Classification of Vitamin D Status Based on Vitamin D Metabolism: A Randomized Controlled Trial in Hypertensive Patients.

Circulating 25-hydroxyvitamin D (25(OH)D) is the generally accepted indicator of vitamin D status. Since hydroxylation of 25(OH)D to 24-25-dihydroxyvitamin D (24,25(OH)2D) is the first step of its catabolism, it has been suggested that a low 24,25(OH)D level and a low vitamin D metabolite ratio (VMR), i.e., 24,25(OH)2D divided by 25(OH)D, may indicate high vitamin D requirements and provide additional diagnostic information beyond serum 25(OH)D. We, therefore, evaluated whether the classification of "functional vitamin D deficiency", i.e., 25(OH)D below 50 nmol/L, 24,25(OH)2D below 3 nmol/L and a VMR of less than 4%, identifies individuals who benefit from vitamin D supplementation. In participants of the Styrian Vitamin D Hypertension trial, a randomized controlled trial (RCT) in 200 hypertensive patients with serum 25(OH)D below 75 nmol/L, who received either 2.800 international units of vitamin D per day or placebo over 8 weeks, 51 participants had functional vitamin D deficiency. In these individuals, there was no treatment effect of vitamin D supplementation on various parameters of bone metabolism and cardiovascular risk except for a significant effect on parathyroid hormone (PTH) and expected changes in vitamin D metabolites. In conclusion, a low vitamin D metabolite profile did not identify individuals who significantly benefit from vitamin D supplementation with regard to bone markers and cardiovascular risk factors. The clinical significance of functional vitamin D deficiency requires further evaluation in large vitamin D RCTs.

Long-term supplementation with 3200 to 4000 IU of vitamin D daily and adverse events: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The upper tolerable intake level for vitamin D in the general population has been set at 4000 international units (IU) daily, but considerable uncertainty remains. We summarized reported harmful effects of a daily vitamin D supplement of 3200-4000 IU in trials lasting ≥ 6 months. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials in several databases and identified 22 trials reporting safety data. Parameters of calcium metabolism, falls, hospitalization, and mortality were assessed. RESULTS: The selected trials comprised a total number of 12,952 participants. All trials used supplemental vitamin D3. The relative risk (RR) of hypercalcemia in the vitamin D vs. control arm was 2.21 (95%CI: 1.26-3.87; 10 studies), with a vitamin D-induced frequency of hypercalcemia of 4 cases per 1000 individuals. Subgroup analysis in trials with > 100 and ≤ 100 study participants revealed an RR of 2.63 (95%CI: 1.30-5.30; 7 studies) and 0.80 (95%CI: 0.24-2.62; 3 studies), respectively (Pinteraction = 0.06). Risks of falls and hospitalization were also significantly increased in the vitamin D arm with an RR of 1.25 (95%CI: 1.01-1.55; 4 studies) and 1.16 (95%CI: 1.01-1.33; 7 studies), respectively. Risks of hypercalciuria, kidney stones, and mortality did not differ significantly between study arms. Quality assessment revealed high risk of incomplete reporting of safety-related outcome data. CONCLUSION: Supplemental vitamin D doses of 3200-4000 IU/d appear to increase the risk of hypercalcemia and some other adverse events in a small proportion of individuals, indicating that this dose is not completely safe. In future studies, rigorous reporting of safety-related outcomes is needed when using moderately high doses of vitamin D.

Hypercalcemia in Pregnancy Due to CYP24A1 Mutations: Case Report and Review of the Literature.

