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.

The effect of vitamin D supplementation on plasma non-oxidised PTH in a randomised clinical trial.

OBJECTIVE: PTH can be oxidised in vivo, rendering it biologically inactive. Non-oxidised PTH (n-oxPTH) may therefore give a better image of the hormonal status of the patient. While vitamin D supplementation decreases total PTH (tPTH) concentration, the effect on n-oxPTH concentration is unexplored. We investigated the effect of vitamin D on n-oxPTH concentration in comparison to tPTH and compared the correlations between parameters of calcium, bone and lipid metabolism with n-oxPTH and tPTH. METHODS: N-oxPTH was measured in 108 vitamin D-insufficient (25(OH)D <75 nmol/L) hypertensive patients, treated with vitamin D (2800 IE daily) or placebo for 8 weeks in the Styrian Vitamin D Hypertension Trial (NCT02136771). We calculated the treatment effect and performed correlation analyses of n-oxPTH and tPTH with parameters of calcium, bone and lipid metabolism and oxidative stress. RESULTS: After treatment, compared to placebo, 25(OH)D concentrations increased, tPTH decreased by 9% (P < 0.001), n-oxPTH by 7% (P = 0.025) and the ratio of n-oxPTH/tPTH increased (P = 0.027). Changes in phosphate and HDL concentration correlated with changes in n-oxPTH, but not tPTH. CONCLUSIONS: tPTH and n-oxPTH decrease upon vitamin D supplementation. Our study suggests that vitamin D supplementation reduces the oxidation of PTH, as we observed a small but significant increase in the non-oxidised proportion of PTH upon treatment. In addition, we found that changes in phosphate and HDL concentration showed a relationship with changes in n-oxPTH, but not tPTH. This may be explained by the biological activity of n-oxPTH. Further research should be carried out to establish the clinical relevance of n-oxPTH.

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 FGF23: a randomized-controlled trial.

PURPOSE: Fibroblast growth factor-23 (FGF23) is critical for phosphate homeostasis. Considering the high prevalence of vitamin D deficiency and the association of FGF23 with adverse outcomes, we investigated effects of vitamin D3 supplementation on FGF23 concentrations. METHODS: This is a post-hoc analysis of the Styrian Vitamin D Hypertension trial, a single-center, double-blind, randomized, placebo-controlled trial, conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two hundred subjects with 25(OH)D concentrations < 30 ng/mL and arterial hypertension were randomized to receive either 2800 IU of vitamin D3 daily or placebo over 8 weeks. Primary outcome was the between-group difference in FGF23 levels at study end while adjusting for baseline values. RESULTS: Overall, 181 participants (mean ± standard deviation age, 60.1 ± 11.3; 48% women) with available c-term FGF23 concentrations were considered for the present analysis. Mean treatment duration was 54 ± 10 days in the vitamin D3 group and 54 ± 9 days in the placebo group. At baseline, FGF23 was significantly correlated with serum phosphate (r = 0.135; p = 0.002). Vitamin D3 supplementation had no significant effect on FGF23 in the entire cohort (mean treatment effect 0.374 pmol/L; 95% confidence interval - 0.024 to 0.772 pmol/L; p = 0.065), but increased FGF23 concentrations in subgroups with baseline 25(OH)D concentrations below 20 ng/mL (n = 70; mean treatment effect 0.973 pmol/L; 95% confidence interval - 0.032 to 1.979 pmol/L; p = 0.019) and 16 ng/mL (n = 40; mean treatment effect 0.593 pmol/L; 95% confidence interval 0.076 to 1.109; p = 0.022). CONCLUSIONS: Vitamin D3 supplementation had no significant effect on FGF23 in the entire study cohort. We did, however, observe an increase of FGF23 concentrations in subgroups with low baseline 25(OH)D.

Rationale and Plan for Vitamin D Food Fortification: A Review and Guidance Paper.

Vitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may also prevent extraskeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications and premature deaths. Vitamin D has a unique metabolism as it is mainly obtained through synthesis in the skin under the influence of sunlight (i.e., ultraviolet-B radiation) whereas intake by nutrition traditionally plays a relatively minor role. Dietary guidelines for vitamin D are based on a consensus that serum 25-hydroxyvitamin D (25[OH]D) concentrations are used to assess vitamin D status, with the recommended target concentrations ranging from ≥25 to ≥50 nmol/L (≥10-≥20 ng/mL), corresponding to a daily vitamin D intake of 10 to 20 µg (400-800 international units). Most populations fail to meet these recommended dietary vitamin D requirements. In Europe, 25(OH)D concentrations <30 nmol/L (12 ng/mL) and <50 nmol/L (20 ng/mL) are present in 13.0 and 40.4% of the general population, respectively. This substantial gap between officially recommended dietary reference intakes for vitamin D and the high prevalence of vitamin D deficiency in the general population requires action from health authorities. Promotion of a healthier lifestyle with more outdoor activities and optimal nutrition are definitely warranted but will not erase vitamin D deficiency and must, in the case of sunlight exposure, be well balanced with regard to potential adverse effects such as skin cancer. Intake of vitamin D supplements is limited by relatively poor adherence (in particular in individuals with low-socioeconomic status) and potential for overdosing. Systematic vitamin D food fortification is, however, an effective approach to improve vitamin D status in the general population, and this has already been introduced by countries such as the US, Canada, India, and Finland. Recent advances in our knowledge on the safety of vitamin D treatment, the dose-response relationship of vitamin D intake and 25(OH)D levels, as well as data on the effectiveness of vitamin D fortification in countries such as Finland provide a solid basis to introduce and modify vitamin D food fortification in order to improve public health with this likewise cost-effective approach.

