A 3 year post-intervention follow-up on mortality in advanced heart failure (EVITA vitamin D supplementation trial).

AIMS: Vitamin D supplementation is widely used in the clinical setting, but its effects on mortality and cardiovascular outcomes in patients with heart failure are unclear. This paper reports outcome data that were collected during follow-up of 3 years after closure of the EVITA trial (a 3 year randomized, placebo-controlled, intervention study with 4000 IU vitamin D daily in patients with advanced heart failure), to capture potential latency effects of vitamin D supplementation on clinical outcomes. METHODS AND RESULTS: The prespecified primary endpoint was overall mortality. Secondary endpoints included hospitalization, mechanical circulatory support implantation, high urgent listing for heart transplantation, and heart transplantation. For group comparisons, we used Cox regression models with a time-dependent categorical covariate. The calculated net difference in circulating 25-hydroxyvitamin D between the vitamin D and placebo groups dropped from 60.9 nmol/L at the end of the active study period to 3.2 nmol/L at the end of the post-intervention period. During the entire 6 year period, 73 patients (36.5%) died in the placebo group and 76 (38.8%) in the vitamin D group. Out of these 149 patients, 36 and 39 died during the first 3 years, and 37 and 37 during the second 3 years, respectively. The hazard ratio (HR) for mortality in the vitamin D versus the placebo group was 1.06 [95% confidence interval (CI): 0.68-1.66] for the first 3 years and 1.07 (95% CI: 0.68-1.70) for the 3 year post-intervention follow-up. Compared with the placebo group, the HRs for hospitalization and for mechanical circulatory support implant were significantly higher in the vitamin D group during vitamin D supplementation (HR = 1.31, 95% CI: 1.01-1.68 and HR = 2.01, 95% CI: 1.08-3.76, respectively) but not after vitamin D discontinuation (HR = 1.10, 95% CI: 0.62-1.94 and HR = 0.99, 95% CI: 0.38-2.56, respectively). There was no significant time-dependent effect on the risk of high urgent listing for heart transplantation and heart transplantation. CONCLUSIONS: No beneficial latency effects of vitamin D supplementation on overall mortality could be demonstrated. Instead, the disappearance of unfavourable findings in the vitamin D group (higher HRs for hospitalization and for mechanical circulatory support implant) after vitamin D discontinuation supports the assumption of adverse vitamin D effects on the cardiovascular system at doses of 4000 IU daily.

Role of Vitamin D in Preventing and Treating Selected Extraskeletal Diseases-An Umbrella Review.

Evidence is accumulating that vitamin D may have beneficial effects on respiratory tract, autoimmune, neuro-degenerative, and mental diseases. The present umbrella review of systematic reviews (SRs) of cohort studies and randomised controlled trials (RCTs), plus single Mendelian randomisation studies aims to update current knowledge on the potential role of vitamin D in preventing and treating these extraskeletal diseases. Altogether, 73 SRs were identified. Observational data on primary prevention suggest an inverse association between vitamin D status and the risk of acute respiratory tract infections (ARI), dementia and cognitive decline, and depression, whereas studies regarding asthma, multiple sclerosis (MS), and type 1 diabetes mellitus (T1DM) are scarce. SRs of RCTs support observational data only for the risk of ARI. No respective RCTs are available for the prevention of chronic obstructive pulmonary disease (COPD), MS, and T1DM. SRs of RCTs indicate beneficial therapeutic effects in vitamin D-deficient patients with asthma and COPD, while effects on major depression and T1DM need to be further elucidated. Mendelian randomisation studies do not consistently support the results of SRs. Since several limitations of the included SRs and existing RCTs do not permit definitive conclusions regarding vitamin D and the selected diseases, further high-quality RCTs are warranted.

Vitamin D supplementation does not prevent the testosterone decline in males with advanced heart failure: the EVITA trial.

