Kelly M. Seamans

Estimation of the dietary requirement for vitamin D in healthy adults

BACKGROUND Knowledge gaps have contributed to considerable variation among international dietary recommendations for vitamin D. OBJECTIVE We aimed to establish the distribution of dietary vitamin D required to maintain serum 25-hydroxyvitamin D [25(OH)D] concentrations above several proposed cutoffs (ie, 25, 37.5, 50, and 80 nmol/L) during wintertime after adjustment for the effect of summer sunshine exposure and diet. DESIGN A randomized, placebo-controlled, double-blind 22-wk intervention study was conducted in men and women aged 20-40 y (n = 238) by using different supplemental doses (0, 5, 10, and 15 microg/d) of vitamin D(3) throughout the winter. Serum 25(OH)D concentrations were measured by using enzyme-linked immunoassay at baseline (October 2006) and endpoint (March 2007). RESULTS There were clear dose-related increments (P < 0.0001) in serum 25(OH)D with increasing supplemental vitamin D(3). The slope of the relation between vitamin D intake and serum 25(OH)D was 1.96 nmol x L(-1) x microg(-1) intake. The vitamin D intake that maintained serum 25(OH)D concentrations of >25 nmol/L in 97.5% of the sample was 8.7 microg/d. This intake ranged from 7.2 microg/d in those who enjoyed sunshine exposure, 8.8 microg/d in those who sometimes had sun exposure, and 12.3 microg/d in those who avoided sunshine. Vitamin D intakes required to maintain serum 25(OH)D concentrations of >37.5, >50, and >80 nmol/L in 97.5% of the sample were 19.9, 28.0, and 41.1 microg/d, respectively. CONCLUSION The range of vitamin D intakes required to ensure maintenance of wintertime vitamin D status [as defined by incremental cutoffs of serum 25(OH)D] in the vast majority (>97.5%) of 20-40-y-old adults, considering a variety of sun exposure preferences, is between 7.2 and 41.1 microg/d.

Existing and potentially novel functional markers of vitamin D status: a systematic review

BACKGROUND Although serum 25-hydroxyvitamin D [25(OH)D] is the currently accepted vitamin D status marker of choice, use of other biomarkers or functional endpoints have been suggested. OBJECTIVE The objective was to systematically review the effectiveness of 25(OH)D, parathyroid hormone (PTH), bone turnover markers, bone mineral density (BMD), and calcium absorption as biomarkers of vitamin D status. DESIGN Methods included a structured search on Ovid MEDLINE, EMBASE (Ovid), and Cochrane CENTRAL; rigorous inclusion/exclusion criteria; data extraction; quality assessment; meta-analysis; and meta-regression. RESULTS Thirty-six vitamin D supplementation randomized controlled trials (RCTs) and 4 before-after studies were included. Vitamin D supplementation significantly raised circulating 25(OH)D in all but one RCT, but the response was highly heterogeneous [weighted mean difference (WMD): 34.1 nmol/L; 95% CI: 28.9, 39.2; 32 RCTs; I2 = 97%). Vitamin D supplementation (without calcium) significantly lowered circulating PTH (WMD: -0.29 pmol/L; 95% CI: -0.56, -0.02; 11 RCTs; I2 = 29%), but this was not apparent in the presence of calcium supplementation. There was a suggestion that whole-body or lumbar spine BMD may be a useful biomarker in older people but not in adolescents. Bone turnover markers were not useful biomarkers of vitamin D status, but 4 before-after studies suggested that intestinal calcium absorption may respond to vitamin D status. CONCLUSIONS This systematic review confirmed that circulating 25(OH)D is a robust and reliable marker of vitamin D status. Further research is needed to clarify which population subgroups show responses of PTH, BMD, and/or calcium absorption in response to changes in vitamin D status.

Estimation of the dietary requirement for vitamin D in free-living adults ≥64 y of age

