Vitamin D and Insulin-Dependent Diabetes: A Systematic Review of Clinical Trials.

(1) Background: Vitamin D supplementation after type 1 diabetes mellitus (T1DM) onset has led to conflicting results on beta-cell preservation. Aim: This paper presents a systematic review to verify whether randomized prospective controlled trials (RCTs) demonstrate that improved vitamin D status confers protection on T1DM. (2) Methods: A systematic review was conducted up until 18 January 2024 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching MEDLINE, MEDLINE In-Process, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials, using keywords "vitamin D", "type 1 diabetes", and "children". (3) Results: Following the above-mentioned search process, 408 articles in PubMed and 791 in Embase met inclusion criteria. After removing duplicates, 471 articles remained. After exclusion criteria, 11 RCTs remained. Because of major heterogeneity in design and outcomes, no meta-analyses were conducted, allowing only for qualitative analyses. There was no strong evidence that vitamin D supplementation has lasting effects on beta-cell preservation or glycemic control in new-onset T1DM. (4) Conclusions: More rigorous, larger studies are needed to demonstrate whether vitamin D improves beta-cell preservation or glycemic control in new-onset T1DM. Because T1DM may cause osteopenia, it is advisable that patients with new onset T1DM have adequate vitamin D stores.

Unraveling the complex interplay between obesity and vitamin D metabolism.

Vitamin D deficiency and obesity are a worldwide health issue. Obesity refers to the accumulation of excessive fats in the body which could lead to the development of diseases. Obese people have low vitamin D levels for several reasons including larger volume of distribution, vitamin D tightly bound in fatty tissues, reduced absorption, and diets with low vitamin D. Accurately measuring vitamin D metabolites is challenging. The Ultra-High-Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS) method was developed and validated for the analysis of vitamin D metabolites in the serum. Blood samples were collected from 452 subjects which consisted of baseline (vitamin D deficient obese subjects), follow-up (supplemented obese subjects), and healthy volunteers. The vitamin D metabolites were separated adequately by the developed UHPLC-MS/MS method. Moreover, the validation criteria for the method were within an acceptable range. The baseline, follow-up and even healthy volunteers were deficient in 25OHD3 and 25OHD2. The baseline and healthy subjects had comparable concentration of vitamin D2 and D3. However, healthy subjects had a higher concentration of 25OHD and its epimer compared to the baseline subjects. The vitamin D3 was increased significantly in the follow- up subjects; therefore, the 25OHD3 was increased significantly compared to the baseline as well; however, the increase was insufficient to achieve the optimal range. The UHPLC-MS/MS method test was applied successfully on estimation of vitamin D metabolites in subjects. This study indicates the significance of taking into account the metabolic and storage effects when evaluating the vitamin D status in obese subjects.

Effects of 25-hydroxycholecalciferol (25-OH-D3) and 1-hydroxycholecalciferol (1-OH-D3) on serum bone biomarkers and calcium and phosphorus balance and concentrations of energy in diets without or with microbial phytase fed to sows in late gestation.

The objective was to test the hypothesis that supplementation of diets for gestating sows with 25-hydroxycholecalciferol (25-OH-D3) or 1-hydroxycholecalciferol (1-OH-D3) affects serum biomarkers for bone and increases Ca and P balance and the apparent total tract digestibility (ATTD) of gross energy (GE), and the concentrations of digestible energy (DE) and metabolizable energy (ME) in diets without or with microbial phytase. Sixty multiparous sows were allotted to 1 of 6 diets. Diets were formulated using a 3 × 2 factorial with 3 inclusions of supplemental vitamin D metabolite (no metabolite, 25-OH-D3, or 1-OH-D3) and 2 inclusion levels of microbial phytase (0 or 1,000 units). Sows were housed individually in metabolism crates and feces and urine were collected quantitatively. Results indicated that there was no difference in the ATTD of dry matter (DM) and GE and concentration of DE among the 3 diets containing microbial phytase, but the ATTD of DM and GE and concentration of DE was greater (P < 0.05) in diets containing 1-OH-D3 compared with the diet without a vitamin D metabolite if phytase was not used (interaction; P < 0.05). In diets without microbial phytase, ME was greater in diets containing either one of the 2 vitamin D metabolites than in the diet without a vitamin D metabolite, but among diets with microbial phytase, the ME of the 1-OH-D3 diet was less than of the 25-OH-D3 diet (interaction; P < 0.05). No effect of microbial phytase on concentrations of DE and ME was observed. There was no interaction between supplementation of microbial phytase and vitamin D metabolites for Ca and P balances, and regardless of metabolite supplementation, use of microbial phytase increased (P < 0.05) the ATTD and retention of Ca and P. Regardless of dietary phytase, the ATTD and retention of Ca and P increased (P < 0.05) for sows fed a diet containing one of the vitamin D metabolites compared with sows fed the diet without a vitamin D metabolite. Serum biomarkers for bone resorption or bone tissue synthesis were not affected by experimental diets. In conclusion, the ATTD of DM and GE, concentrations of DE and ME, and Ca and P balance in phytase-free diets fed to sows in late gestation were increased by supplementation with 1-OH-D3 or 25-OH-D3, but no differences between the 2 vitamin D metabolites were observed. Supplementation of diets with microbial phytase increased Ca and P balance, but did not affect DE and ME of diets.

