The relationship between vitamin D intake and serum 25-hydroxyvitamin D in young children: a meta-regression to inform WHO/FAO vitamin D intake recommendations.

BACKGROUND: This work was commissioned by the WHO and FAO to inform their update of the vitamin D requirements for children below 4 years old. OBJECTIVE: The objective of this work was to undertake multi-level and multivariable dose-response modelling of serum 25OHD to total vitamin D intake in children below 4 years of age and to derive updated vitamin D requirements for young children. METHODS: Systematically identified randomized controlled trials among healthy children from 2 weeks up to 3.9 years of age provided with daily vitamin D supplements or vitamin D-fortified foods were included. Linear and non-linear random effects multi-level meta-regression models with and without covariates were fitted and compared. Inter-individual variability was included by simulating the individual serum 25OHD responses. The percentage of individuals reaching set minimal and maximal serum 25OHD thresholds were calculated and used to derive vitamin D requirements. RESULTS: A total of 31 trials with 186 data points, from North America, Europe, Asia and Australasia/Oceania, with latitudes ranging from 38°S to 61°N, and with participants of likely mostly light or medium skin pigmentation, were included; in 29 studies the children received vitamin D supplements and in two studies the children received vitamin D fortified milks with or without supplements. The dose-response relationship between vitamin D intake and serum 25OHD was best fitted with the unadjusted quadratic model; adding additional covariates, such as age, did not significantly improve the model. At a vitamin D intake of 10 µg/d, 97.3% of the individuals were predicted to achieve a minimal serum 25OHD threshold of 28 nmol/L. At a vitamin D intake of 35 µg/d, 1.4% of the individuals predicted to reach a maximal serum 25OHD threshold of 200 nmol/L. CONCLUSIONS: In conclusion, this paper details the methodological steps taken to derive vitamin D requirements in children below 4 years of age, including the addition of an inter-individual variability component.

Vitamin D fortification of foods - sensory, acceptability, cost, and public acceptance considerations.

In terms of vitamin D food fortification, there are a number of important considerations in relation to selection of the food vehicle and fortificant. While there has been much research focus on the ability of fortified foods to improve vitamin D status, other considerations, such as sensory properties and acceptability, cost, and public attitudes around vitamin D-fortified foods, have received less attention. Thus, the present narrative review aimed to summarize the existing knowledge around these important considerations. In summary, its findings suggest that: i) vitamin D addition to various food vehicles, at levels consistent with the supply of part or all the recommended intake, does not alter their sensory characteristics or overall acceptability; ii) overall, vitamin D fortification of foods is relatively cost-effective, despite the fact that some attitudinal studies highlighted participant concerns about the potential cost/expense of vitamin D-fortified foods; iii) evidence from various attitudinal studies suggest a high level of acceptance and/or purchase intention (i.e., extent to which customers are willing and inclined to buy) of vitamin D-fortified food products by the general public; and iv) there have been repeated calls for vitamin D public health educational/information campaigns to help educate consumers about the health risks associated with vitamin D deficiency and nutritional benefits associated with consumption of vitamin D-fortified foods. Such campaigns could positively mediate attitudes and acceptance of vitamin D-fortified foods amongst the public, and could also help address misconceptions and allay fears around vitamin D for concerned individuals. Lastly, the findings of the present review also highlight the existence of between-country differences, even within Europe, in relation to attitudes and purchase intention of vitamin D-fortified foods and the perceived appropriateness of certain food vehicles for vitamin D fortification, as well as the best mix of communication channels for a vitamin D public health educational/information campaign.

Serum 25-hydroxyvitamin D threshold and risk of rickets in young children: a systematic review and individual participant data meta-analysis to inform the development of dietary requirements for vitamin D.