BACKGROUND Older adults may be more prone to developing vitamin D deficiency than younger adults. Dietary requirements for vitamin D in older adults are based on limited evidence. OBJECTIVE The objective was to establish the dietary intake of vitamin D required to maintain serum 25-hydroxyvitamin D [25(OH)D] concentrations above various cutoffs between 25 and 80 nmol/L during wintertime, which accounted for the effect of summer sunshine exposure and diet. DESIGN A randomized, placebo-controlled, double-blind, 22-wk intervention was conducted in men and women aged >/=64 y (n = 225) at supplemental levels of 0, 5, 10, and 15 microg vitamin D(3)/d from October 2007 to March 2008. RESULTS Clear dose-related increments (P < 0.0001) in serum 25(OH)D were observed with increasing supplemental vitamin D(3) intakes. The slope of the relation between total vitamin D intake and serum 25(OH)D was 1.97 nmol . L(-1) . microg intake(-1). The vitamin D intake that maintained serum 25(OH)D concentrations >25 nmol/L in 97.5% of the sample was 8.6 microg/d. Intakes were 7.9 and 11.4 microg/d in those who reported a minimum of 15 min daily summer sunshine exposure or less, respectively. The intakes required to maintain serum 25(OH)D concentrations of >37.5, >50, and >80 nmol/L in 97.5% of the sample were 17.2, 24.7, and 38.7 microg/d, respectively. CONCLUSION To ensure that the vitamin D requirement is met by the vast majority (>97.5%) of adults aged >/=64 y during winter, between 7.9 and 42.8 microg vitamin D/d is required, depending on summer sun exposure and the threshold of adequacy of 25(OH)D. This trial was registered at http://www.controlled-trials.com/ISRCTN20236112 as ISRCTN registration no. ISRCTN20236112.

An Updated Systematic Review and Meta-Analysis of the Efficacy of Vitamin D Food Fortification

Food fortification is a potentially effective public health strategy to increase vitamin D intakes and circulating 25-hydroxyvitamin D [25(OH)D] concentrations. We updated a previous systematic review to evaluate current evidence from randomized controlled intervention studies in community-dwelling adults of the effect of fortified foods on 25(OH)D concentrations. Ovid MEDLINE, PubMed, CINAHL, Embase, and Cochrane Central Register of Controlled Trials were searched for randomized controlled intervention studies with vitamin D-fortified foods in free-living adults and data on circulating 25(OH)D. Two reviewers independently screened 441 papers for eligibility and extracted the relevant data. A meta-analysis of the absolute mean change in circulating 25(OH)D concentrations was conducted using a random effects model. Sixteen studies from 15 publications were included, of which 14 showed a significant effect of fortified foods on 25(OH)D concentrations. Heterogeneity was high (P = <0.0001, I(2) = 89%) and was partly explained by dose, latitude (range, 3-60°), and baseline 25(OH)D (range, 24.0-83.6 nmol/L). When combined in a random effects analysis (n = 1513; 767 treated, 746 controls), a mean individual intake of ~11 μg/d (440 IU/d) from fortified foods (range, 3-25 μg/d) increased 25(OH)D by 19.4 nmol/L (95% CI: 13.9, 24.9), corresponding to a 1.2 nmol/L (95% CI: 0.72, 1.68) increase in 25(OH)D for each 1 μg ingested. Vitamin D food fortification increases circulating 25(OH)D concentrations in community-dwelling adults. Safe and effective food-based strategies could increase 25(OH)D across the population distribution and prevent vitamin D deficiency with potential benefit for public health.

Relative effectiveness of oral 25-hydroxyvitamin D3 and vitamin D3 in raising wintertime serum 25-hydroxyvitamin D in older adults

BACKGROUND The relative potency of 25-hydroxyvitamin D3 to vitamin D3 needs to be better defined so that food-composition tables can better reflect the true vitamin D nutritive value of certain foods. OBJECTIVE We performed a randomized, controlled intervention study in apparently healthy, free-living adults to investigate whether the intake of 25-hydroxyvitamin D3 is 5 times more potent in raising serum 25-hydroxyvitamin D [25(OH)D] during winter compared with an equivalent amount of vitamin D3. DESIGN A randomized, placebo-controlled, double-blind intervention study was conducted in adults aged ≥50 y (n = 56) who consumed a placebo, 20 μg vitamin D3, or 7 or 20 μg 25-hydroxyvitamin D3 daily throughout 10 wk of winter. Serum 25(OH)D was measured by using an enzyme-linked immunoassay, and serum albumin-corrected calcium (S-Ca) was assessed colorimetrically at the baseline, midpoint, and endpoint of the study. RESULTS The mean (±SD) increases (per microgram of vitamin D compound) in serum 25(OH)D concentrations over baseline after 10 wk of supplementation were 0.96 ± 0.62, 4.02 ± 1.27, and 4.77 ± 1.04 nmol · L(-1) · μg intake(-1) for the 20-μg vitamin D3/d and 7- and 20-μg 25-hydroxyvitamin D3/d groups, respectively. A comparison of the 7- and 20-μg 25-hydroxyvitamin D3/d groups with the 20-μg vitamin D3/d group yielded conversion factors of 4.2 and 5, respectively. There was no effect of treatment on S-Ca concentrations and no incidence of hypercalcemia (S-Ca >2.6 nmol/L). CONCLUSIONS Each microgram of orally consumed 25-hydroxyvitamin D3 was about 5 times more effective in raising serum 25(OH)D in older adults in winter than an equivalent amount of vitamin D3. This conversion factor could be used in food-compositional tables for relevant foods. This study was registered at clinicaltrials.gov as NCT01398202.