The role of vitamin D is to increase absorption of calcium and phosphorus in the gastrointestinal tract and maintain serum concentrations of calcium, but dietary vitamin D needs to be converted to an active form by 2-hydroxylation steps that take place in the liver and the kidneys. The conversion efficiency to active vitamin D may be increased if pre-hydroxylated metabolites rather than vitamin D are provided, which also increases calcium and phosphorus utilization. In a previous experiment it was also demonstrated that a vitamin D metabolite increases energy absorption in gestating sows. It is possible that use of a vitamin D metabolite and phytase have additive effects and the hypothesis, therefore, was that supplementation of a vitamin D metabolite increases calcium and phosphorus balance and energy digestibility in diets fed to gestating sows without or with microbial phytase. Results indicated that in diets without phytase, the 2 vitamin D metabolites increased energy concentration in diets by increasing apparent energy digestibility. There was no interaction between supplementation of phytase and vitamin D metabolites for calcium and phosphorus balances. Use of phytase and vitamin D metabolites increased calcium and phosphorus digestibility and retention.

Correlation between vitamin D metabolites and rheumatoid arthritis with osteoporosis by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

INTRODUCTION: Our aim is to study the correlation between vitamin D metabolites and osteoporosis in rheumatoid arthritis (RA) by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). At the same time, other influencing factors and serum biomarkers of osteoporosis in patients with RA were studied. MATERIALS AND METHODS: Patients with RA admitted from January 2020 to December 2020 were selected at our hospital. The subjects were divided into the normal bone mineral density (BMD), osteopenia, and osteoporosis groups. The differences of vitamin D (VD) metabolites among groups were compared. The Pearson correlation coefficient was used to analyze the relationship between BMD and various parameters. The relationship between BMD and influencing factors was studied by a multiple linear regression equation. RESULTS: A total of 287 patients with RA were included. RA patients with 25-hydroxy vitamin D [25(OH)D] deficiency accounted for 43.63% and 25(OH)D insufficient levels accounted for 31.37%. There were 31 cases (10.80%) in the normal BMD group, 161 cases (56.10%) in the osteopenia group, and 95 cases (33.10%) in the osteoporosis group. The BMD of L1-4 (T- score) was negatively correlated with age (P < 0.05), course of disease (P < 0.05), and erythrocyte sedimentation rate (ESR) (P < 0.05), and positively correlated with 25(OH)D3 (P < 0.05). The multiple linear regression model results showed that age and 25(OH)D3 were independent predictors of BMD; this explained 22.11% of the total variation. CONCLUSIONS: VD deficiency and insufficient are common in RA patients. RA patients can be appropriately supplemented with VD. VD3 may be a better choice.

From urban dust and marine sediment to Ginkgo biloba and human serum-a top ten list of Standard Reference Materials (SRMs).