PURPOSE: Observational studies indicate a positive association between circulating 25-hydroxyvitamin D (25OHD) and testosterone (T) concentrations. Because low 25OHD concentrations and T deficiency are considered to be a generalized phenomenon in patients with advanced heart failure (HF), we aimed to investigate whether vitamin D supplementation has beneficial effects on T indices in these patients. METHODS: In a pre-specified secondary analysis of the EVITA (effect of vitamin D on mortality in heart failure) randomized controlled trial, we analyzed in male subjects with 25OHD concentrations < 75 nmol/L the effect of a daily vitamin D3 supplement of 4000 IU for 3 years (n = 71) vs. placebo (n = 62) on total T (TT), sex hormone-binding globulin (SHBG), free T (fT), and bioactive T (BAT). We assessed changes from baseline until study termination and between-group differences at study termination. RESULTS: 25OHD increased in the placebo group from 36.6 nmol/L by 9.2 nmol/L (95% CI 3.2-15.1 nmol/L; P = 0.003) and in the vitamin D group from 36.5 nmol/L by 63.9 nmol/L (95% CI 52.6-75.3 nmol/L; P < 0.001), with a significant between-group difference at study termination (P < 0.001). TT and SHBG concentrations did not change significantly, neither in the placebo group nor in the vitamin D group (P = 0.845-0.082), but concentrations of fT and BAT declined significantly in both groups (P = 0.025-0.008). At study termination, there were no between-group differences in TT (P = 0.612), SHBG (P = 0.393), fT (P = 0.861), or BAT (P = 0.960). CONCLUSIONS: In male patients with advanced HF and low 25OHD concentrations, a daily vitamin D3 supplement of 4000 IU for 3 years did not prevent the decline in testosterone indices.

Daily Supplementation with 4000 IU Vitamin D3 for Three Years Does Not Modify Cardiovascular Risk Markers in Patients with Advanced Heart Failure: The Effect of Vitamin D on Mortality in Heart Failure Trial.

BACKGROUND/AIMS: We aimed to investigate the effect of a moderately high vitamin D dose on lipid parameters and biochemical markers of vascular calcification (VC) in patients with established cardiovascular disease. METHODS: We included in this pre-specified secondary analysis of a randomized controlled trial 161 patients with advanced heart failure and 25-hydroxyvitamin D (25OHD) concentrations < 75 nmol/L (vitamin D group: n = 80; placebo group: n = 81), who received a daily vitamin D3 supplement of 4,000 IU for 3 years. We assessed between-group differences of the lipid parameters total-cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and triglycerides, and the VC markers fetuin-A and non-phosphorylated undercarboxylated matrix gla protein (MGP) at study termination, with adjustment for baseline values. RESULTS: Lipid parameters, the percentage of patients with dyslipoproteinemia, and VC markers did not differ significantly between groups at study termination (p values: 0.395-0.939). Likewise, vitamin D achieved no significant treatment effect on these markers in subgroup analyses in patients with 25OHD concentrations < 30 nmol/L, nonusers of lipid-lowering drugs, or diabetic patients (p values: 0.245-0.998). CONCLUSION: Our data indicate that vitamin D does not improve the lipid profile and does not influence the calcification inhibitors fetuin-A and non-phosphorylated undercarboxylated MGP in patients with advanced heart failure.

Effects of Vitamin D Supplementation on Renin and Aldosterone Concentrations in Patients with Advanced Heart Failure: The EVITA Trial.

OBJECTIVE: 1,25-Dihydroxyvitamin D (1,25([OH]2D) is considered to be a negative endogenous regulator of the renin-angiotensin-aldosterone system (RAAS), but the effect of vitamin D supplementation on the RAAS is inconclusive. DESIGN: In this prespecified secondary analysis of a randomized controlled trial, we assessed in 165 patients with heart failure (vitamin D group: n = 83; placebo group: n = 82) the effect of three years of vitamin D supplementation with 4000 IU daily on parameters of the RAAS (renin and aldosterone) and on circulating 1,25(OH)2D, plasma phosphate, and fibroblast growth factor (FGF)-23. We assessed age- and baseline-adjusted between-group differences at study termination. RESULTS: Almost all patients were under treatment with beta-blockers, inhibitors of the RAAS, and diuretics. Initially, the frequency of concentrations above the laboratory-specific reference range (renin: >23.9 mIU/L; aldosterone: >232 ng/L) in the vitamin D and placebo group was 87.7% and 92.7%, respectively (renin), and 24.1% and 32.5%, respectively (aldosterone). Vitamin D increased adjusted 1,25(OH)2D concentrations significantly (mean treatment effect and 95% CI: 18.3 pmol/L,7.3 to 29.3 pmol/L; P < 0.001) but had no significant effects on phosphate (0.18 mmol/L, -0.00 to 0.35 mmol/L; P = 0.051), FGF-23 (685 RU/mL, -213 to 1585 RU/mL; P = 0.134), renin (312 mIU/L, -279 to 902 ng/L; P = 0.298), or aldosterone (-0.19 ng/L, -5.09 to 4.70 ng/L; P = 0.938). Vitamin D supplementation was, however, associated with an increase in renin concentrations in the subgroup with baseline 25-hydroxyvitamin D below 30 nmol/L (n = 67; 1365 mIU/, 343 to 2386 mIU/L; P = 0.010). CONCLUSIONS: In patients with advanced heart failure treated according to evidence-based guidelines, vitamin D supplementation did not significantly influence parameters of the RAAS in the entire study cohort but was associated with an increase in plasma renin concentrations in the subgroup with low baseline 25-hydroxyvitamin D concentrations.