Vitamin D supplementation and lipoprotein metabolism: A randomized controlled trial.

BACKGROUND: Vitamin D deficiency is associated with an unfavorable lipid profile, but whether and how vitamin D supplementation affects lipid metabolism is unclear. OBJECTIVE: To examine the effects of vitamin D supplementation on lipid and lipoprotein parameters. METHODS: This is a post hoc analysis of the single-center, double-blind, randomized, placebo-controlled Styrian Vitamin D Hypertension Trial (2011-2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D concentrations of <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for 8 weeks. RESULTS: One hundred sixty-three participants (62.2 [53.1-68.4] years of age; 46% women) had available lipid data and were included in this analysis. Vitamin D supplementation significantly increased total cholesterol, triglycerides, very-low-density lipoprotein (VLDL) triglycerides, low-density lipoprotein (LDL) triglycerides, high-density lipoprotein (HDL) triglycerides, apolipoprotein B (ApoB), LDL-ApoB, ApoCII, ApoCIII, phospholipids, and ApoE (P < .05 for all). Except for ApoCII and ApoCIII and HDL-triglycerides, all other treatment effects remained statistically significant after adjustment for multiple testing with the Benjamini and Hochberg false discovery rate method. There was a nonsignificant increase in LDL cholesterol. Furthermore, no significant effects were seen on free fatty acids, lipoprotein (a), ApoAI, ApoAII, VLDL cholesterol, VLDL-ApoB, HDL cholesterol, LDL diameter, and VLDL diameter. CONCLUSIONS: The effects of vitamin D on lipid metabolism are potentially unfavorable. They require further investigation in view of the wide use of vitamin D testing and treatment.

Hormonal Contraceptive Use Is Associated With Higher Total but Unaltered Free 25-Hydroxyvitamin D Serum Concentrations.

Context: Intake of hormonal contraceptives (HC) is associated with higher total 25-hydroxyvitamin D [25(OH)D] concentrations, but the effect of HC on free 25(OH)D is unclear. Objective: We investigated whether free 25(OH)D concentrations differ according to use of HC. Design: This is a post hoc analysis of a randomized open trial. Setting: This study was conducted from 13 January to 9 May, 2016, at a clinical research organization in Esslingen, Germany. Participants: We included 201 apparently healthy women of childbearing age. Intervention: Participants were randomly assigned to receive a daily multimicronutrient supplement for 8 weeks; the supplement contained 200 IU (n =100) or 800 IU (n = 101) of vitamin D3. Main Outcome Measures: Primary outcome was the difference in free 25(OH)D between users and nonusers of HC. Results: Overall, 176 participants [median (25th to 75th percentiles) age: 25 (22 to 29) years] with available free 25(OH)D were included in the present analysis. At baseline, total 25(OH)D was significantly higher in users (n = 110) than in nonusers (n = 66) of HC [49.2 (33.4 to 63.4) vs 39.1 (23.8 to 52.5) nmol/L; P < 0.001], whereas there was no difference in free 25(OH)D [7.87 (6.50 to 10.11) vs 7.88 (6.35 to 10.12) pmol/L; P = 0.923]. These results were confirmed after multimicronutrient supplementation and in subgroups according to treatment allocation. Conclusions: Use of HC was associated with, on average, 26% higher total 25(OH)D, whereas free 25(OH)D values did not differ according to use of HC. These findings are relevant for epidemiological studies, but the physiological implications remain to be clarified.

Vitamin D: Current Guidelines and Future Outlook.

Vitamin D is of public health interest because its deficiency is common and is associated with musculoskeletal diseases, as well as extraskeletal diseases, such as cancer, cardiovascular diseases, and infections. Several health authorities have reviewed the existing literature and published nutritional vitamin D guidelines for the general population. There was a wide consensus that serum 25-hydroxyvitamin D [25(OH)D] concentration should be used to assess vitamin D status and intake, and that musculoskeletal, and not extraskeletal, effects of vitamin D should be the basis for nutritional vitamin D guidelines. Recommended target levels for 25(OH)D range from 25 to 50 nmol/l (10 to 20 ng/ml), corresponding to a vitamin D intake of 400 to 800 International Units (10 to 20 µg) per day. It is of concern that significant sections of the general population do not meet these recommended vitamin D levels. This definitely requires action from a public health perspective.

Effects of Vitamin D Supplementation on IGF-1 and Calcitriol: A Randomized-Controlled Trial.

