Tracking of serum 25-hydroxyvitamin D during 21 years.

BACKGROUND/OBJECTIVES: Our objective was to evaluate the degree of tracking for serum levels of 25-hydroxyvitamin D [25(OH)D] over time, by using data from three previously conducted surveys of the Tromsø study collected in the years 1994/1995 (Tromsø 4), 2007/2008 (Tromsø 6), and 2015/2016 (Tromsø 7). SUBJECTS/METHODS: Subjects with valid 25(OH)D measurements in all three surveys were included. 25(OH)D z-scores were used to adjust for seasonal variation. Z-scores and sextiles were used to illustrate tracking of 25(OH)D. RESULTS: 1702 subjects (572 males, 1130 females) fulfilled the inclusion criteria. Median (5th, 95th percentiles) age for these subjects was 55 (33, 65) years in Tromsø 4, and mean (SD) 25(OH)D levels were 57 (18) nmol/L, 59 (19) nmol/L, and 72 (21) nmol/L for Tromsø 4, Tromsø 6, and Tromsø 7, respectively. There was significant tracking of serum 25(OH)D over the 21 years period between the surveys of the Tromsø study. The correlation coefficient r between 25(OH)D z-scores from Tromsø 4 and Tromsø 6 was 0.40, and declined to 0.29 for the correlation between Tromsø 4 and Tromsø 7. Twenty-six percent of the subjects in the lowest 25(OH)D z-score sextile in Tromsø 4 were in the three highest sextiles of 25(OH)D in Tromsø 7. Similarly, 35% of those in the highest sextile in Tromsø 4 were in the lowest three sextiles in Tromsø 7. CONCLUSIONS: The degree of tracking for serum 25(OH)D declines over time, and the use of a single serum 25(OH)D measurement as an indicator of the vitamin-D status is questionable if used in long-lasting observational studies.

Four months vitamin D supplementation to vitamin D insufficient individuals does not improve muscular strength: A randomized controlled trial.

MAIN OBJECTIVE: The inconsistent results on the effects of vitamin D on muscle strength reported by intervention trials may partly be explained by inclusion of vitamin D sufficient individuals. The main objective was to study whether vitamin D supplementation will improve muscle strength in men and women with low serum vitamin D status, as measured by 25-hydroxyvitamin D (25(OH)D) at baseline. METHODS: 417 men and women aged 40-80 years were included and randomized to receive a loading dose of 100 000 IU (2500 ug) vitamin D3 followed by 20 000 IU (500 ug)/week, or placebo. Muscle strength was tested by dynamometers at baseline and after four months. RESULTS: Serum 25(OH)D levels increased from 32.6±11.1 nmol/l to 88.8±19.4 nmol/l (p<0.01) in the vitamin D group, while remaining low in the placebo group (baseline and final levels at 35.1±13.6 nmol/l and 30.7 ±9.7 nmol/l respectively). Muscle strength (hip flexion, biceps flexion, pectorals and handgrip strength) did not change in any of the groups. The results were the same in analyses stratified on sex, 25(OH)D above/below 25 nmol/L (10 ng/ml); smoking status; and BMI above/below 27 kg/m2. CONCLUSION: These data does not support vitamin D supplementation for improving muscle strength.

Smoking and other determinants of bone turnover.

The balance between bone resorption and formation may be assessed by measurement of bone turnover markers (BTMs), like carboxyl-terminal cross-linked telopeptide of type 1 collagen (CTX-1) and procollagen type 1 amino-terminal propeptide (P1NP). Smoking has been shown to influence bone turnover and to reduce bone mass density (BMD), the exact mechanism for this is, however, not settled. In this post-hoc study including 406 subjects (mean age 51.9 years), we aimed to study the impact of smoking on bone turnover. Moreover, we wanted to assess the inter-correlation between substances regulating bone metabolism and BTMs, as well as tracking over time. BMD measurements and serum analyses of CTX-1, P1NP, osteoprotegerin (OPG), receptor activator of nuclear factor ĸB ligand (RANKL), Dickkopf-1 (DKK1), sclerostin, tumor necrosis factor-α (TNF-α), and leptin were performed. Repeated serum measurements were made in 195 subjects after four months. Adjustments were made for sex, age, body mass index (BMI), smoking status, insulin resistance, serum calcium, parathyroid hormone, 25-hydroxyvitamin D and creatinine. Smokers had higher levels of DKK1 and OPG, and lower levels of RANKL, as reflected in lower BTMs and BMD compared to non-smokers. There were strong and predominantly positive inter-correlations between BTMs and the other substances, and there was a high degree of tracking with Spearman's rho from 0.72 to 0.92 (P < 0.001) between measurements four months apart. In conclusion, smokers exhibited higher levels of DKK1 and OPG and a lower bone turnover than did non-smokers. The strong inter-correlations between the serum parameters illustrate the coupling between bone resorption and formation and crosstalk between cells.