A systematic review and meta-regression analysis of the vitamin D intake-serum 25-hydroxyvitamin D relationship to inform European recommendations

The present study used a systematic review approach to identify relevant randomised control trials (RCT) with vitamin D and then apply meta-regression to explore the most appropriate model of the vitamin D intake-serum 25-hydroxyvitamin D (25(OH)D) relationship to underpin setting reference intake values. Methods included an updated structured search on Ovid MEDLINE; rigorous inclusion/exclusion criteria; data extraction; and meta-regression (using different model constructs). In particular, priority was given to data from winter-based RCT performed at latitudes >49·5°N (n 12). A combined weighted linear model meta-regression analyses of natural log (Ln) total vitamin D intake (i.e. diet and supplemental vitamin D) v. achieved serum 25(OH)D in winter (that used by the North American Dietary Reference Intake Committee) produced a curvilinear relationship (mean (95 % lower CI) serum 25(OH)D (nmol/l) = 9·2 (8·5) Ln (total vitamin D)). Use of non-transformed total vitamin D intake data (maximum 1400 IU/d; 35 μg/d) provided for a more linear relationship (mean serum 25(OH)D (nmol/l) = 0·044 × (total vitamin D)+33·035). Although inputting an intake of 600 IU/d (i.e. the RDA) into the 95 % lower CI curvilinear and linear models predicted a serum 25(OH)D of 54·4 and 55·2 nmol/l, respectively, the total vitamin D intake that would achieve 50 (and 40) nmol/l serum 25(OH)D was 359 (111) and 480 (260) IU/d, respectively. Inclusion of 95 % range in the model to account for inter-individual variability increased the predicted intake of vitamin D needed to maintain serum 25(OH)D ≥ 50 nmol/l to 930 IU/d. The model used to describe the vitamin D intake-status relationship needs to be considered carefully when setting new reference intake values in the Europe.

Vitamin D status and measures of cognitive function in healthy older European adults

Background/Objectives:Data from human studies that have investigated the association between vitamin D status and cognitive function in elderly adults are conflicting. The objective of this study was to assess vitamin D status (reflected by serum 25-hydroxyvitamin D (25(OH)D)) in older European subjects (n=387; aged 55–87 years) and examine its association with measures of cognitive function.Subjects/Methods:Serum 25(OH)D was assessed using enzyme-linked immunosorbent assay, whereas measures of cognitive function were assessed using a comprehensive Cambridge Neuropsychological Testing Automated Battery (CANTAB).Results:In all, 12, 36 and 64% of subjects had serum 25(OH)D concentrations <30, <50 and <80 nmol/l, respectively, throughout the year. Serum 25(OH)D was significantly and inversely correlated with four assessments within the spatial working memory (SWM) test parameter (SWM between errors (r=−0.166; P=0.003); SWM between errors 8 boxes (r=−0.134; P=0.038); SWM strategy (r=−0.246; P<0.0001); and SWM total errors (r=−0.174; P<0.003)). When subjects were stratified on the basis of tertiles (T) of serum 25(OH)D (<47.6 (T1); 47.6–85.8 (T2); and >85.8 (T3) nmol/l), fewer errors in SWM test scores occurred in subjects in the third T when compared with the first T (P<0.05–0.084). Stratification by sex showed that these differences between tertiles strengthened (P<0.001–0.043) in the females, but the differences were not significant (P>0.6) in males.Conclusions:Vitamin D insufficiency, but not deficiency, is widespread in the older population of several European countries. Low vitamin D status was associated with a reduced capacity for SWM, particularly in women.

The 3 Epimer of 25-Hydroxycholecalciferol Is Present in the Circulation of the Majority of Adults in a Nationally Representative Sample and Has Endogenous Origins

