Guri Grimnes

No significant effect on bone mineral density by high doses of vitamin D3 given to overweight subjects for one year.

BackgroundIn meta-analyses supplementation with vitamin D appears to reduce incidence of fractures, and in cross-sectional studies there is a positive association between serum 25-hydroxyvitamin D (25(OH)D) levels and bone mineral density (BMD). However, the effect of supplementation with high doses of vitamin D on BMD is more uncertain and could in theory have both positive and negative effects.MethodsThe study was a one year, double blind placebo-controlled intervention trial performed at the University Hospital of North Norway. 421 subjects, 21 - 70 years old, were included and 312 completed the study. The subjects were randomized to vitamin D3 40.000 IU per week (DD group), vitamin D3 20.000 IU per week (DP group), or placebo (PP group). All subjects were given 500 mg calcium daily. Serum 25(OH)D, osteoprotegrin (OPG), receptoractivator of nuclear factor-kappaB ligand (RANKL), and BMD at the lumbar spine and the hip were measured before and at the end of the study.ResultsAt baseline the mean serum 25(OH)D levels were 58 nmol/L (all subjects) and increased to 141 and 100 nmol/L in the DD and DP groups, respectively. After one year, no significant differences were found between the three groups regarding change in BMD, serum OPG or RANKL.ConclusionsSupplementation with high doses of vitamin D for one year does not appear to have a negative effect on BMD in healthy subjects. In order to disclose a positive effect, subjects with low BMD and/or low serum 25(OH)D levels need to be studied.Trial registrationThe trial was registered at ClinicalTrials.gov (NCT00243256).

Vitamin D deficiency in Europe: pandemic?

Background: Vitamin D deficiency has been described as being pandemic, but serum 25-hydroxyvitamin D [25(OH)D] distribution data for the European Union are of very variable quality. The NIH-led international Vitamin D Standardization Program (VDSP) has developed protocols for standardizing existing 25(OH)D values from national health/nutrition surveys. Objective: This study applied VDSP protocols to serum 25(OH)D data from representative childhood/teenage and adult/older adult European populations, representing a sizable geographical footprint, to better quantify the prevalence of vitamin D deficiency in Europe. Design: The VDSP protocols were applied in 14 population studies [reanalysis of subsets of serum 25(OH)D in 11 studies and complete analysis of all samples from 3 studies that had not previously measured it] by using certified liquid chromatography–tandem mass spectrometry on biobanked sera. These data were combined with standardized serum 25(OH)D data from 4 previously standardized studies (for a total n = 55,844). Prevalence estimates of vitamin D deficiency [using various serum 25(OH)D thresholds] were generated on the basis of standardized 25(OH)D data. Results: An overall pooled estimate, irrespective of age group, ethnic mix, and latitude of study populations, showed that 13.0% of the 55,844 European individuals had serum 25(OH)D concentrations <30 nmol/L on average in the year, with 17.7% and 8.3% in those sampled during the extended winter (October–March) and summer (April–November) periods, respectively. According to an alternate suggested definition of vitamin D deficiency (<50 nmol/L), the prevalence was 40.4%. Dark-skinned ethnic subgroups had much higher (3- to 71-fold) prevalence of serum 25(OH)D <30 nmol/L than did white populations. Conclusions: Vitamin D deficiency is evident throughout the European population at prevalence rates that are concerning and that require action from a public health perspective. What direction these strategies take will depend on European policy but should aim to ensure vitamin D intakes that are protective against vitamin D deficiency in the majority of the European population.

Tracking of Serum 25-Hydroxyvitamin D Levels During 14 Years in a Population-based Study and During 12 Months in an Intervention Study

Low serum 25-hydroxyvitamin D (25(OH)D) levels are associated with risk factors for cardiovascular disease, and they also appear to predict later development of type 2 diabetes, cancer, and an increased mortality rate. These predictions are all based on a single 25(OH)D measurement, but so far there are no known reports on tracking of serum 25(OH)D levels. In the present Norwegian study, serum 25(OH)D levels were measured 1) in 2,668 subjects in the 1994 and 2008 Tromsø surveys and 2) every third month for 1 year in 94 subjects randomly assigned to placebo in a vitamin D intervention study. There was a marked seasonal variation in 25(OH)D, and, depending on the method of adjusting for season, the correlation coefficient between serum 25(OH)D measurements from 1994 and 2008 ranged from 0.42 to 0.52. In the 1-year intervention study, the correlation between baseline and 12-month values was 0.80. Apart from the effect of season, changes in weight, intake of vitamin D, and physical activity were related to change in serum 25(OH)D levels. Tracking of serum 25(OH)D appears similar to that for blood pressure and serum lipids, and it provides some support for the use of a single 25(OH)D measurement to predict future health outcomes.