PURPOSE: The objective of this systematic review was to determine a minimum serum 25-hydroxyvitamin D (25OHD) threshold based on the risk of having rickets in young children. This work was commissioned by the WHO and FAO within the framework of the update of the vitamin D requirements for children 0-3 years old. METHODS: A systematic search of Embase was conducted to identify studies involving children below  4 years of age with serum 25OHD levels and radiologically confirmed rickets, without any restriction related to the geographical location or language. Study-level and individual participant data (IPD)-level random effects multi-level meta-analyses were conducted. The odds, sensitivity and specificity for rickets at different serum 25OHD thresholds were calculated for all children as well as for children with adequate calcium intakes only. RESULTS: A total of 120 studies with 5412 participants were included. At the study-level, children with rickets had a mean serum 25OHD of 23 nmol/L (95% CI 19-27). At the IPD level, children with rickets had a median and mean serum 25OHD of 23 and 29 nmol/L, respectively. More than half (55%) of the children with rickets had serum 25OHD below 25 nmol/L, 62% below 30 nmol/L, and 79% below 40 nmol/L. Analysis of odds, sensitivities and specificities for nutritional rickets at different serum 25OHD thresholds suggested a minimal risk threshold of around 28 nmol/L for children with adequate calcium intakes and 40 nmol/L for children with low calcium intakes. CONCLUSION: This systematic review and IPD meta-analysis suggests that from a public health perspective and to inform the development of dietary requirements for vitamin D, a minimum serum 25OHD threshold of around 28 nmol/L and above would represent a low risk of nutritional rickets for the majority of children with an adequate calcium intake.

Vitamin D Status During Adolescence and the Impact of Lifestyle Changes: 2 Years' Follow-up From the Fit Futures Study.

CONTEXT: Longitudinal data regarding vitamin D status in adolescence is scarce. This study presents population-based data from an Arctic adolescent population (n = 589) at 16 and 18 years. OBJECTIVE: The aims of this study were to investigate changes in vitamin D status during 2 years in adolescence, and whether lifestyle changes were associated with serum 25-hydroxyvitamin D (s-25(OH)D) at follow-up. METHODS: Fit Futures is a longitudinal study at 69°N in Norway. Participants had their s-25(OH)D levels analyzed in their first and third year of upper secondary school (median age 16 and 18 years), in Fit Futures 1 (FF1) and Fit Futures 2 (FF2), respectively. Self-reported lifestyle habits were registered through questionnaires. The association between lifestyle changes and s-25(OH)D levels at follow-up were calculated by regression analyses, controlling for baseline s-25(OH)D levels. RESULTS: Longitudinal data were available for 309 girls and 280 boys. The proportion of adolescents with s-25(OH)D <50 nmol/L were 73.7% in FF1 and 77.1% in FF2, while the proportion <30 nmol/L constituted 35.7% in FF1 and 40.9% in FF2. Of those with s-25(OH)D <30 nmol/L (severe vitamin D deficiency) in FF1, 73.3% remained severely deficient in FF2. Among boys, an increase in UV exposure was significantly associated with higher s-25(OH)D levels in FF2 (beta; CI [nmol/L] 12.9; 9.1, 16.7). In girls, decreased vitamin/mineral supplement intake was significantly associated with lower s-25(OH)D at FF2 (-6.7; -10.2, -3.1), while increased UV (10.8; 7.0, 14.7) and combined hormonal contraceptive exposure (12.1; 6.0, 18.1) in FF2 was significantly associated with higher s-25(OH)D levels in FF2. CONCLUSION: Severe vitamin D deficiency was prevalent throughout adolescence. Lifestyle changes may alter s-25(OH)D levels in this age group.

Strategic food vehicles for vitamin D fortification and effects on vitamin D status: A systematic review and meta-analysis of randomised controlled trials.

There has been growing interest in the potential of vitamin D food fortification in Europe as a means of addressing low vitamin D status. The WHO-FAO suggest that choosing a suitable food vehicle and ensuring the combination of the food vehicle and the fortificant will be efficacious and effective are of key importance to a successful food fortification programme. Our key objective was to conduct a systematic review and meta-analysis to investigate the effect of various animal- and plant-based food vehicles fortified with vitamin D (as D3 or D2) on circulating 25-hydroxyvitamin D [25(OH)D] concentrations. A list of prioritised food vehicles was established and we searched PubMed, Embase, Scopus and Web of Science for randomised controlled trials (RCTs) which used these vehicles individually, and which met prespecified criteria. The searches identified 49 papers which described suitable RCTs using vitamin D-fortified bread/savoury biscuits (n = 5), orange juice (n = 5), UV-mushrooms (n = 8), cheese (n = 3), yogurt (n = 5), fluid milk (n = 13), powdered milk (n = 5), eggs (n = 2), edible oils (n = 4), or breakfast cereal (n = 1). No suitable RCTs were identified for rice, maize flour, butter, margarine or dairy spreads, plant-based milk or yogurt alternatives. Random-effects meta-analyses of each food vehicle individually indicated weighted mean differences (WMD) in 25(OH)D in the range ∼9-35 nmol/L (3-15 RCT arms, depending on vehicle), and all statistically significant (P < 0.01-0.0001), with the exception of UV-mushrooms (P = 0.06). Heterogeneity was variable (I2 =33-99%, depending on vehicle), but subgroup analysis based on vitamer and dose reduced it in some instances. Sub-group analysis on the basis of whether the food vehicles were from plant-based or animal-based origin showed no significant difference in WMD (15.2 versus 15.9 nmol/L, respectively; P = 0.48). These results support the use of various animal- and plant-based food vehicles for vitamin D fortification to improve circulating 25(OH)D concentrations in populations. This work was registered with PROSPERO as CRD42023439883.