Pathogenic mutations of CYP24A1 lead to an impaired catabolism of vitamin D metabolites and should be considered in the differential diagnosis of hypercalcemia with low parathyroid hormone concentrations. Diagnosis is based on a reduced 24,25-dihydroxyvitamin D to 25-hydroxyvitamin D ratio and confirmed by genetic analyses. Pregnancy is associated with an upregulation of the active vitamin D hormone calcitriol and may thus particularly trigger hypercalcemia in affected patients. We present a case report and a narrative review of pregnant women with CYP24A1 mutations (13 women with 29 pregnancies) outlining the laboratory and clinical characteristics during pregnancy and postpartum and the applied treatment approaches. In general, pregnancy triggered hypercalcemia in the affected women and obstetric complications were frequently reported. Conclusions on drugs to treat hypercalcemia during pregnancy are extremely limited and do not show clear evidence of efficacy. Strictly avoiding vitamin D supplementation seems to be effective in preventing or reducing the degree of hypercalcemia. Our case of a 24-year-old woman who presented with hypercalcemia in the 24th gestational week delivered a healthy baby and hypercalcemia resolved while breastfeeding. Pathogenic mutations of CYP24A1 mutations are rare but should be considered in the context of vitamin D supplementation during pregnancy.

Effects of Vitamin D Supplementation on 24-Hour Blood Pressure in Patients with Low 25-Hydroxyvitamin D Levels: A Randomized Controlled Trial.

Accumulating evidence suggests that potential cardiovascular benefits of vitamin D supplementation may be restricted to individuals with very low 25-hydroxyvitamin D (25(OH)D) concentrations; the effect of vitamin D on blood pressure (BP) remains unclear. We addressed this issue in a post hoc analysis of the double-blind, randomized, placebo-controlled Styrian Vitamin D Hypertension Trial (2011−2014) with 200 hypertensive patients with 25(OH)D levels <30 ng/mL. We evaluated whether 2800 IU of vitamin D3/day or placebo (1:1) for 8 weeks affects 24-hour systolic ambulatory BP in patients with 25(OH)D concentrations <20 ng/mL, <16 ng/mL, and <12 ng/mL and whether achieved 25(OH)D concentrations were associated with BP measures. Taking into account correction for multiple testing, p values < 0.0026 were considered significant. No significant treatment effects on 24-hour BP were observed when different baseline 25(OH)D thresholds were used (all p-values > 0.30). However, there was a marginally significant trend towards an inverse association between the achieved 25(OH)D level with 24-hour systolic BP (−0.196 per ng/mL 25(OH)D, 95% CI (−0.325 to −0.067); p = 0.003). In conclusion, we could not document the antihypertensive effects of vitamin D in vitamin D-deficient individuals, but the association between achieved 25(OH)D concentrations and BP warrants further investigations on cardiovascular benefits of vitamin D in severe vitamin D deficiency.

Critical Appraisal of Large Vitamin D Randomized Controlled Trials.

As a consequence of epidemiological studies showing significant associations of vitamin D deficiency with a variety of adverse extra-skeletal clinical outcomes including cardiovascular diseases, cancer, and mortality, large vitamin D randomized controlled trials (RCTs) have been designed and conducted over the last few years. The vast majority of these trials did not restrict their study populations to individuals with vitamin D deficiency, and some even allowed moderate vitamin D supplementation in the placebo groups. In these RCTs, there were no significant effects on the primary outcomes, including cancer, cardiovascular events, and mortality, but explorative outcome analyses and meta-analyses revealed indications for potential benefits such as reductions in cancer mortality or acute respiratory infections. Importantly, data from RCTs with relatively high doses of vitamin D supplementation did, by the vast majority, not show significant safety issues, except for trials in critically or severely ill patients or in those using very high intermittent vitamin D doses. The recent large vitamin D RCTs did not challenge the beneficial effects of vitamin D regarding rickets and osteomalacia, that therefore continue to provide the scientific basis for nutritional vitamin D guidelines and recommendations. There remains a great need to evaluate the effects of vitamin D treatment in populations with vitamin D deficiency or certain characteristics suggesting a high sensitivity to treatment. Outcomes and limitations of recently published large vitamin D RCTs must inform the design of future vitamin D or nutrition trials that should use more personalized approaches.

Randomized trial of vitamin D versus placebo supplementation on markers of systemic inflammation in hypertensive patients.