Fundamental knowledge gaps in relation to the 3 epimer of 25-hydroxycholecalciferol [3-epi-25(OH)D₃] limit our understanding of its relevance for vitamin D nutrition and health. The aims of this study were to characterize the 3-epi-25(OH)D₃ concentrations in a nationally representative sample of adults and explore its determinants. We also used data from a recent randomized controlled trial (RCT) of supplemental cholecalciferol (vitamin D₃) conducted in winter in older adults to directly test the impact of changes in vitamin D status on serum 3-epi-25(OH)D3 concentrations. Serum 25-hydroxycholecalciferol [25(OH)D₃] and 3-epi-25(OH)D₃ concentrations (via LC-tandem mass spectrometry) from our vitamin D₃ RCT in adults (aged ≥50 y) and data on dietary, lifestyle, and biochemical characteristics of participants of the recent National Adult Nutrition Survey in Ireland (aged 18-84 y; n = 1122) were used in the present work. In the subsample of participants who had serum 3-epi-25(OH)D₃ concentrations greater than the limit of quantification (n = 1082; 96.4%), the mean, 10th, 50th (median), and 90th percentile concentrations were 2.50, 1.05, 2.18, and 4.30 nmol/L, respectively, whereas the maximum 3-epi-25(OH)D₃ concentration was 15.0 nmol/L. A regression model [explaining 29.9% of the variability in serum 3-epi-25(OH)D₃] showed that age >50 y, vitamin D supplement use, dietary vitamin D, meat intake, season of blood sampling, and sun exposure habits were significant positive determinants, whereas increasing waist circumference and serum 25-hydroxyergocalciferol concentration were significant negative determinants. The RCT data showed that mean serum 25(OH)D₃ and 3-epi-25(OH)D₃ concentrations increased (49.3% and 42.1%, respectively) and decreased (-28.0% and -29.1%, respectively) significantly (P < 0.0001) with vitamin D₃ (20 μg/d) and placebo supplementation, respectively, over 15 wk of winter. In conclusion, we provide data on serum 3-epi-25(OH)D₃ in a nationally representative sample of adults. Our combined observational and RCT data might suggest that both dietary supply and dermal synthesis of vitamin D₃ contribute to serum 3-epi-25(OH)D₃ concentration.

Cholecalciferol Supplementation throughout Winter Does Not Affect Markers of Bone Turnover in Healthy Young and Elderly Adults

Although there have been several studies of the effect of vitamin D status on bone turnover in the elderly, the findings are unclear, and, furthermore, to date very few have investigated this in young adults. The objective of these randomized, placebo-controlled, double-blind, 2-center intervention studies was to investigate the effect of cholecalciferol supplementation (0, 5, 10, and 15 microg cholecalciferol/d) throughout winter time on indices of vitamin D status and bone turnover in young (aged 20-40 y; n = 215) and elderly (aged > or = 64 y; n = 204) adults, with relatively high mean calcium intakes of 976 and 874 mg/d, respectively. Fasting serum concentrations of 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, bone-specific alkaline phosphatase, and carboxyterminal collagen crosslinks were measured by enzyme immunoassays at baseline and endpoint. Fok I and Taq I vitamin D receptor (VDR) genotypes were determined by real-time PCR. Endpoint serum 25(OH)D increased (P < 0.0001) in a dose-related manner with increasing supplemental cholecalciferol (up to 15 microg/d) in 20-40-y olds and up to 10 microg/d in > or = 64-y olds. Endpoint serum PTH was lower (P < 0.05) in the 3 cholecalciferol-supplemented groups compared with that in the placebo group in > or = 64-y olds, but cholecalciferol supplementation did not affect other markers in either cohort and there was no significant interaction with VDR genotype. In conclusion, cholecalciferol supplementation alone throughout winter did not affect bone turnover markers in apparently healthy young and elderly adults, even when stratified by VDR genotype.

Incremental Cholecalciferol Supplementation up to 15 μg/d Throughout Winter at 51–55° N Has No Effect on Biomarkers of Cardiovascular Risk in Healthy Young and Older Adults

Two separate, identical, double-blind, randomized, placebo-controlled intervention studies were carried out in the south and north of Ireland (51-55°N). Men and women aged 20-40 y (n = 202) and ≥64 y (n = 192) received cholecalciferol at doses of 0 (P), 5 (D3-5), 10 (D3-10), or 15 (D3-15) μg/d (0-600 IU) during wintertime. Serum 25-hydroxyvitamin D [s25(OH)D], intact parathyroid hormone, systolic and diastolic blood pressure, fasting lipids, glucose and insulin, HOMA-IR, high-sensitivity CRP, matrix metalloproteinase-9, and its inhibitor (tissue inhibitor metalloproteinase-1) were measured at baseline (October) and 22 wk later at endpoint (March). Vitamin D receptor Fok I and Taq I genotypes were analyzed and dietary intakes of vitamin D and calcium were assessed. In young adults, s25(OH)D decreased from baseline to endpoint (P < 0.001), except in the D3-15 group, who maintained the baseline concentration of ~70 nmol/L. Older adults had lower s25(OH)D at baseline (median, 54.2 nmol/L) and concentrations increased in the D3-10 and D3-15 groups (P < 0.001). There were no significant effects of supplementation on cardiovascular disease (CVD) risk biomarkers in either age group. Fasting glucose and total and HDL cholesterol were lower (P < 0.05) in older adults with the Fok 1 ff genotype than in those with FF or Ff. Putative effects of vitamin D on cardio-metabolic health will only be evident at higher intakes than the current RDA and possibly in individuals at particular risk of low s25(OH)D and/or CVD risk.