Effect of vitamin D on all-cause mortality in heart failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily.

AIMS: Circulating 25-hydroxyvitamin D (25OHD) levels <75 nmol/L are associated with a nonlinear increase in mortality risk. Such 25OHD levels are common in heart failure (HF). We therefore examined whether oral vitamin D supplementation reduces mortality in patients with advanced HF. METHODS AND RESULTS: Four hundred HF patients with 25OHD levels <75 nmol/L were randomized to receive 4000 IU vitamin D daily or matching placebo for 3 years. Primary endpoint was all-cause mortality. Key secondary outcome measures included hospitalization, resuscitation, mechanical circulatory support (MCS) implant, high urgent listing for heart transplantation, heart transplantation, and hypercalcaemia. Initial 25OHD levels were on average <40 nmol/L, remained around 40 nmol/L in patients assigned to placebo and plateaued around 100 nmol/L in patients assigned to vitamin D. Mortality was not different in patients receiving vitamin D (19.6%; n = 39) or placebo (17.9%; n = 36) with a hazard ratio (HR) of 1.09 [95% confidence interval (CI): 0.69-1.71; P = 0.726]. The need for MCS implant was however greater in patients assigned to vitamin D (15.4%, n = 28) vs. placebo [9.0%, n = 15; HR: 1.96 (95% CI: 1.04-3.66); P = 0.031]. Other secondary clinical endpoints were similar between groups. The incidence of hypercalcaemia was 6.2% (n = 10) and 3.1% (n = 5) in patients receiving vitamin D or placebo (P = 0.192). CONCLUSION: A daily vitamin D dose of 4000 IU did not reduce mortality in patients with advanced HF but was associated with a greater need for MCS implants. Data indicate caution regarding long-term supplementation with moderately high vitamin D doses. TRIAL REGISTRATION INFORMATION: clinicaltrials.gov Idenitfier: NCT01326650.

Calciotropic and Phosphaturic Hormones in End-Stage Heart Failure Patients Supported by a Left-Ventricular Assist Device.

BACKGROUND: Calcium and phosphate are central for myocardial contractility and energy metabolism, and low levels of the calciotropic hormone 1,25-dihydroxyvitamin D (1,25(OH)2D), as well as high levels of the phosphaturic hormone fibroblast growth factor (FGF)-23, are independently associated with poor clinical outcome in heart failure (HF) patients. We therefore aimed to investigate the postoperative time course of the aforementioned hormones in HF patients supported with a left-ventricular assist device (LVAD) implant. METHODS: For the present study, stored biobank plasma samples of 69 patients, collected before LVAD implantation (t0) and 12 days (t1), 30 days (t2), 83 days (t3), and 300 days (t4) post-intervention, were used to measure circulating FGF-23, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), 1,25(OH)2D, and kidney function. RESULTS: Most patients were male and had baseline INTERMACS levels and cardiac index values ≤ 3 and ≤ 2.7 L/min/m2, respectively. There were significant time effects on estimated glomerular filtration rate (eGFR), FGF-23 and 1,25(OH)2D, but not on PTH or 25OHD. Notably, eGFR values increased and FGF-23 levels decreased only transiently, whereas 1,25(OH)2D increased continuously until t4. The rise in 1,25(OH)2D was largely influenced by those patients who survived the first post-implant year, and was not seen in non-survivors. Variations in 1,25(OH)2D levels could only partly be explained by eGFR values or FGF-23, 25OHD, and PTH levels (multiple R2 = 0.305;P<0.001). CONCLUSIONS: The present study indicates that LVAD implantation has only transient effects on circulating FGF-23 levels, but is associated with a continuous increase in circulating 1,25(OH)2D levels, especially in survivors.