Vitamin D status of 3-year-old children in Denmark: determinants and associations with bone mineralisation and blood lipids.

PURPOSE: Low vitamin D status is a global problem and has been associated with reduced skeletal and cardiometabolic health. However, evidence in young children is lacking. We, therefore, aimed to characterise vitamin D status in toddlers, identify its determinants, and explore if vitamin D status was associated with bone mineralisation and lipid profile. METHODS: We used cross-sectional data from 3-year-old children (n = 323) living in Denmark (latitude: 55°N). Bone mineralisation (n = 108) was measured by DXA. Blood samples were analysed for serum 25-hydroxyvitamin D (s-25(OH)D) by LC-MS/MS, triacylglycerol, and total, low- and high density lipoprotein cholesterol. RESULTS: Mean ± SD s-25(OH)D was 69 ± 23 nmol/L, but varied with season. During winter, 38% had inadequate s-25(OH)D (< 50 nmol), whereof 15% had deficiency (< 30 nmol/L); these numbers were only 7 and 1% during summer. In terms of status determinants, supplement use (66% were users) was associated with s-25(OH)D (P < 0.001), whereas dietary vitamin D intake (median [25-75th percentile] of 1.3 [0.9-1.9] µg/d), sex, parental education, BMI, and physical activity were not. There were no associations between s-25(OH)D and blood lipids or bone measurements, using either unadjusted or adjusted regression models. CONCLUSION: More than 1/3 of Danish toddlers had inadequate vitamin D intake during winter, but acceptable mean vitamin D status. In addition to season, supplement use was the main determinant of vitamin D status, which was, however, not associated with bone mineralisation or lipid profile. The results support recommendations of vitamin D supplements during winter at northern latitudes, but potential health effects need further investigation.

Fresh Beef and Lamb Consumption in Relation to Nutrient Intakes and Markers of Nutrition and Health Status among the Population Aged 5-90 Years in Ireland.

The dietary role of meat is under scrutiny for health and environmental reasons, yet a growing body of evidence proposes that advice to limit red meat consumption is unnecessarily restrictive. The aim of this study was to investigate the role of 'fresh beef and lamb' in the diet of the population (5-90 years) in Ireland and its association with markers of nutrition and health status. Analyses are based on data from three nationally representative dietary surveys in the Republic of Ireland. Dietary intake data were estimated using food records, and nutrient intakes were estimated based on UK and Irish food composition tables. Biochemical samples were collected and analysed using standard procedures. 'Fresh beef and lamb' (defined as beef/lamb that had not undergone any preserving process other than chilling/freezing/quick-freezing) was consumed by 68-84% of the population and intakes ranged from 19 to 43 g/d across age groups. It made important contributions to intakes of protein, monounsaturated fat, vitamins D, B12, niacin, iron and zinc while also contributing relatively small proportions of total fat, saturated fat and salt. Higher consumption of 'fresh beef and lamb' was associated with higher intakes of protein, niacin, vitamins B6, B12, zinc and potassium (but also total fat) and lower intakes of carbohydrate and total sugars (but also dietary fibre). In adults, older adults and WCBA, higher consumption of 'fresh beef and lamb' was not associated with increased risk factors of cardio-metabolic diseases nor was it associated with better or poorer nutritional status for vitamins D, B12 or iron. This study adds to the evidence base on the contribution of 'fresh beef and lamb' in the diet and may be useful to policymakers updating guidance for healthy diets from sustainable food systems.

Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group.

Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration.

