on mortality in subgroup analyses of trials at low risk of bias compared with trials at high risk of bias; of trials using placebo compared with trials using no intervention in the control group; of trials with no risk of industry bias compared with trials with risk of industry bias; of trials assessing primary prevention compared with trials assessing secondary prevention; of trials including participants with vitamin D level below 20 ng/mL at entry compared with trials including participants with vitamin D levels equal to or greater than 20 ng/mL at entry; of trials including ambulatory participants compared with trials including institutionalised participants; of trials using concomitant calcium supplementation compared with trials without calcium; of trials using a dose below 800 IU per day compared with trials using doses above 800 IU per day; and of trials including only women compared with trials including both sexes or only men. Vitamin D3 statistically significantly decreased cancer mortality (RR 0.88 (95% CI 0.78 to 0.98); P = 0.02; I(2) = 0%; 44,492 participants; 4 trials). Vitamin D3 combined with calcium increased the risk of nephrolithiasis (RR 1.17 (95% CI 1.02 to 1.34); P = 0.02; I(2) = 0%; 42,876 participants; 4 trials). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18 (95% CI 1.17 to 8.68); P = 0.02; I(2) = 17%; 710 participants; 3 trials). AUTHORS' CONCLUSIONS Vitamin D3 seemed to decrease mortality in elderly people living independently or in institutional care. Vitamin D2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium increased nephrolithiasis. Both alfacalcidol and calcitriol increased hypercalcaemia. Because of risks of attrition bias originating from substantial dropout of participants and of outcome reporting bias due to a number of trials not reporting on mortality, as well as a number of other weaknesses in our evidence, further placebo-controlled randomised trials seem warranted.