Circulating 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Concentrations and Postoperative Infections in Cardiac Surgical Patients: The CALCITOP-Study.

BACKGROUND: Vitamin D has immunomodulatory properties and seems to reduce the risk of infections. Whether low vitamin D concentrations are independent risk factors for nosocomial postoperative infections in surgical patients remains to be studied in detail. METHODS: In 3,340 consecutive cardiac surgical patients, we investigated the association of circulating 25-hydroxyvitamin D (25OHD; indicator of nutritional vitamin D status) and 1,25-dihydroxyvitamin D (1,25[OH]2D; active vitamin D hormone) with nosocomicial infections. The primary endpoint was a composite of thoracic wound infection, sepsis, and broncho-pulmonary infection. Vitamin D status was measured on the last preoperative day. Infections were assessed until discharge. Logistic regression analysis was used to examine the association between vitamin D metabolite concentrations and the composite endpoint. RESULTS: The primary endpoint was reached by 5.6% (n = 186). In patients who reached and did not reach the endpoint, in-hospital mortality was 13.4% and 1.5%, respectively (P<0.001). Median (IQR) 25OHD and 1,25(OH)2D concentrations were 43. 2 (29.7-61.9) nmol/l and 58.0 (38.5-77.5) pmol/l, respectively. Compared with the highest 1,25(OH)2D quintile (>81.0 pmol/l), the multivariable-adjusted odds ratio of infection was 2.57 (95%CI:1.47-4.49) for the lowest 1,25(OH)2D quintile (<31.5 pmol/l) and 1.85 (95%CI:1.05-3.25) for the second lowest quintile (31.5-49.0 pmol/l). There was no significant association between 25OHD concentrations and the primary endpoint. CONCLUSIONS: Our data indicate an independent association of low 1,25(OH)2D levels with the risk of postoperative infections in cardiac surgical patients. Future studies should pay more attention on the clinical relevance of circulating 1,25(OH)2D and its regulation.

Measurement of Circulating 1,25-Dihydroxyvitamin D: Comparison of an Automated Method with a Liquid Chromatography Tandem Mass Spectrometry Method.

Background. The clinical relevance of circulating 1,25-dihydroxyvitamin D (1,25(OH)2D) is probably underappreciated, but variations in the measurement of this difficult analyte between different methods limit comparison of results. Methods. In 129 clinical samples, we compared a new automated assay with a commercially available liquid chromatography tandem mass spectrometry (LC-MS/MS) kit. Results. Median (interquartile range) 1,25(OH)2D concentrations with the automated assay and the LC-MS/MS method were 26.6 pg/mL (18.5-39.0 pg/mL) and 23.6 pg/mL (16.1-31.3 pg/mL), respectively (P = 0.001). Using the method-specific cut-offs for deficient 1,25(OH)2D levels (<20 pg/mL for the automated assay and <17 pg/mL for the LC-MS/MS method), the percentage of patients classified as 1,25(OH)2D deficient was 28.7% and 27.1%, respectively. However, concordance between the two methods for deficient levels was only 62% and the concordance correlation coefficient was poor (0.534). The regression equation resulted in an intercept of -1.99 (95% CI: -7.33-1.31) and a slope of 1.27 (95% CI: 1.04-1.52) for the automated assay. The mean bias with respect to the mean of the two methods was -3.8 (1.96 SD: -28.3-20.8) pg/mL for the LC-MS/MS method minus the automated assay. Conclusions. The two methods show only modest correlation and further standardization is required to improve reliability and comparability of 1,25(OH)2D test procedures.

Vitamin D Supplementation and Hemoglobin Levels in Hypertensive Patients: A Randomized Controlled Trial.