During the past 40 years, the National Institute of Standards and Technology (NIST) has developed over 180 natural matrix Standard Reference Materials® (SRMs) for the determination of trace organic constituents in environmental, clinical, food, and dietary supplement matrices. A list of the Top Ten SRMs intended for organic analysis was identified based on selection criteria including analytical challenge to assign certified values, challenges in material preparation, novel matrices, longevity, widespread use, and unique design concept or intended use. The environmental matrix SRMs include air particulate matter, marine sediment, mussel tissue, and human serum with the focus on contaminants such as polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), chlorinated pesticides, and polybrominated diphenyl ethers (PBDEs). Human serum and plasma SRMs for clinical diagnostic markers including vitamin D metabolites represent clinical analysis, whereas infant formula, multivitamin/multielement tablets, and Ginkgo biloba constitute the food and dietary supplement matrices on the list. Each of the SRMs on the Top Ten list is discussed relative to the selection criteria and significance of the material, and several overall lessons learned are summarized.

Association of vitamin D metabolites with cognitive function and brain atrophy in elderly individuals - the Austrian stroke prevention study.

BACKGROUND: Vitamin D is a well-established regulator of calcium and phosphate metabolism that has neurotrophic and neuroprotective properties. Deficiency of vitamin D has been proposed to promote cognitive dysfunction and brain atrophy. However, existing studies provide inconsistent results. Here we aimed to investigate the association between vitamin D metabolites, cognitive function and brain atrophy in a cohort of well-characterized community-dwelling elderly individuals with normal neurological status and without history of stroke and dementia. METHODS: 25(OH)D3, 25(OH)D2 and 24,25(OH)2D3 were measured by liquid-chromatography tandem mass-spectrometry in serum samples from 390 community-dwelling elderly individuals. All participants underwent thorough neuropsychiatric tests capturing memory, executive function and visuopractical skills. In 139 of these individuals, MRI of the brain was performed in order to capture neurodegenerative and vascular changes. RESULTS: Total 25(OH)D (ß=0.003, 0.037), 24,25(OH)2D3 (ß=0.0456, p=0.010) and vitamin D metabolite ratio (VMR) (ß=0.0467, p=0.012) were significantly related to memory function. Adjustment for multiple testing weakened these relationships, but trends (p≤0.10) remained. 24,25(OH)2D3 and VMR showed similar trends also for visuopractical skills and global cognitive function. No significant relationships existed between vitamin D metabolites and MRI derived indices of neurodegeneration and vascular changes. Sub-group analyses of individuals with low concentrations of 25(OH)D and 24,25(OH)2D3 showed significantly worse memory function compared to individuals with normal or high concentrations. CONCLUSIONS: Vitamin D deficient individuals appear to have a modest reduction of memory function without structural brain atrophy. Future studies should explore if vitamin D supplementation can improve cognitive function.

Association between Serum Vitamin D Metabolites and Metabolic Function in Healthy Asian Adults.

The association between low vitamin D status and the development of type 2 diabetes mellitus is well established; however, intervention trials that increased serum vitamin D (through ultraviolet B exposure or dietary supplementation) provide mixed outcomes. Recent evidence suggests that metabolites directly related to vitamin D receptor activation-1α,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3-may be better markers of vitamin D repletion status. We tested the hypothesis that a vitamin D metabolite (VDM) index, calculated as the sum of normalized fasting serum concentrations of 1α,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3, is associated with metabolic function. We measured subcutaneous and visceral adipose tissue volume, intrahepatic triglyceride content, maximum oxygen uptake, insulin sensitivity (4 h hyperinsulinemic-euglycemic clamp), and insulin secretion (3 h meal tolerance test with mathematical modeling) and calculated the VDM index in 65 healthy Asian adults. Subjects with a low VDM index had lower peripheral insulin sensitivity and beta-cell function compared to subjects with a high VDM index (both p < 0.05), matched for age, sex, BMI, and serum 25-hydroxyvitamin D3. Serum 25-hydroxyvitamin D3 was not associated with peripheral insulin sensitivity or beta-cell function. Our results suggest that, rather than enhancing vitamin D substrate availability, upregulation of vitamin D action is more likely to lead to improvements in glucose homeostasis.

Vitamin D Metabolite Profile in Cholecalciferol- or Calcitriol-Supplemented Healthy and Mammary Gland Tumor-Bearing Mice.