Effects of vitamin D supplementation on bone turnover markers and other bone-related substances in subjects with vitamin D deficiency.

In observational studies, vitamin D deficiency is a risk factor for low bone density and future fractures, whereas a causal relation has been difficult to show in randomized controlled trials (RCTs). Similarly, vitamin D deficiency has been associated with increased bone turnover, but RCTs with vitamin D have not shown conclusive effects. This could be due to inclusion of vitamin D sufficient subjects and low vitamin D doses. In the present study 399 subjects with mean baseline serum 25-hydroxyvitamin D (25(OH)D) 34.0 nmol/L completed a four months intervention with vitamin D3 20,000 IU per week versus placebo. Mean serum 25(OH)D increased to 89.0 nmol/L in the vitamin D group and decreased slightly in the placebo group. A small, but significant, decrease in the bone formation marker procollagen of type 1 amino-terminal propeptide (P1NP) was seen in the vitamin D group as compared to the placebo group (mean delta P1NP -1.2 pg/mL and 1.5 ng/mL, respectively, P < 0.01). No significant effects were seen on serum carboxyl-terminal telopeptide of type 1 collagen (CTX-1), Dickkopf-1, sclerostin, tumor necrosis factor-alpha, osteoprotegerin, receptor activator of nuclear factor ĸB ligand, or leptin. Subgroup analyses on subjects with low baseline serum 25(OH)D did not yield additional, significant results. In subjects with high baseline serum parathyroid hormone (PTH) > 6.5 pmol/L and post-intervention decrease in PTH, the decrease in P1NP was more pronounced, they also exhibited significantly reduced serum CTX-1 and increased serum sclerostin. In conclusion, supplementation with vitamin D appears to suppress bone turnover, possibly mediated by PTH reduction. Our findings need to be confirmed in even larger cohorts with vitamin D insufficient subjects.

Vitamin D supplementation has no effect on cognitive performance after four months in mid-aged and older subjects.

BACKGROUND: Low serum 25-hydroxyvitamin D (25(OH)D) levels are associated with impaired cognitive function, but the effect of vitamin D supplementation on cognitive function is uncertain. METHODS: 422 subjects were included in a randomized controlled trial with vitamin D (cholecalciferol) 100,000 IU given as a bolus dose followed by 20,000 IU per week versus placebo for four months. Cognitive function was evaluated with verbal recall test, coding test and tapping test. RESULTS: 374 subjects (mean age 52 years, 198 males) had complete cognitive tests both at baseline and at end of study. Mean baseline serum 25(OH)D level was 34 nmol/L. At baseline there were no significant associations between serum 25(OH)D and the three separate cognitive tests. At the end of the study mean serum 25(OH)D levels were 89 nmol/L and 31 nmol/L in the vitamin D and placebo groups, respectively. At the end of the study, there were no statistically significant differences between the two groups regarding change in the cognitive test scores. Nor did sub-group analyses based on gender, age, baseline serum 25(OH)D and cognitive test scores reveal significant differences between the two groups at the end of the study. CONCLUSIONS: Vitamin D supplementation did not improve cognitive function during a four months intervention in mid-aged and older subjects. TRIAL REGISTRATION: ClinicalTrials.govNCT02750293.

No improvement in depressive symptoms by vitamin D supplementation: results from a randomised controlled trial.

In observational studies, vitamin D deficiency is associated with depressive symptoms. However, randomised controlled trials (RCT) with vitamin D supplementation have not been conclusive. In the present study 206 subjects were randomised to vitamin D (100 000 IU (2500 µg) as a bolus dose followed by 20 000 IU (500 µg) per week) and 202 to placebo. The Beck Depression Inventory-II (BDI-II) was filled in at baseline and after 4 months at the end of the study. At baseline the mean age was 51·4 and 52·5 years and mean serum 25-hydroxyvitamin D (25(OH)D) 32·5 and 35·1 nmol/l in the vitamin D and placebo groups, respectively. Among the 408 subjects, 193 had a BDI-II score >4, and forty-five had a score >13. Twenty-three subjects were using anti-depressant or mood-stabilising drugs. At the end of the study, there were no significant differences in Δ BDI-II score (score at the end of the study minus score at baseline), regardless of analysing all subjects, subjects with or without psycopharmaca, or if performing subgroup analyses based on baseline and final serum 25(OH)D levels combined with categories of baseline BDI-II scores >4 or >13. In conclusion, we have not been able to demonstrate any significant effect of vitamin D supplementation on depressive symptoms. However, few of our subjects were clinically depressed. Future RCT should include subjects with more severe vitamin D deficiency as well as more depressed subjects than in our study. In such a setting vitamin D may probably be more relevant as an augmenter of standard antidepressant medication/treatment.