BACKGROUND AND AIMS: Animal and cell models indicated that vitamin D modulates inflammatory activity, which is considered relevant in the pathogenesis of arterial hypertension and cardiovascular diseases. We therefore aimed to investigate the effect of vitamin D supplementation on systemic markers of inflammation in a cohort of hypertensive patients. METHODS AND RESULTS: The Styrian Vitamin D Hypertension Trial is a single-centre, double-blind, placebo-controlled study conducted from 2011 to 2014 in Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxy-vitamin-D (25(OH)D) concentration below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day or placebo for 8 weeks. The present investigation is a post-hoc analysis using analysis of co-variance (ANCOVA). Outcome measures were biomarkers of inflammation including CRP, leukocytes including subtypes and leukocyte-to-lymphocyte ratio, leucine and kynurenic acid. A total of 187 participants (mean age 60.1 ± 11.3years; 47% women; mean baseline 25(OH)D 21.1 ± 5.6 ng/mL) completed the trial. ANCOVA revealed a mean treatment effect for none of the respective outcomes and no significant results were detected in various subgroup analyses. CONCLUSION: Vitamin D3 supplementation in hypertensive patients with insufficient 25(OH)D concentrations has no significant effect on lowering markers of systemic inflammation. Further studies investigating the effect of vitamin D on other inflammatory pathways and in populations with severe vitamin D deficiency and a significant inflammatory burden are required. REGISTRATION: ClinicalTrials.gov Identifier: NCT02136771; EudraCT No. 2009-018,125-70. Start Date: 2011-04-06.

Vitamin D and Cardiovascular Disease: An Updated Narrative Review.

During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied.

Effects of Vitamin D Supplementation on Surrogate Markers of Fertility in PCOS Women: A Randomized Controlled Trial.

Vitamin D (VD) might play an important role in polycystic ovary syndrome (PCOS) and female fertility. However, evidence from randomized controlled trials (RCT) is sparse. We examined VD effects on anti-Müllerian hormone (AMH) and other endocrine markers in PCOS and non-PCOS women. This is a post hoc analysis of a single-center, double-blind RCT conducted between December 2011 and October 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. We included 180 PCOS women and 150 non-PCOS women with serum 25-hydroxyvitamin D (25(OH)D) concentrations <75 nmol/L in the trial. We randomized subjects to receive 20,000 IU of VD3/week (119 PCOS, 99 non-PCOS women) or placebo (61 PCOS, 51 non-PCOS women) for 24 weeks. Outcome measures were AMH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, dehydroepiandrosterone sulfate, and androstenedione. In PCOS women, we observed a significant treatment effect on FSH (mean treatment effect 0.94, 95% confidence interval [CI] 0.087 to 1.799, p = 0.031) and LH/FSH ratio (mean treatment effect -0.335, 95% CI -0.621 to 0.050, p = 0.022), whereas no significant effect was observed in non-PCOS women. In PCOS women, VD treatment for 24 weeks had a significant effect on FSH and LH/FSH ratio but no effect on AMH levels.

Genetic Components of 25-Hydroxyvitamin D Increase in Three Randomized Controlled Trials.

The 25-Hydroxyvitamin D (25[OH)D) serum concentration depends on vitamin D intake, endogenous vitamin D production and genetic factors. The latter have been demonstrated in large genome-wide association studies indicating that single nucleotide polymorphisms (SNPs) in genes related to the vitamin D metabolism are as important for serum 25(OH)D levels as the influence of season. The mechanism on how these SNPs influence serum 25(OH)D levels are still unclear. The aim of the present study was to investigate the genetic effects of ten selected SNPs related to vitamin D metabolism on 25-hydroxyvitamin D increase (∆25(OH)D) after vitamin D supplementation in three randomized controlled trials. Genotypes of SNPs related to vitamin D metabolism were determined in 411 participants with 25(OH)D concentrations < 75 nmol/l receiving 20,000 IU cholecalciferol per week for 8 or 12 weeks after study inclusion. For the vitamin D receptor (VDR) rs10783219 polymorphism, the minor A-allele was associated with lower ∆25(OH)D values in the entire study population (p = 0.022), which was not consistent in all three cohorts when analysed separately. VDR rs10783219 might therefore be a genetic modulator of increasing 25-hydroxyvitamin D concentrations. Considering the wide-spread use of vitamin D supplementation, future large and well-designed randomized controlled trials (RCTs) should investigate the clinical impact of this polymorphism.