To analyze if the prometastatic activity of calcitriol (active vitamin D3 metabolite), which was previously observed in a 4T1 breast cancer model, is also found in other breast cancers, and to assess the impact of various schemes of vitamin D supply, we used 4T1 and E0771 mouse metastatic and 67NR nonmetastatic cells in this study. BALB/c and C57BL/6 healthy and tumor-bearing mice were exposed to a control (1000 IU), low- (100 IU), and high- (5000 IU) vitamin D3 diets. Additionally, from day 7 of tumor transplantation, the 1000 and 100 IU groups were gavaged with calcitriol (+cal). After 8 weeks of feeding, plasma levels of 25(OH)D3, 24,25(OH)2D3, and 3-epi-25(OH)D3 were significantly lower in calcitriol-treated and vitamin D-deficient groups than in the control, whereas the levels of all metabolites were increased in the 5000 IU group. The ratio of 25(OH)D3:24,25(OH)2D3 was increased in both calcitriol-treated groups, whereas the ratio of 25(OH)D3:3-epi-25(OH)D3 was increased only in the 100 IU group but decreased in the 5000 IU group. In contrast to E0771, 4T1 lung metastasis was accelerated in all vitamin D-supplemented mice, as well as in the deficient group with an increased inflammatory response. 67NR tumor growth was transiently inhibited in the 1000 IU+cal group, but single metastases were observed in the 5000 and 100 IU groups. Based on the results, we conclude that various schemes of vitamin D supply and vitamin D deficiency led to similar metabolite profiles irrespective of the mice strain and tumor burden. However, depending on the type of breast cancer, different effects on tumor growth and metastasis were noticed.

Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications.

BACKGROUND: Vitamin D deficiency is diagnosed by total serum 25-hydroxyvitamin D (25(OH)D) concentration and is associated with poor health and increased mortality; however, some populations have low 25(OH) D concentrations without manifestations of vitamin D deficiency. The Vitamin D Metabolite Ratio (VMR) has been suggested as a superior indicator of vitamin D status. Therefore, VMR was determined in a population with type 2 diabetes at high risk for vitamin D deficiency and correlated with diabetic complications. RESEARCH DESIGN AND METHODS: Four hundred sisty patients with type 2 diabetes (T2D) were recruited, all were vitamin D3 supplement naive. Plasma concentration of 25-hydroxyvitamin D3 (25(OH)D3) and its metabolites 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and its epimer, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3), were measured by LC-MS/MS analysis. VMR-1 was calculated as a ratio of 24,25(OH)2D3:25(OH)D3; VMR-2 as a ratio of 1,25(OH)2D3:25(OH)D3; VMR-3 was calculated as a ratio of 3-epi-25(OH)D3: 25(OH)D3. RESULTS: An association means that there were significant differences between the ratios found for those with versus those without the various diabetic complications studied. VMR-1 was associated with diabetic retinopathy (p = 0.001) and peripheral artery disease (p = 0.012); VMR-2 associated with hypertension (p < 0.001), dyslipidemia (p < 0.001), diabetic retinopathy (p < 0.001), diabetic neuropathy (p < 0.001), coronary artery disease (p = 0.001) and stroke (p < 0.05). VMR-3 associated with hypertension (p < 0.05), dyslipidemia (p < 0.001) and coronary artery disease (p < 0.05). CONCLUSIONS: In this cross sectional study, whilst not causal, VMR-2 was shown to be the superior predictor of diabetic and cardiovascular complications though not demonstrative of causality in this cross-sectional study population over VMR-1, VMR-3 and the individual vitamin D concentration measurements; VMR-2 associated with both microvascular and cardiovascular indices and therefore may have utility in predicting the development of diabetic complications.

Validation and Determination of 25(OH) Vitamin D and 3-Epi25(OH)D3 in Breastmilk and Maternal- and Infant Plasma during Breastfeeding.

Vitamin D deficiency in pregnant women and their offspring may result in unfavorable health outcomes for both mother and infant. A 25hydroxyvitamin D (25(OH)D) level of at least 75 nmol/L is recommended by the Endocrine Society. Validated, automated sample preparation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were used to determine the vitamin D metabolites status in mother-infant pairs. Detection of 3-Epi25(OH)D3 prevented overestimation of 25(OH)D3 and misclassification of vitamin D status. Sixty-three percent of maternal 25(OH)D plasma levels were less than the recommended level of 25(OH)D at 3 months. Additionally, breastmilk levels of 25(OH)D decreased from 60.1 nmol/L to 50.0 nmol/L between six weeks and three months (p < 0.01). Furthermore, there was a positive correlation between mother and infant plasma levels (p < 0.01, r = 0.56) at 3 months. Accordingly, 31% of the infants were categorized as vitamin D deficient (25(OH)D < 50 nmol/L) compared to 25% if 3-Epi25(OH)D3 was not distinguished from 25(OH)D3. This study highlights the importance of accurate quantification of 25(OH)D. Monitoring vitamin D metabolites in infant, maternal plasma, and breastmilk may be needed to ensure adequate levels in both mother and infant in the first 6 months of infant life.