Vitamin D supplementation does not improve CVD risk factors in vitamin D-insufficient subjects.

OBJECTIVE: Low serum 25(OH)D levels are associated with cardiovascular disease (CVD) and some of its risk factors. However, in interventional studies, the effects of vitamin D supplementation have been uncertain, possibly due to inclusion of vitamin D-sufficient subjects. Our aim was therefore to examine effects of vitamin D supplementation on CVD risk factors in vitamin D-insufficient subjects. DESIGN: Double-blinded randomized controlled trial. METHODS: A 4-month interventional study with high-dose vitamin D (100,000 IU loading dose, followed by 20,000 IU/week) or placebo with measurements of blood pressure, lipids (total-, LDL- and HDL-cholesterol, triglycerides, apolipoproteins A1 and B), and glucose metabolism parameters (blood glucose, HbA1c, serum human receptors for advanced glycation end products (sRAGE), insulin, C-peptide and HOMA-IR). RESULTS: A total of 422 subjects with mean serum 25(OH)D level 34 nmol/L were included, with 411 subjects completing the study. Serum 25(OH)D levels increased with 56 nmol/L and decreased with 4 nmol/L in the vitamin D and placebo group, respectively. We found no statistically significant differences between the two groups in any of the measured CVD risk factors, except for a minor increase in sRAGE in the vitamin D group. Stratified analyses of subjects with low baseline serum 25(OH)D levels alone, or combined with blood pressure, lipid and HOMA-IR values above the median for the cohort, did not skew the results in favour of vitamin D supplementation. CONCLUSION: Supplementation with vitamin D in subjects with baseline vitamin D insufficiency does not improve CVD risk factor profile.

C3-epimerization of 25-hydroxyvitamin D increases with increasing serum 25-hydroxyvitamin D levels and shows a high degree of tracking over time.

OBJECTIVE: Evaluate the effects of serum 25-hydroxyvitamin D (25(OH)D) levels, vitamin D binding protein (DBP) and genetic factors on C3-epimerization of 25(OH)D and follow the tracking of the epimer during one year. DESIGN: Cross-sectional and longitudinal study. METHODS: Data from eight previously conducted, Tromsø based studies (3 observational, 5 randomized controlled trials) were combined. 25(OH)D serum samples were re-analyzed with a LC-MS/MS method that also resolves and measures the metabolite C3-epi-25(OH)D3. Data on vitamin D binding protein (DBP) phenotype (based on single nucleotide polymorphisms (SNPs) rs4588 and rs7041) and genetic determinants for serum 25(OH)D (SNPs rs2282679, rs10741657, rs3829251 and rs6013897) were collected where available. RESULTS: 2219 subjects were included. Median (5th, 95th percentiles) baseline serum values of 25(OH)D3, C3-epi-25(OH)D3, and %-C3-epi-25(OH)D3 were 49.1 (22.1, 92.8) nmol/L, 2.3 (0.9, 6.0) nmol/L and 4.4 (2.7, 8.4) %, respectively. The highest baseline values were 230.5 nmol/L for 25(OH)D3, 79.7 nmol/L for C3-epi-25(OH)D3 and 48.2% for %-C3-epi-25(OH)D3. There was a strong correlation between serum 25(OH)D3 and C3-epi-25(OH)D3. The %-C3-epi-25(OH)D3 value increased with increasing serum 25(OH)D3, but leveled off at ~7% at a 25(OH)D3 concentration of ~120-140 nmol/L. There was a significant degree of tracking for %-C3-epi-25(OH)D3 (correlation coefficient rho between baseline and 1-year values 0.39, P < 0.001). The %-C3-epi-25(OH)D3 level was not related to serum DBP level, DBP phenotype nor to SNPs related to serum 25(OH)D3 level. The serum 25(OH)D3 level could explain less than 3% of %-C3-epi-25(OH)D3 variation. CONCLUSIONS: There are considerable individual and reproducible differences in percent C3-epimerization of uncertain clinical importance.