Effects of vitamin D supplementation on metabolic and endocrine parameters in healthy premenopausal women: A randomized controlled trial.

BACKGROUND & AIMS: Vitamin D supplementation may affect glycemic as well as hormonal regulation. Thus, the aim of the current study was to investigate whether vitamin D supplementation has any significant effects on metabolic and endocrine parameters in healthy premenopausal women. Primary outcome measure was the plasma glucose area under the curve (AUCgluc). METHODS: The current study was a single-center, double-blind, randomized placebo-controlled trial that was conducted at the Medical University of Graz, Austria, between March 2013 and October 2017. One-hundred and fifty healthy premenopausal women with 25-hydroxyvitamin D [25(OH)D] concentrations <75 nmol/L once weekly received either 20,000 IU of cholecalciferol or placebo (2:1 ratio) over a total of 24 weeks. RESULTS: In total, 127 women [age 36.2 ± 8.7 years; BMI 25.3 ± 5.6 kg/m2; baseline 25(OH)D 55.8 ± 19.7 nmol/L] completed the study. Vitamin D supplementation had no significant effect on AUCgluc (mean treatment effect 11.70; p = 0.069), while it had a significant treatment effect on homeostatic model assessment-insulin resistance (HOMA-IR; mean treatment effect 0.31; p = 0.019) and quantitative insulin-sensitivity check index (QUICKI; mean treatment effect -0.019; p = 0.013). There was no significant effect on the remaining secondary outcome parameters. CONCLUSIONS: In this randomized-controlled trial in healthy premenopausal women, there was a significant treatment effect of vitamin D supplementation on HOMA-IR and QUICKI, while there was no significant treatment effect on AUCgluc.

The Effect of Vitamin D Supplementation on its Metabolism and the Vitamin D Metabolite Ratio.

25-hydroxyvitamin D (25(OH)D) is commonly measured to assess vitamin D status. Other vitamin D metabolites such as 24,25-dihydroxyvitamin D (24,25(OH)2D) provide additional insights into vitamin D status or metabolism. Earlier studies suggested that the vitamin D metabolite ratio (VMR), calculated as 24,25(OH)2D/25(OH)D, could predict the 25(OH)D increase after vitamin D supplementation. However, the evidence for this additional value is inconclusive. Therefore, our aim was to assess whether the increase in 25(OH)D after supplementation was predicted by the VMR better than baseline 25(OH)D. Plasma samples of 106 individuals (25(OH)D < 75 nmol/L) with hypertension who completed the Styrian Vitamin D Hypertension Trial (NC.T.02136771) were analyzed. Participants received vitamin D (2800 IU daily) or placebo for 8 weeks. The treatment effect (ANCOVA) for 25(OH)D3, 24,25(OH)2D3 and the VMR was 32 nmol/L, 3.3 nmol/L and 0.015 (all p < 0.001), respectively. Baseline 25(OH)D3 and 24,25(OH)2D3 predicted the change in 25(OH)D3 with comparable strength and magnitude. Correlation and regression analysis showed that the VMR did not predict the change in 25(OH)D3. Therefore, our data do not support routine measurement of 24,25(OH)2D3 in order to individually optimize the dosage of vitamin D supplementation. Our data also suggest that activity of 24-hydroxylase increases after vitamin D supplementation.

Effects of Vitamin D Supplementation on Body Composition and Metabolic Risk Factors in Men: A Randomized Controlled Trial.