Epidemiological evidence suggests that circulating 25-hydroxyvitamin D (25OHD) levels are inversely associated with hemoglobin (Hb) levels and anemia risk. We evaluated whether vitamin D supplementation improves Hb levels and reduces anemia risk in hypertensive patients. Two hundred patients with 25OHD levels <75 nmol/L who attended the Styrian Vitamin D Hypertension Trial were included, of whom 188 completed the trial. Patients randomly received 2800 IU vitamin D3 daily or a matching placebo for eight weeks. Initially, the prevalence of anemic status (Hb levels <12.5 g/dL) and deficient 25OHD levels (<30 nmol/L) was 6.5% and 7.5%, respectively. All anemic patients had 25OHD levels >50 nmol/L. The mean (95% confidence interval) vitamin D effect on Hb levels was 0.04 (-0.14 to 0.22) g/dL (P = 0.661). Moreover, vitamin D treatment did not influence anemic status significantly (P > 0.999). Likewise, vitamin D had no significant effect on Hb levels in the subgroups of anemic patients or in patients with initial 25OHD levels <30 nmol/L. In conclusion, a daily vitamin D supplement of 2800 IU for eight weeks did not improve Hb levels or anemic status in hypertensive patients. Future trials should focus on anemic patients with deficient 25OHD levels (e.g., <30 nmol/L). This trial is registered with clinicaltrials.gov [NCT02136771].

Effect of Vitamin D or Activated Vitamin D on Circulating 1,25-Dihydroxyvitamin D Concentrations: A Systematic Review and Metaanalysis of Randomized Controlled Trials.

BACKGROUND: Evidence is accumulating that circulating 1,25-dihydroxyvitamin D [1,25(OH)2D] concentrations are inversely related to overall mortality. METHODS: We searched PubMed, Embase and ISI Web of Science for randomized controlled trials with a control group receiving a placebo instead of vitamin D/activated vitamin D and performed a metaanalysis to evaluate the effect of oral vitamin D/activated vitamin D on circulating 1,25(OH)2D concentrations using a random effects model. RESULTS: We included 52 vitamin D intervention groups (4796 individuals) and 14 intervention groups with activated vitamin D (668 individuals). Vitamin D supplements increased circulating 1,25(OH)2D by 12.2 pmol/L (95% CI, 7.8-16.5 pmol/L) and 18.8 pmol/L (95% CI, 9.2-28.4 pmol/L) if only studies with a low risk of bias in study design and reporting were considered (n = 18). There was significant heterogeneity among studies (Cohran's Q P < 0.001, I(2) = 91%). The incremental effect was larger in studies using vitamin D alone compared with coadministration of calcium supplements (18.6 pmol/L; 95% CI, 12.7-24.4 pmol/L vs 4.9 pmol/L; 95% CI, -0.4 to 10.2 pmol/L; P = 0.001), and if quantification was performed with RIA vs other methods (17.1 pmol/L; 95% CI, 11.1-23.1 pmol/L vs 6.9 pmol/L; 95% CI, 1.0-12.8 pmol/L; P = 0.02). Activated vitamin D increased the mean circulating 1,25(OH)2D by 20.5 pmol/L (95% CI, 8.3-32.7 pmol/L; P = 0.04). Again, there was evidence for significant heterogeneity among studies (Cochran Q = 85.4; P < 0.001; I(2) = 87%), but subgroup analysis did not identify parameters significantly influencing the increment in 1,25(OH)2D concentrations. CONCLUSIONS: Both vitamin D and activated vitamin D significantly increase circulating 1,25(OH)2D concentrations, but in vitamin D users this increase is suppressed by calcium coadministration.

Independent association of circulating vitamin D metabolites with anemia risk in patients scheduled for cardiac surgery.

BACKGROUND: Preoperative anemia is considered an independent risk factor of poor clinical outcome in cardiac surgical patients. Low vitamin D status may increase anemia risk. METHODS: We investigated 3,615 consecutive patients scheduled for cardiac surgery to determine the association between preoperative anemia (hemoglobin [Hb] <12.5 g/dL) and circulating levels of the vitamin D metabolites 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25[OH]2D). RESULTS: Of the study cohort, 27.8 % met the criteria for anemia. In patients with deficient 25OHD levels (<30 nmol/l) mean Hb concentrations were 0.5 g/dL lower than in patients with adequate 25OHD levels (50.0-125 nmol/l; P<0.001). Regarding 1,25(OH)2D, mean Hb concentrations were 1.2 g/dL lower in the lowest 1,25(OH)2D category (<40 pmol/l) than in the highest 1,25(OH)2D category (>70 pmol/l; P<0.001). In multivariable-adjusted logistic regression analyses, the odds ratios for anemia of the lowest categories of 25OHD and 1,25(OH)2D were 1.48 (95%CI:1.19-1.83) and 2.35 (95%CI:1.86-2.97), compared with patients who had adequate 25OHD levels and 1,25(OH)2D values in the highest category, respectively. Anemia risk was greatest in patients with dual deficiency of 25OHD and 1,25(OH)2D (multivariable-adjusted OR = 3.60 (95%CI:2.40-5.40). Prevalence of deficient 25OHD levels was highest in anemia of nutrient deficiency, whereas low 1,25(OH)2D levels were most frequent in anemia of chronic kidney disease. CONCLUSION: This cross-sectional study demonstrates an independent inverse association between vitamin D status and anemia risk. If confirmed in clinical trials, preoperative administration of vitamin D or activated vitamin D (in case of chronic kidney disease) would be a promising strategy to prevent anemia in patients scheduled for cardiac surgery.