UK Nutrition Research Partnership 'Hot Topic' workshop: Vitamin D-A multi-disciplinary approach to (1) elucidate its role in human health and (2) develop strategies to improve vitamin D status in the UK population.

Vitamin D is truly unique-not a 'vital' amine in the true sense of the word, but rather a prohormone, which is produced in the skin during exposure to sunlight (UVB radiation at 290-315 nm) and which can also be obtained from food and from supplements. A high prevalence of low vitamin D status has been reported across the world in a wide range of population groups, and this includes communities living in low latitude areas despite the abundance of sunlight. It is accepted that vitamin D status is reflected by the level of the circulating metabolite 25-hydroxyvitamin D (25[OH]D), which is produced by hepatic hydroxylation of vitamin D, derived either from the skin from UV exposure or the gut from oral intake. Vitamin D has been associated with a wide range of health outcomes, but controversies remain as to their exact nature and extent and whether associations are in the causal pathway. In order to enable wider discussions on this nutrient, a 'Hot Topic' Vitamin D Workshop achieved funding from the UK Nutrition Research Partnership Medical Research Council call. The objectives of the workshop were (1) to elucidate the role of vitamin D in human health and (2) develop strategies to improve vitamin D status in the UK population. This paper provides a detailed resume of the discussions of the workshop; of the presentations and concomitant Q&As; and of identified areas for future research.

Adequacy of calcium and vitamin D nutritional status in a nationally representative sample of Irish teenagers aged 13-18 years.

CONTEXT AND PURPOSE: In light of the key roles of vitamin D and calcium in adolescent bone health, there is a critical need for representative data on nutritional status for both micronutrients in teenagers. The present work used data from the recent representative National Teens' Food Survey II (2019-2020) to assess calcium and vitamin D intakes of teenagers in Ireland, including adequacy of such intakes, as well as, for the first time, to characterise serum 25-hydroxyvitamin D (25(OH)D) concentrations and their determinants. METHODS: Usual calcium and vitamin D intake estimates were generated using food intake data (via 4-day weighed food records) from a nationally representative sample of teenagers aged 13-18 years in Ireland (n 428). Serum 25(OH)D was measured (via LC-MS/MS) in the 57.5% (n 246) who provided a blood sample. RESULTS: Sixty-seven and 94% of Irish teenagers had intakes of calcium and vitamin D below the respective Estimated Average Requirements values, reflecting a high degree of inadequacy of intake for both micronutrients (and higher in girls than boys; P < 0.001). In addition, 21.7% and 33.1% of teenagers had serum 25(OH)D < 30 nmol/L (risk of vitamin D deficiency) and 30-49.9 nmol/L (inadequacy), respectively. Extended winter sampling, being aged 16-18 years, low total vitamin D intake, being overweight/obese or being of non-white skin type were significant (P < 0.05) predictors of serum 25(OH)D < 30 nmol/L. CONCLUSIONS: There was a high prevalence of inadequacy of intake of calcium and vitamin D in Irish teenagers, and a fifth were at increased risk of vitamin D deficiency.

Individual participant data (IPD)-level meta-analysis of randomised controlled trials to estimate the vitamin D dietary requirements in dark-skinned individuals resident at high latitude.

CONTEXT AND PURPOSE: There is an urgent need to develop vitamin D dietary recommendations for dark-skinned populations resident at high latitude. Using data from randomised controlled trials (RCTs) with vitamin D3-supplements/fortified foods, we undertook an individual participant data-level meta-regression (IPD) analysis of the response of wintertime serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among dark-skinned children and adults residing at ≥ 40° N and derived dietary requirement values for vitamin D. METHODS: IPD analysis using data from 677 dark-skinned participants (of Black or South Asian descent; ages 5-86 years) in 10 RCTs with vitamin D supplements/fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D intake estimates across a range of 25(OH)D thresholds. RESULTS: To maintain serum 25(OH)D concentrations ≥ 25 and 30 nmol/L in 97.5% of individuals, 23.9 and 27.3 µg/day of vitamin D, respectively, were required among South Asian and 24.1 and 33.2 µg/day, respectively, among Black participants. Overall, our age-stratified intake estimates did not exceed age-specific Tolerable Upper Intake Levels for vitamin D. The vitamin D intake required by dark-skinned individuals to maintain 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L was 66.8 µg/day. This intake predicted that the upper 2.5% of individuals could potentially achieve serum 25(OH)D concentrations ≥ 158 nmol/L, which has been linked to potential adverse effects in older adults in supplementation studies. CONCLUSIONS: Our IPD-derived vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25, 30 and 50 nmol/L are substantially higher than the equivalent estimates for White individuals. These requirement estimates are also higher than those currently recommended internationally by several agencies, which are based predominantly on data from Whites and derived from standard meta-regression based on aggregate data. Much more work is needed in dark-skinned populations both in the dose-response relationship and risk characterisation for health outcomes. TRAIL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42018097260).