Vitamin D might play a role in metabolic processes and obesity. We therefore examined vitamin D effects on metabolic markers and obesity in a randomized controlled trial (RCT). This is a post-hoc analysis of the Graz Vitamin D&TT-RCT, a single-center, double-blind, randomized placebo-controlled trial. We included 200 healthy men with serum 25-hydroxyvitamin D (25(OH) D) levels <75 nmol/L. Subjects received 20,000 IU of vitamin D3/week (n = 100) or placebo (n = 100) for 12 weeks. Outcome measures were metabolic markers, anthropometric measures, and body composition assessed by Dual-energy X-ray absorptiometry. One-hundred and ninety-two men completed the study. We found a significant treatment effect on fasting glucose/fasting insulin ratio (-5.3 (-10.4 to -0.2), p = 0.040), whereas we observed no significant effect on the remaining outcome parameters. In subgroup analyses of men with baseline 25(OH)D levels <50 nmol/L (n = 80), we found a significant effect on waist circumference (1.6 (0.3 to 2.9) cm, p = 0.012), waist-to-hip ratio (0.019 (0.002 to 0.036), p = 0.031), total body fat (0.029 (0.004 to 0.055) %, p = 0.026), and android fat (1.18 (0.11 to 2.26) %, p = 0.010). In middle-aged healthy men, vitamin D treatment had a negative effect on insulin sensitivity. In vitamin D deficient men, vitamin D has an unfavorable effect on central obesity and body composition.

Effects of Vitamin D Supplementation on Bone Turnover and Bone Mineral Density in Healthy Men: A Post-Hoc Analysis of a Randomized Controlled Trial.

Vitamin D is well known for its effects on calcium and mineral metabolism. However, vitamin D effects on bone turnover markers (BTMs), which are used together with bone mineral density (BMD) to evaluate bone health, are less clear. We therefore examined vitamin D effects on BTMs (beta-cross laps (CTX) and osteocalcin (OC)) and BMD in a post-hoc analysis of a randomized controlled trial (RCT). This is a post-hoc analysis of the Graz Vitamin D&TT-RCT, a single-center, double-blind, randomized placebo-controlled trial conducted between December 2012 and November 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. A total of 200 healthy men with serum 25-hydroxyvitamin D (25(OH)D) levels <75 nmol/L participated in the trial. Subjects were randomized to receive 20,000 IU of vitamin D3/week (n = 100) or placebo (n = 100) for 12 weeks. Outcome measures were BTMs, BMD, and trabecular bone score (TBS). A total of 192 men (mean age and 25(OH)D: 43 (±13) years and 54.9 (±18.3) nmol/L, respectively) completed the study. We found no significant treatment effect on BTMs, BMD, or TBS (p > 0.05 for all). In middle-aged healthy men, vitamin D treatment for 12 weeks had no significant effect on BTMs or BMD.

Vitamin D testing and treatment: a narrative review of current evidence.

Vitamin D testing and treatment is a subject of controversial scientific discussions, and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25[OH]D) concentrations of ≥50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25-30 nmol/L (10-12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D, we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.

Effects of vitamin D supplementation on androgens in men with low testosterone levels: a randomized controlled trial.

PURPOSE: It has been hypothesized that vitamin D is associated with androgen levels in men. We, therefore, aimed to evaluate whether vitamin D supplementation increases serum total testosterone (TT) levels in men with low TT levels at baseline. METHODS: The Graz Vitamin D&TT-RCT is a single-center, double-blind, randomized placebo-controlled trial conducted between March 2013 and November 2017 at the endocrine outpatient clinic at the Medical University of Graz, Austria. One-hundred healthy men with serum TT levels < 10.4 nmol/l and 25-hydroxyvitamin D [25(OH)D] levels < 75 nmol/l participated in the trial. Subjects were randomized to receive 20,000 IU of vitamin D3/week (n = 50) or placebo (n = 50) for 12 weeks. Primary outcome was TT measured using mass spectrometry. Secondary outcomes were free testosterone, free androgen index, sex hormone-binding globulin, estradiol, follicle-stimulating hormone, luteinizing hormone, metabolic characteristics, and body composition. RESULTS: Ninety-four men [mean age and 25(OH)D: 47 (± 12) years and 56.3 (± 18.3) nmol/l, respectively] completed the study. We found no significant treatment effect on serum TT or on the remaining secondary outcome variables. CONCLUSION: Vitamin D treatment had no effect on serum TT levels in middle-aged healthy men with low TT levels.