25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and postoperative outcome in cardiac surgery.

CONTEXT: Several cohort studies have reported U-shaped or inverse J-shaped associations between circulating 25-hydroxyvitamin D [25OHD] and clinical outcomes. OBJECTIVE: We aimed to investigate in cardiac surgical patients the association of preoperative 25OHD and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels with the risk of major adverse cardiac and cerebrovascular events (MACCE). DESIGN: A prospective cohort study of adult cardiac surgical patients in 2012-2013 was used. SETTING: The study was conducted at the Heart and Diabetes Center North Rhine-Westphalia, Germany. PATIENTS: A total of 3371 adult patients participated in the study. INTERVENTION: None Measurements: The main outcome measure was MACCE until discharge. We categorized vitamin D metabolite levels into subgroups and performed multivariable-adjusted logistic regression analysis to estimate odds ratios (ORs) of MACCE. Moreover, we performed multiple regression analysis to assess the association of 25OHD and circulating 1,25(OH)2D3 with preoperative parameters. RESULTS: As compared with patients in the 25OHD reference category (75-100 nmol/L), the multivariable-adjusted odds ratios (OR) of MACCE was significantly higher in patients with deficient 25OHD levels (< 30 nmol/L) (OR = 2.06 [95%CI: 1.24-3.43]), but was comparable in patients with 25OHD levels > 100 nmol/L (OR = 1.16 [95% CI: 0.56-2.37]). Poor kidney function was an important predictor of high 25OHD (>100 nmol/L) and low 1,25(OH)2D3 levels. 1,25(OH)2D3 was not independently associated with the incidence of MACCE. CONCLUSIONS: In cardiac surgical patients, deficient but not high 25OHD levels are independently associated with the risk of MACCE. Cohort studies should consider potential interrelationships between kidney function, circulating vitamin D metabolite levels, and clinical outcome.

Vitamin D supplementation, body weight and human serum 25-hydroxyvitamin D response: a systematic review.

PURPOSE: There is considerable variation in incremental circulating 25-hydroxyvitamin D (25OHD) levels on vitamin D supplements, even when similar age groups and identical vitamin D doses are compared. We therefore aimed to investigate the importance of body weight for the dose-response relation in circulating 25OHD. METHODS: We performed a systematic review of randomized placebo-controlled vitamin D supplementation trials in all age groups ≥10 years to clarify the influence of body weight and other parameters on incremental circulating 25OHD levels (difference between baseline and in-study values) in vitamin D-deficient and non-deficient individuals. RESULTS: We included 144 cohorts from 94 independent studies, published from 1990 to November 2012, in our systematic review. There was a logarithmic association between vitamin D dose per kg body weight per day and increment in circulating 25OHD. In multivariable regression analysis, vitamin D dose per kg body weight per day could explain 34.5% of variation in circulating 25OHD. Additional significant predictors were type of supplement (vitamin D2 or vitamin D3), age, concomitant intake of calcium supplements and baseline 25OHD, explaining 9.8, 3.7, 2.4 and 1.9%, respectively, of the variation in circulating 25OHD. CONCLUSIONS: This systematic review demonstrates that body weight is an important predictor of variation in circulating 25OHD in cohorts on vitamin D supplements. Our model provides an estimate of the daily vitamin D dose that is necessary for achieving adequate circulating 25OHD levels in vitamin D-insufficient or vitamin D-deficient individuals/cohorts with different body weights and ages.