Vitamin D biomarkers for Dietary Reference Intake development in children: a systematic review and meta-analysis.

BACKGROUND: Circulating 25-hydroxyvitamin D [25(OH)D] has been the accepted vitamin D exposure/intake biomarker of choice within recent DRI exercises, but use of other vitamin D-related biomarkers as well as functional markers has been suggested. These may be of value in future vitamin D DRI exercises, such as the FAO/WHO's one for young children. OBJECTIVES: To systematically review the usefulness of circulating 25(OH)D, parathyroid hormone (PTH), free and bioavailable 25(OH)D, C3-epimer of 25(OH)D, vitamin D3, 24,25-dihydroxyvitamin D [24,25(OH)2D], and bone turnover markers and calcium absorption as vitamin D biomarkers for DRI development in children. METHODS: Methods included structured searches of published articles, full-text reviews, data extraction, quality assessment, meta-analysis, and random-effects meta-regression. RESULTS: Fifty-nine vitamin D supplementation randomized controlled trials (RCTs) were included (39 in infants/children as the priority group and the remainder in adults since pediatric studies were absent/limited). Vitamin D supplementation significantly raised circulating 25(OH)D in infants and children, but the response was highly heterogeneous [weighted mean difference (WMD): 27.7 nmol/L; 95% CI: 22.9, 32.5; 27 RCTs; I2 = 93%]. Meta-regression suggested an increase by 1.7 nmol/L (95% CI: 0.7, 2.6) in serum 25(OH)D per each 100-IU increment in vitamin D intake (P = 0.0005). Vitamin D supplementation had a significant effect on circulating 24,25(OH)2D (WMD: 3.4 nmol/L; 95% CI: 2.4, 4.5; 13 RCTs; I2 = 95%), with a dose-response relation (+0.15 nmol/L per 100 IU; 95% CI: -0.01, 0.29). With circulating PTH, although there was a significant effect of vitamin D on WMD (P = 0.05), there was no significant dose-response relation (P = 0.32). Pediatric data were too limited in relation to the usefulness of the other biomarkers. CONCLUSIONS: Circulating 25(OH)D may be a useful biomarker of vitamin D exposure/intake for DRI development in infants and children. Circulating 24,25(OH)2D also showed some promise, but further data are needed, especially in infants and children.

Implementation strategies for improving vitamin D status and increasing vitamin D intake in the UK: current controversies and future perspectives: proceedings of the 2nd Rank Prize Funds Forum on vitamin D.

A multi-disciplinary expert group met to discuss vitamin D deficiency in the UK and strategies for improving population intakes and status. Changes to UK Government advice since the 1st Rank Forum on Vitamin D (2009) were discussed, including rationale for setting a reference nutrient intake (10 µg/d; 400 IU/d) for adults and children (4+ years). Current UK data show inadequate intakes among all age groups and high prevalence of low vitamin D status among specific groups (e.g. pregnant women and adolescent males/females). Evidence of widespread deficiency within some minority ethnic groups, resulting in nutritional rickets (particularly among Black and South Asian infants), raised particular concern. Latest data indicate that UK population vitamin D intakes and status reamain relatively unchanged since Government recommendations changed in 2016. Vitamin D food fortification was discussed as a potential strategy to increase population intakes. Data from dose-response and dietary modelling studies indicate dairy products, bread, hens' eggs and some meats as potential fortification vehicles. Vitamin D3 appears more effective than vitamin D2 for raising serum 25-hydroxyvitamin D concentration, which has implications for choice of fortificant. Other considerations for successful fortification strategies include: (i) need for 'real-world' cost information for use in modelling work; (ii) supportive food legislation; (iii) improved consumer and health professional understanding of vitamin D's importance; (iv) clinical consequences of inadequate vitamin D status and (v) consistent communication of Government advice across health/social care professions, and via the food industry. These areas urgently require further research to enable universal improvement in vitamin D intakes and status in the UK population.