Vitamin D and metabolic health with special reference to the effect of vitamin D on serum lipids

Considering that the vitamin D receptor as well as the 1-α-hydroxylase enzyme that converts 25-hydroxyvitamin D (25(OH)D) to its active form 1,25-dihydroxyvitamin D have been found in tissues throughout the body, it is likely that vitamin D is important for more than the calcium balance. Accordingly, low serum levels of 25(OH)D have been associated with mortality, cardiovascular disease, type 2 diabetes, hypertension and obesity. Low serum levels of 25(OH)D have also been associated with an unfavourable lipid profile, which could possible explain the relation with cardiovascular disease and mortality. However, the relation between vitamin D and lipids have so far received little attention and is therefore the main focus of the present review. A PubMed search identified 22 cross-sectional studies where serum levels of 25(OH)D and lipids were related and that included a minimum of 500 subjects, and 10 placebo-controlled double-blind intervention studies with vitamin D where more than 50 subjects were included. In all the cross-sectional studies serum 25(OH)D was positively associated with high-density lipoprotein cholesterol (HDL-C) resulting in a favourable low-density lipoprotein cholesterol (LDL-C) (or total cholesterol) to HDL-C ratio. There was also a uniform agreement between studies on a negative relation between serum 25(OH)D and triglycerides (TG). On the other hand, the intervention studies gave divergent results, with some showing a positive and some a negative effect of vitamin D supplementation. However, none of the intervention studies were specifically designed for evaluating the relation between vitamin D and lipids, none had hyperlipemia as an inclusion criterion, and none were sufficiently powered. In only one study was a significant effect seen with an 8% (0.28 mmol/L) increase in serum LDL-C and a 16% (0.22 mmol/L) decrease in serum TG in those given vitamin D as compared to the placebo group. Accordingly, the effect of vitamin D supplementation on serum lipids is at present uncertain. Considering the numerous other promising vitamins and minerals that when properly tested have been disappointing, one should wait for the results of forthcoming vitamin D intervention studies before drawing conclusions on potential beneficial effects of vitamin D.

Low serum 25-hydroxyvitamin D levels are associated with increased all-cause mortality risk in a general population: the Tromsø study.

OBJECTIVE Ecologic and observational studies have suggested an association between serum 25-hydroxyvitamin D (25(OH)D) levels and cardiovascular disease (CVD) risk factors, CVD mortality, and cancer mortality. Based on this, low serum 25(OH)D levels should be associated with higher all-cause mortality in a general population. This hypothesis was tested in the present study. DESIGN The Tromsø study is a longitudinal population-based multipurpose study initiated in 1974 with focus on lifestyle-related diseases. Our data are based on the fourth Tromsø study carried out in 1994-1995. METHODS Information about death and cause of death was registered by obtaining information from the National Directory of Residents and the Death Cause Registry. Serum 25(OH)D was measured in 7161 participants in the fourth Tromsø study. Results are presented for smokers (n=2410) and non-smokers (n=4751) separately as our immunoassay seems to overestimate 25(OH)D levels for smokers. RESULTS During a mean 11.7 years of follow-up, 1359 (19.0%) participants died. In multivariate regression models, there was a significantly increased risk of all-cause mortality (hazard ratio (HR) 1.32, confidence interval (CI) 1.07-1.62) among non-smoking participants in the lowest 25(OH)D quartile when compared with participants in the highest quartile. Equivalent results for smokers were not significant (HR 1.06, CI 0.83-1.35). CONCLUSIONS Low serum 25(OH)D levels were associated with increased all-cause mortality for non-smokers, but the results did not reach statistical significance for smokers. However, low 25(OH)D levels are known to be associated with impaired general health, and randomized controlled studies are needed to address the question of causality.

High serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile

Background/Objectives:Low serum 25-hydroxyvitamin D (25(OH)D) concentrations are related to increased mortality. One possible explanation could be an association between serum 25(OH)D and serum lipids.Subjects/Methods:The study was performed at the University of Tromsø, Northern Norway. In total, 8018 nonsmoking and 2087 smoking subjects were included in a cross-sectional study performed in 2008, and 1762 nonsmoking and 397 smoking subjects in a longitudinal study from 1994/1995 to 2008. Nonfasting serum 25(OH)D, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C ratio and triacylglycerol (TAG) were measured.Results:After adjustment for gender, age, sample month and body mass index in the cross-sectional study, there was a significant increase in serum TC, HDL-C and LDL-C, and a significant decrease in serum LDL-C/HDL-C ratio and TAG across increasing serum 25(OH)D quartiles. For serum HDL-C and TAG in nonsmokers the differences between the means for the highest and lowest serum 25(OH)D quartiles were 6.0 and 18.5%, respectively. In the longitudinal study, an increase in serum 25(OH)D was associated with a significant decrease in serum TAG.Conclusions:There is a cross-sectional association between serum 25(OH)D and serum lipids, and a longitudinal association over 14 years between serum 25(OH)D and TAG, which may contribute to explain the relation between low serum 25(OH)D concentrations and mortality.