Vitamin-D dysregulation in early- and late-onset preeclampsia: A gestational-age matched study.

Vitamin D deficiency has been associated with preeclampsia, however, vitamin D supplementation studies have shown equivocal data on amelioration of this disease. We hypothesize that women with preeclampsia have an altered endogenous vitamin D homeostasis that counteracts the beneficial effects of vitamin D supplementation. Our study population consisted of 66 maternal/neonate dyads: 16 early-onset (<34 weeks) preeclampsia (EOP), 16 early-onset controls (EOC), 17 late-onset (≥34 weeks) preeclampsia (LOP), and 17 late-onset controls (LOC). Plasma levels of 25-OH-D and the bioactive metabolite 1α,25-(OH)2-D were studied by ELISA. Placental expression of vitamin D transporters (cubulin and megalin), metabolic genes (CYP2R1, CYP27B1, CYP24A1), and vitamin D binding protein (GC), were studied by real-time PCR, and the nuclear and cytosolic levels of the vitamin D receptor (VDR) protein were analyzed by immunoblotting. Maternal admission, maternal postpartum, and umbilical cord blood levels of 1α,25-(OH)2-D and placental nuclear vitamin D receptor protein levels, were significantly lower in EOP compared to EOC. In contrast LOP was characterized by lower 25-OH-D levels in maternal postpartum and cord blood, and decreased placental cubulin expression compared to LOC. Both EOP and LOP showed decreased placental expression of CYP2R1 and GC compared to controls. Multivariable linear regression analysis demonstrated that preeclampsia was a significant predictor of decreased 1α,25-(OH)2-D levels in early-onset subjects, while maternal BMI, but not preeclampsia, was the main predictor of decreased 25-OH-D in late-onset subjects. The highest positive correlation between the two vitamin D metabolites was observed in LOC umbilical cord blood. Finally, paired analysis of maternal metabolites before and after delivery indicated that women without preeclampsia had better maintenance of vitamin D levels. We conclude that EOP is characterized by decreased bioactivation of vitamin D and VDR in association with fetal growth restriction (FGR). In contrast, LOP is characterized by decreased 25-OH-D levels in association with decreased placental CYP2R1 and cubulin expression; and uncoupling of the 25-OH-D with the 1α,25-(OH)2-D metabolite.

Association of vitamin D2 and D3 with type 2 diabetes complications.

AIMS: Vitamin D measurement is a composite of vitamin D2 (25(OH)D2) and D3 (25(OH)D3) levels, and its deficiency is associated with the development of type 2 diabetes (T2DM) and diabetic complications; vitamin D deficiency may be treated with vitamin D2 supplements. This study was undertaken to determine if vitamin D2 and D3 levels differed between those with and without T2DM in this Middle Eastern population, and the relationship between diabetic microvascular complications and vitamin D2 and vitamin D3 levels in subjects with T2DM. METHODS: Four hundred ninety-six Qatari subjects, 274 with and 222 without T2DM participated in the study. Plasma levels of total vitamin D2 and D3 were measured by LC-MS/MS analysis. RESULTS: All subjects were taking vitamin D2 and none were taking D3 supplements. Vitamin D2 levels were higher in diabetics, particularly in females, and higher levels were associated with hypertension and dyslipidemia in the diabetic subjects (p < 0.001), but were not related to diabetic retinopathy or nephropathy. Vitamin D3 levels measured in the same subjects were lower in diabetics, particularly in females (p < 0.001), were unrelated to dyslipidemia or hypertension, but were associated with retinopathy (p < 0.014). Neither vitamin D2 nor vitamin D3 were associated with neuropathy. For those subjects with hypertension, dyslipidemia, retinopathy or neuropathy, comparison of highest with lowest tertiles for vitamin D2 and vitamin D3 showed no difference. CONCLUSIONS: In this Qatari cohort, vitamin D2 was associated with hypertension and dyslipidemia, whilst vitamin D3 levels were associated with diabetic retinopathy. Vitamin D2 levels were higher, whilst vitamin D3 were lower in diabetics and females, likely due to ingestion of vitamin D2 supplements.