Global differences in vitamin D status and dietary intake: a review of the data.

Background: Internationally, concern has been repeatedly raised about the little notable progress in the collection, analysis and use of population micronutrient status and deficiency data globally. The need for representative status and intake data for vitamin D has been highlighted as a research priority for well over a decade. Aim and methods: A narrative review which aims to provide a summary and assessment of vitamin D nutritional status data globally. This review divides the world into the Food and Agriculture Organisation's (FAO) major regions: the Americas, Europe, Oceania, Africa and Asia. Emphasis was placed on published data on the prevalence of serum 25-hydroxyvitamin D (25(OH)D) < 25/30 and <50 nmol/L (reflecting vitamin D deficiency and inadequacy, respectively) as well as vitamin D intake, where possible from nationally representative surveys. Results: Collating data from the limited number of available representative surveys from individual countries might suggest a relatively low overall prevalence of vitamin D deficiency in South America, Oceania and North America, whereas there is more moderate prevalence in Europe and Asia, and possibly Africa. Overall, the prevalence of serum 25(OH)D < 25/30 and <50 nmol/L ranges from ~5 to 18% and 24 to 49%, respectively, depending on FAO world region. Usual intakes of vitamin D can also vary by FAO world region, but in general, with a few exceptions, there are very high levels of inadequacy of vitamin D intake. Conclusions: While the burden of vitamin D deficiency and inadequacy varies by world regions and not just by UVB availability, the global burden overall translates into enormous numbers of individuals at risk.

Global View of Per Capita Daily Vitamin D Supply Estimates as Proxy Measures for Vitamin D Intake Data.

Nationally representative data on vitamin D intake can inform on the adequacy of dietary supply of vitamin D in a population, but such data is lacking for a majority of countries. Estimates of average per capita supply of vitamin D, as calculated using information from the Food and Agriculture Organisation of the United Nations (FAO) national food balance sheets (FBSs) can be used as proxy measures for vitamin D intake within a population. In the present work, FAO national FBSs (from 2004 to 2017) for 173 to 178 countries around the globe were used to generate such average per capita vitamin D supply estimates. For countries where food fortification with vitamin D was common, the estimates accounted for this. Using the 2004-2013 FBS data, there was a large range in average per capita vitamin D supply ranging from 0.3 (Ethiopia) to 17.8 (Maldives) µg/d. Globally, 40, 60, 70, four, two, and two countries had average per capita vitamin D supply estimates <1.5, 1.6-3, 3.1-5.5, 5.6-7.5, 7.6-10, and >10 µg/d, respectively. Pelagic fish was the major contributory food commodity (supplying 53%-86%) in countries with supply >7.6 µg/d. Median per capita vitamin D supply estimates for constituent countries within Africa, Americas, Asia, Europe, and Oceania were 1.4, 2.7, 2.8, 4.1, and 4.7 µg/d, respectively. These overall supply trends were mirrored in the newer, 2014-2017 FBS data. Fortification of milk and dairy or wheat flour with vitamin D had an important impact on the vitamin D supply estimates (average increments of 1.6 and 3.1 µg/d, respectively). Overall, the work showed how the per capita daily vitamin D supply estimates, as surrogate for vitamin D intake data, can highlight countries where inadequacy of supply may be of concern. It also shows how fortification of food with vitamin D can have an important impact on addressing low vitamin D intake. © 2021 The Author. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Safety of Vitamin D Food Fortification and Supplementation: Evidence from Randomized Controlled Trials and Observational Studies.

The safety considerations of food-based solutions for vitamin D deficiency prevention, such as fortification and supplementation, are critical. On the basis of collective data from 20 randomized controlled trials (RCTs) and 20 national healthy surveys, as well as prospective cohort studies (PCSs) across the ODIN project ("Food-based solutions for optimal vitamin D nutrition and health through the life cycle", FP7-613977), we analyzed the potential safety issues arising from vitamin D intakes and/or supplementation. These adverse consequences included high serum 25-hydroxyvitamin D (S-25(OH)D) concentrations (>125 nmol/L), high serum calcium concentrations, and vitamin D intakes in excess of the tolerable upper intake levels (ULs). In the RCTs (n = 3353, with vitamin D doses from 5-175 µg/day), there were no reported adverse effects. The prevalence of high S-25(OH)D was <10% when vitamin D supplements were administered, and <0.1% for fortified foods. Elevated serum calcium was observed among <0.5% in both administration types. No ODIN RCT participants exceeded the age-specific ULs. In observational studies (n = 61,082), the prevalence of high 25(OH)D among children/adolescents, adults, and older adults was <0.3%, with no evidence of adverse effects. In conclusion, high S-25(OH)D concentrations >125 nmol/L were rare in the RCTs and PCSs, and no associated adverse effects were observed.