Serum 25-Hydroxyvitamin D Levels Are Strongly Related to Systolic Blood Pressure But Do Not Predict Future Hypertension

Vitamin D receptors have been detected in vascular smooth muscle cells, and 1,25-dihydroxyvitamin D inhibits the renin mRNA expression. Epidemiological studies show an inverse relation between serum 25-hydoxyvitamin D levels and blood pressure, and low serum 25-hydoxyvitamin D levels are reported to be predictors of future development of hypertension. This may indicate an important role for vitamin D in blood pressure regulation. In the present study, 25-hydoxyvitamin D was measured in sera collected in 1994 from 4125 subjects who did not use blood pressure medication, and thereafter measurement was repeated in 2008 for 2385 of these subjects. In sera from 1994 there was a significant decrease in age, body mass index, and systolic blood pressure and a significant increase in physical activity score across increasing 25-hydoxyvitamin D quartiles. After adjusting for sex, age, body mass index, and physical activity, the difference in systolic blood pressure between the lowest and highest serum 25-hydoxyvitamin D quartiles was 3.6 mm Hg. After adjustment for confounders, serum 25-hydoxyvitamin D from 1994 did not predict future hypertension or increase in blood pressure, nor was there any significant association between change in serum 25-hydoxyvitamin D from 1994 to 2008 and change in blood pressure. Our results do not support a causal role for vitamin D in blood pressure regulation, and large randomized clinical trials, preferably including subjects with hypertension and/or low serum 25-hydoxyvitamin D levels, are greatly needed to clarify whether vitamin D supplementation affects the blood pressure.

Baseline serum 25‐hydroxyvitamin D concentrations in the Tromsø Study 1994–95 and risk of developing type 2 diabetes mellitus during 11 years of follow‐up

Diabet. Med. 27, 1107–1115 (2010)

The Relationship between Serum TSH and Bone Mineral Density in Men and Postmenopausal Women: The Tromsø Study

BACKGROUND Hyperthyroidism is associated with osteoporosis, and it has recently been suggested that thyroid-stimulating hormone (TSH) has bone protective properties. We wanted to explore the relationship between serum TSH and bone mineral density (BMD) in a healthy population. METHODS This study included 993 postmenopausal females and 968 males with valid measurements of BMD at the hip and forearm in the fifth Tromsø study conducted in 2001. Participants with major diseases or medication affecting BMD or thyroid function were excluded. The subjects were divided into six different groups based on the 2.5 and 97.5 percentiles of serum TSH and the quartiles in between. Multiple linear regression adjusting for age; weight; height; smoking status; physical activity level; and for women, use of hormonal replacement therapy was used in the analyses. RESULTS After multivariate adjustment, the 28 men and 18 women with serum TSH below the 2.5 percentile had significantly lower BMD at the ultradistal (women) and distal (both sexes) forearm than the 921 men and 950 women with serum TSH in the normal range. Also, the 25 postmenopausal women with serum TSH above the 97.5 percentile had significantly higher BMD at the femoral neck than women with serum TSH in the normal range. Across the normal range of serum TSH, there was no association between TSH and BMD, and serum TSH as a continuous variable had no effect on BMD in the multiple linear regression model. CONCLUSIONS Within the normal range of serum TSH, serum TSH was not associated with BMD. The small groups of men and women with serum TSH consistent with hyperthyroidism had lower BMD at the forearm than those with serum TSH in the normal range.

Polymorphisms Related to the Serum 25-Hydroxyvitamin D Level and Risk of Myocardial Infarction, Diabetes, Cancer and Mortality. The Tromsø Study

Objective Low serum 25(OH)D levels are associated with cardiovascular risk factors, and also predict future myocardial infarction (MI), type 2 diabetes (T2DM), cancer and all-cause mortality. Recently several single nucleotide polymorphisms (SNPs) associated with serum 25-hydroxyvitamin D (25(OH)D) level have been identified. If these relations are causal one would expect a similar association between these SNPs and health. Methods DNA was prepared from subjects who participated in the fourth survey of the Tromsø Study in 1994–1995 and who were registered with the endpoints MI, T2DM, cancer or death as well as a randomly selected control group. The endpoint registers were complete up to 2007–2010. Genotyping was performed for 17 SNPs related to the serum 25(OH)D level. Results A total of 9528 subjects were selected for genetic analyses which were successfully performed for at least one SNP in 9471 subjects. Among these, 2025 were registered with MI, 1092 with T2DM, 2924 with cancer and 3828 had died. The mean differences in serum 25(OH)D levels between SNP genotypes with the lowest and highest serum 25(OH)D levels varied from 0.1 to 7.8 nmol/L. A genotype score based on weighted risk alleles regarding low serum 25(OH)D levels was established. There was no consistent association between the genotype score or individuals SNPs and MI, T2DM, cancer, mortality or risk factors for disease. However, for rs6013897 genotypes (located at the 24-hydroxylase gene (CYP24A1)) there was a significant association with breast cancer (P<0.05). Conclusion Our results do not support nor exclude a causal relationship between serum 25(OH)D levels and MI, T2DM, cancer or mortality, and our observation on breast cancer needs confirmation. Further genetic studies are warranted, particularly in populations with vitamin D deficiency. Trial Registration ClinicalTrials.gov NCT01395303