Measuring Vitamin D Status in Chronic Inflammatory Disorders: How does Chronic Inflammation Affect the Reliability of Vitamin D Metabolites in Patients with IBD?

Evidence gained from recent studies has generated increasing interest in the role of vitamin D in extraskeletal functions such as inflammation and immunoregulation. Although vitamin D deficiency has been implicated in the pathophysiology of inflammatory diseases including inflammatory bowel disease (IBD), evidence as to whether vitamin D supplementation may cure or prevent chronic disease is inconsistent. Since 25OH-vitamin D (25OHD) has been suggested to be an acute-phase protein, its utility as a vitamin D status marker is therefore questionable. In this study, possible interactions of vitamin D and inflammation were studied in 188 patients with IBD, with high-sensitivity C-reactive protein (hsCRP) levels ≥ 5 mg/dL and/or fecal calprotectin ≥ 250 µg/g defined as biochemical evidence of inflammatory activity. Levels of 25OHD and vitamin D-binding protein (VDBP) were determined by ELISA, and 1,25-dihydroxyvitamin D (1,25OHD) and dihydroxycholecalciferol (24,25OHD) by LC-MS/MS. Free and bioavailable vitamin D levels were calculated with the validated formula of Bikle. Serum 1,25OH2D and vitamin D binding protein (VDBP) levels were shown to differ between the inflammatory and noninflammatory groups: patients with inflammatory disease activity had significantly higher serum concentrations of 1,25OH2D (35.0 (16.4-67.3) vs. 18.5 (1.2-51.0) pg/mL, p < 0.001) and VDBP (351.2 (252.2-530.6) vs. 330.8 (183.5-560.3) mg/dL, p < 0.05) than patients without active inflammation. Serum 24,25OH2D levels were negatively correlated with erythrocyte sedimentation rate (ESR) (-0.155, p = 0.049) while concentrations of serum 1,25OH2D correlated positively with hsCRP (0.157, p = 0.036). Correlations with serum VDBP levels were found for ESR (0.150, p = 0.049), transferrin (0.160, p = 0.037) and hsCRP (0.261, p < 0.001). Levels of serum free and bioavailable 25OHD showed a negative correlation with ESR (-0.165, p = 0.031, -0.205, p < 0.001, respectively) and hsCRP (-0.164, p = 0.032, -0.208, p < 0.001 respectively), and a moderate negative correlation with fecal calprotectin (-0.377, p = 0.028, -0.409, p < 0.016, respectively). Serum total 25OHD concentration was the only vitamin D parameter found to have no specific correlation with any of the inflammatory markers. According to these results, the traditional parameter, total 25OHD, still appears to be the best marker of vitamin D status in patients with inflammatory bowel disease regardless of the presence of inflammation.

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.

Vitamin D and Acute Respiratory Infections-The PODA Trial.

BACKGROUND: There is considerable heterogeneity in clinical trials examining the role of vitamin D in the prevention of acute respiratory infections (ARIs). METHODS: The primary aim of the Physical Performance, Osteoporosis, and Vitamin D in Older African-American Women (PODA) trial was the prevention of bone loss and decline in physical performance. A questionnaire about ARIs was administered every 3 months for 3 years to 260 black American women in a double-blind randomized clinical trial that had a placebo group and a vitamin D supplementation group. The serum 25(OH)D level was maintained >30 ng/mL in the vitamin D group. RESULTS: Serum 25(OH)D was maintained >30 ng/mL in 90% of the active group, whereas levels approximated those associated with the recommended dietary allowance (20 ng/mL) in the placebo group. There was no difference in occurrence of ARIs in the treatment group vs the placebo group. ARIs were not related to total or free 25(OH)D, which were measured at baseline and annually for 36 months. CONCLUSIONS: Vitamin D supplementation sufficient to maintain serum 25(OH)D >30 ng/mL does not prevent ARIs in older African American women. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01153568.

Is calcifediol better than cholecalciferol for vitamin D supplementation?