Increasing evidence suggests a possible interaction between vitamin D and insulin-like growth factor-1 (IGF-1). We aimed to investigate effects of vitamin D supplementation on IGF-1 (primary outcome) and calcitriol (1,25(OH)2D) concentrations (secondary outcome). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial-a single-center, double-blind, randomized, placebo-controlled trial (RCT) conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two-hundred subjects with arterial hypertension and 25(OH)D concentrations <30 ng/mL were randomized to either receive 2800 IU of vitamin D daily or placebo for eight weeks. A total of 175 participants (mean ± standard deviation age, 60 ± 11 years; 49% women) with available IGF-1 concentrations were included in the present analysis. At baseline, IGF-1 concentrations were significantly correlated with 1,25(OH)2D (r = 0.21; p = 0.005) but not with 25(OH)D (r = -0.008; p = 0.91). In the RCT, vitamin D had no significant effect on IGF-1 (mean treatment effect 3.1; 95% confidence interval -5.6 to 11.9 ng/mL; p = 0.48), but it increased 1,25(OH)2D concentrations (mean treatment effect 9.2; 95% confidence interval 4.4 to 13.9 pg/mL; p ≤ 0.001). In this RCT, in hypertensive patients with low 25(OH)D concentrations, there was no significant effect of vitamin D supplementation on IGF-1 concentrations. However, we observed a cross-sectional correlation between 1,25(OH)2D and IGF-1 and an increase of 1,25(OH)2D after vitamin D supplementation.

Vitamin-D concentrations, cardiovascular risk and events - a review of epidemiological evidence.

Vitamin D has long been established as an elemental factor of bone physiology. Beyond mineral metabolism, the expression of the vitamin D receptor has been identified throughout the cardiovascular (CV) system. Experimental studies showed beneficial effects of vitamin D on heart and vessels, but vitamin D intoxication in animals also led to hypercalcemia and vascular calcification. Our knowledge has been extended by epidemiological studies that showed that 25-hydroxyvitamin D (25(OH)D) levels are inversely associated with an increased CV risk itself, but also with established CV risk factors, such as arterial hypertension, endothelial dysfunction and atherosclerosis. Conversely, randomized controlled trials could not document significant and consistent effects of vitamin D supplementation on CV risk or events. Potential explanations may lie in differences in reference ranges or the possibility that low vitamin D in CV disease is only an epiphenomenon. In the latter case, the key question is why low 25(OH)D levels are such a strong predictor of health. While we wait for new data, the current conclusion is that vitamin D is a strong risk marker for CV risk factors and for CV diseases itself.

Effects of Vitamin D Supplementation on Bone Turnover Markers: A Randomized Controlled Trial.

Bone turnover markers (BTMs) are used to evaluate bone health together with bone mineral density and fracture assessment. Vitamin D supplementation is widely used to prevent and treat musculoskeletal diseases but existing data on vitamin D effects on markers of bone resorption and formation are inconsistent. We therefore examined the effects of vitamin D supplementation on bone-specific alkaline phosphatase (bALP), osteocalcin (OC), C-terminal telopeptide (CTX), and procollagen type 1 N-terminal propeptide (P1NP). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial, a single-center, double-blind, randomized, placebo-controlled trial (RCT) performed at the Medical University of Graz, Austria (2011-2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D (25[OH]D) levels <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for eight weeks. One hundred ninety-seven participants (60.2 ± 11.1 years; 47% women) were included in this analysis. Vitamin D had no significant effect on bALP (mean treatment effect (MTE) 0.013, 95% CI -0.029 to 0.056 µg/L; p = 0.533), CTX (MTE 0.024, 95% CI -0.163 to 0.210 ng/mL, p = 0.802), OC (MTE 0.020, 95% CI -0.062 to 0.103 ng/mL, p = 0.626), or P1NP (MTE -0.021, 95% CI -0.099 to 0.057 ng/mL, p = 0.597). Analyzing patients with 25(OH)D levels <50 nmol/L separately (n = 74) left results largely unchanged. In hypertensive patients with low 25(OH)D levels, we observed no significant effect of vitamin D supplementation for eight weeks on BTMs.

Beneficial Effects of UV-Radiation: Vitamin D and beyond.

Aside from its well-known effects on bone and mineral metabolism, vitamin D may also play an important role in extra-skeletal processes like immunologic diseases, cancer, or cardiovascular diseases. Even though meta-analyses showed that vitamin D supplementation reduces fractures, falls, and overall mortality, its potential benefits did not find universal acclaim. Several health care authorities published Recommended Dietary Allowances (RDAs) for vitamin D, most of them ranging from 600 to 800 international units (IU) per day, corresponding to a serum level of 25-hydroxyvitamin D of at least 20 ng/mL (50 nmol/L). However, studies conducted in the general population revealed a much lower overall intake of vitamin D than the proposed RDAs. Thus, strategies to increase the vitamin D intake in the general population, e.g., food fortification or vitamin D supplementation, are needed to match the existing evidence and recommendations. Therefore, several currently ongoing projects aim to investigate the effect of vitamin D supplementation in the general population and try to establish food-based solutions to improve vitamin D status.