Effects of vitamin D and high dairy protein intake on bone mineralization and linear growth in 6- to 8-year-old children: the D-pro randomized trial.

BACKGROUND: Vitamin D and dairy protein may stimulate bone mineralization and linear growth in children, but previous studies show inconsistent results and have not examined their combined effects. OBJECTIVES: To investigate combined and separate effects of vitamin D supplementation and high-protein (HP) compared with normal-protein (NP) yogurt intake on children's bone mineralization and linear growth. METHODS: In a 2 × 2-factorial trial, 200 healthy, 6- to 8-year-old, Danish, children with light skin (55°N) were randomized to 20 µg/d vitamin D3 or placebo and to substitute 260 g/d dairy with HP (10 g protein/100 g) or NP (3.5 g protein/100 g) yogurt for 24 weeks during an extended winter. Outcomes were total body less head (TBLH) and lumbar spine bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) by dual-energy X-ray absorptiometry, height, and biomarkers of bone turnover and growth. The primary outcome was TBLH BMD. RESULTS: In total, 184 children (92%) completed the study. The baseline serum 25-hydroxyvitamin D was 80.8 ± 17.2 nmol/L, which increased by 7.2 ± 14.1 nmol/L and decreased by 32.3 ± 17.5 nmol/L with vitamin D and placebo, respectively. The baseline protein intake was 15.4 ± 2.4 energy percentage (E%), which increased to 18.3 ± 3.4 E% with HP. There were no vitamin D-yogurt interactions and no main effects of either intervention on TBLH BMD. However, vitamin D supplementation increased lumbar spine BMD and TBLH BMC compared to placebo, whereas HP groups showed lower increments in lumbar spine BMD, TBLH BMC and BA, and plasma osteocalcin compared to NP groups. Height, growth factors, and parathyroid hormone levels were unaffected. CONCLUSIONS: Although there were no effects on whole-body BMD, vitamin D increased bone mass and spinal BMD, whereas high compared with normal dairy protein intake had smaller incremental effects on these outcomes. This supports a recommended vitamin D intake of around 20 µg/d during winter but not use of HP dairy products for improved bone mineralization among healthy, well-nourished children. This trial was registered at clinicaltrials.gov as NCT03956732.

Individual participant data (IPD)-level meta-analysis of randomised controlled trials with vitamin D-fortified foods to estimate Dietary Reference Values for vitamin D.

CONTEXT AND PURPOSE: Individual participant data-level meta-regression (IPD) analysis is superior to meta-regression based on aggregate data in determining Dietary Reference Values (DRV) for vitamin D. Using data from randomized controlled trials (RCTs) with vitamin D3-fortified foods, we undertook an IPD analysis of the response of winter serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among children and adults and derived DRV for vitamin D. METHODS: IPD analysis using data from 1429 participants (ages 2-89 years) in 11 RCTs with vitamin D-fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D DRV estimates across a range of serum 25(OH)D thresholds using unadjusted and adjusted models. RESULTS: Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25 and ≥ 30 nmol/L are 6 and 12 µg/day, respectively (unadjusted model). The intake estimates to maintain 90%, 95% and 97.5% of concentrations ≥ 50 nmol/L are 33.4, 57.5 and 92.3 µg/day, respectively (unadjusted) and 17.0, 28.1 and 43.6 µg/day, respectively (adjusted for mean values for baseline serum 25(OH)D, age and BMI). CONCLUSIONS: IPD-derived vitamin D intakes required to maintain 90%, 95% and 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L are much higher than those derived from standard meta-regression based on aggregate data, due to the inability of the latter to capture between person-variability. Our IPD provides further evidence that using food-based approaches to achieve an intake of 12 µg/day could prevent vitamin D deficiency (i.e., serum 25(OH)D < 30 nmol/L) in the general population.