Modest and even severe vitamin D deficiency is widely prevalent around the world. There is consensus that a good vitamin D status is necessary for bone and general health. Similarly, a better vitamin D status is essential for optimal efficacy of antiresorptive treatments. Supplementation of food with vitamin D or using vitamin D supplements is the most widely used strategy to improve the vitamin status. Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are the most widely used compounds and the relative use of both products depends on historical or practical reasons. Oral intake of calcifediol (25OHD3) rather than vitamin D itself should also be considered for oral supplementation. We reviewed all publications dealing with a comparison of oral cholecalciferol with oral calcifediol as to define the relative efficacy of both compounds for improving the vitamin D status. First, oral calcifediol results in a more rapid increase in serum 25OHD compared to oral cholecalciferol. Second, oral calcifediol is more potent than cholecalciferol, so that lower dosages are needed. Based on the results of nine RCTs comparing physiologic doses of oral cholecalciferol with oral calcifediol, calcifediol was 3.2-fold more potent than oral cholecalciferol. Indeed, when using dosages ≤ 25 µg/day, serum 25OHD increased by 1.5 ± 0.9 nmol/l for each 1 µg cholecalciferol, whereas this was 4.8 ± 1.2 nmol/l for oral calcifediol. Third, oral calcifediol has a higher rate of intestinal absorption and this may have important advantages in case of decreased intestinal absorption capacity due to a variety of diseases. A potential additional advantage of oral calcifediol is a linear dose-response curve, irrespective of baseline serum 25OHD, whereas the rise in serum 25OHD is lower after oral cholecalciferol, when baseline serum 25OHD is higher. Finally, intermittent intake of calcifediol results in fairly stable serum 25OHD compared with greater fluctuations after intermittent oral cholecalciferol.

25-Hydroxyvitamin D Threshold for the Effects of Vitamin D Supplements on Bone Density: Secondary Analysis of a Randomized Controlled Trial.

Most trials of vitamin D supplementation have shown no benefits on bone mineral density (BMD), although severe vitamin D deficiency causes osteomalacia, which is associated with profound BMD deficits. Recently, the ViDA-BMD study from New Zealand demonstrated a threshold of baseline 25-hydroxyvitamin D (25OHD; 30 nmol/L) below which vitamin D supplementation did benefit BMD. We have now reexamined data from a similar trial in Aberdeen to determine whether a baseline 25OHD threshold of 30 nmol/L is also observed in that database. The Aberdeen study recruited 305 postmenopausal women in late winter and randomized them to receive placebo, vitamin D 400 IU/d, or vitamin D 1000 IU/d over 1 year. As previously reported, BMD loss at the hip was reduced by vitamin D 1000 IU/d only, and there was no significant treatment effect of either dose at the lumbar spine. In the present analysis, when the trial participants were grouped according to whether their baseline 25OHD was ≤30 nmol/L or above this threshold, significant treatment effects were apparent at both the spine and hip in those with baseline 25OHD ≤30 nmol/L, but no significant effects were apparent in those with baseline 25OHD above this level. There was evidence of a similar threshold for effects on parathyroid hormone, but no groups showed changes in bone turnover markers during the study. It is concluded that vitamin D supplements only increase bone density in adults with nadir 25OHD ≤30 nmol/L. This moves us further toward a trial-based definition of vitamin D deficiency in adults with adequate calcium intakes and suggests that supplement use should be targeted accordingly. Future trials of vitamin D supplementation should focus on individuals with 25OHD concentrations in this range. © 2018 American Society for Bone and Mineral Research.

A sorafenib-sparing effect in the treatment of thyroid carcinoma cells attained by co-treatment with a novel isoflavone derivative and 1,25 dihydroxyvitamin D3.

BACKGROUND: Sorafenib improves progression-free survival in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma, but causes severe side effects. Estrogens may accelerate thyroid carcinoma cell growth. Our group recently reported that isoflavone derivative 7-(O)-carboxymethyl daidzein conjugated to N-t-boc-hexylenediamine (cD-tboc), a novel anti-estrogenic compound, retards the growth of both thyroid carcinoma cell lines and cultured human carcinoma cells. Vitamin D receptor (VDR) is expressed in malignant cells and responds to 1,25 dihydroxyvitamin D3 (1.25D) by decreased proliferative activity in vitro. The purpose of this study was to examine the effects of vitamin D metabolites (VDM) on the expression of estrogen receptors (ERs), VDR, and 1OHase mRNA, and to evaluate the inhibitory effect of low doses of sorafenib in combination with cDtboc and VDM on cell proliferation in cultured human papillary thyroid carcinoma (PTC). METHODS: In 19 cultured PTC specimens and 19 normal thyroid specimens, harvested during thyroidectomies from the same patients, expression levels of ERα, ERß, VDR, and 1 alpha-hydroxylase (1OHase) mRNA (by quantitative real-time PCR) were determined at baseline and after treatment with VMD. Cell proliferation was determined by measurement of 3[H] thymidine incorporation after treatment with sorafenib alone, sorafenib with added 1.25D or cD-tboc, and sorafenib with both 1.25D and cD-tboc added. RESULTS: 1,25D increased mRNA expression of all tested genes in the malignant and normal thyroid cells, while the ERα mRNA of the normal cells was unaffected. 1.25D dose-dependently inhibited cell proliferation in the malignant cells. The inhibitory effect of sorafenib on cell proliferation in the malignant cells was amplified after the addition of cDtboc and 1.25D, such that the maximal inhibition was not only greater, but also had been attained at a 10-fold lower concentration of sorafenib (20 µg/ml). This inhibition was similar to that of the generally used concentration of sorafenib (200 µg/ml) alone. CONCLUSIONS: The demonstration that low concentrations of cDtboc and 1.25D markedly amplify the inhibitory effect of sorafenib on the growth of human PTC supports the use of a 10-fold lower concentration of sorafenib. The findings may promote a new combination treatment for progressive radioactive iodine-refractory PTC.

Effects of cholecalciferol supplementation on serum and urinary vitamin D metabolites and binding protein in HIV-infected youth.

Vitamin D insufficiency is widespread in HIV-infected patients. HIV and/or antiretroviral therapy (ART), particularly efavirenz (EFV), may interfere with vitamin D metabolism. However, few data from randomized, controlled trials exist. Here, we investigate changes in vitamin D metabolites and binding protein (VDBP) after 6 months of supplementation in a randomized, active-control, double-blind trial investigating 2 different monthly cholecalciferol (vitamin D3) doses [60,000 (medium) or 120,000 (high) IU/month] vs. a control arm of 18,000 IU/month in 8-25year old HIV-infected youth on ART with HIV-1 RNA <1000 copies/mL and baseline 25-hydroxycholecalciferol (25(OH)D3) ≤30ng/mL. A matched healthy uninfected group was enrolled in a similar parallel study for comparison. Changes after 6 months were analyzed as intent-to-treat within/between groups [control group (low dose) vs. combined supplementation doses (medium+high)]. At 6 months, 55% vs. 82% of subjects in control and supplementation groups, respectively, reached 25(OH)D3 ≥30ng/mL (P=0.01) with no difference between medium and high doses (both 82% ≥30ng/mL). There were few differences for those on EFV vs. no-EFV, except serum VDBP decreased in EFV-treated subjects (both within- and between-groups P≤0.01). There were no significant differences between the HIV-infected vs. healthy uninfected groups. The major finding of the present study is that cholecalciferol supplementation (60,000 or 120,000 IU/month) effectively raises serum 25(OH)D3 in the majority of HIV-infected subjects, regardless of EFV use. Notably, response to supplementation was similar to that of uninfected subjects.

Metabolomics: A potential way to know the role of vitamin D on multiple sclerosis.

The literature about the influence of vitamin D on multiple sclerosis (MS) is very controversial, possibly as a result of the way through which the research on the subject has been conducted. The studies developed so far have been focused exclusively on gene expression: the effect of a given vitamin D metabolite on target receptors. The influence of the vitamin D status (either natural or after supplementation) on MS has been studied by measurement of the 25 monohydroxylated metabolite (also known as circulating form), despite the 1,25 dihydroxylated metabolite is considered the active form. In the light of the multiple metabolic pathways in which both forms of vitamin D (D2 and D3) are involved, monitoring of the metabolites is crucial to know the activity of the target enzymes as a function of both the state of the MS patient and the clinical treatment applied. The study of metabolomics aspects is here proposed to clarify the present controversy. In "omics" terms, our proposal is to take profit from up-stream information-thus is, from metabolomics to genomics-with a potential subsequent step to systems biology, if required.