Estimation of the dietary requirement for Vitamin D in white children aged 4-8 y: A randomized, controlled, dose-response trial

ArticleinAmerican Journal of Clinical Nutrition 104(5) · October 2016with 65 Reads
Abstract
Background: Children in northern latitudes are at high risk of vitamin D deficiency during winter because of negligible dermal vitamin D3 production. However, to our knowledge, the dietary requirement for maintaining the nutritional adequacy of vitamin D in young children has not been investigated. Objective: We aimed to establish the distribution of vitamin D intakes required to maintain winter serum 25-hydroxyvitamin D [25(OH)D] concentrations above the proposed cutoffs (25, 30, 40, and 50 nmol/L) in white Danish children aged 4-8 y living at 55°N. Design: In a double-blind, randomized, controlled trial 119 children (mean age: 6.7 y) were assigned to 0 (placebo), 10, or 20 μg vitamin D3/d supplementation for 20 wk. We measured anthropometry, dietary vitamin D, and serum 25(OH)D with liquid chromatography-tandem mass spectrometry at baseline and endpoint. Results: The mean ± SD baseline serum 25(OH)D was 56.7 ± 12.3 nmol/L (range: 28.7-101.4 nmol/L). Serum 25(OH)D increased by a mean ± SE of 4.9 ± 1.3 and 17.7 ± 1.8 nmol/L in the groups receiving 10 and 20 μg vitamin D3/d, respectively, and decreased by 24.1 ± 1.2 nmol/L in the placebo group (P < 0.001). A nonlinear model of serum 25(OH)D as a function of total vitamin D intake (diet and supplements) was fit to the data. The estimated vitamin D intakes required to maintain winter serum 25(OH)D >30 (avoiding deficiency) and >50 nmol/L (ensuring adequacy) in 97.5% of participants were 8.3 and 19.5 μg/d, respectively, and 4.4 μg/d was required to maintain serum 25(OH)D >40 nmol/L in 50% of participants. Conclusions: Vitamin D intakes between 8 and 20 μg/d are required by white 4-8-y-olds during winter in northern latitudes to maintain serum 25(OH)D >30-50 nmol/L depending on chosen serum 25(OH)D threshold. This trial was registered at clinicaltrials.gov as NCT02145195.

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  • ... Our hypothesis is that the method used to perform the dose-response vitamin D-25(OH)D analysis, on which DRVs are based, has a profound effect on the recommendation issued, regardless of the serum 25(OH)D target selected or other sources of heterogeneity. Thus, the objectives of this study were firstly to perform an IPD meta-regression using individual subject data (n = 882) from seven selected winter-based RCTs of the vitamin D intake-serum 25(OH)D dose-response, where raw data were available to the authors [17][18][19][20][21][22][23], in order to establish recommendations for vitamin D. Secondly, we wished to contrast these IPD-derived results against results from a standard meta-regression based on aggregate data derived from the same RCTs. ...
    ... For three of the seven RCTs [17,19,22], concentrations of total 25(OH)D (i.e., 25(OH)D 2 plus 25(OH)D 3 ) in all serum samples were measured at the laboratory of the Cork Centre for Vitamin D and Nutrition Research using a Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method that has been described in detail elsewhere [24,25] and is certified by the Centers for Disease Control and Prevention's (CDC) Vitamin D Standardization Certification Program [26] and monitored on an on-going basis by participation in the Vitamin D External Quality Assessment Scheme (Charing Cross Hospital, London, UK). The intra-assay coefficient of variation (CV) of the method was <5% for all 25-hydroxyvitamin D metabolites, while the inter-assay CV was <6%. ...
    ... A collection of seven RCTs, where raw data (n = 882 individuals) were available to the authors, was included in the present analysis. These RCTs were conducted in: 4-8 year-old children [17], 11 year-old girls [18], 14-18 year-old adolescents [19], adults aged 20-40 years [20], 50+ years [21,22], and 65+ years [23], and were all implemented using the same study design, analytical platform for serum 25(OH)D, and dietary assessment method. Most of these RCTs were among the 44 used collectively in the IOM, NORDEN, and EFSA exercises for deriving DRVs [1,10,11]. ...
    Article
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    Dietary Reference Values (DRVs) for vitamin D have a key role in the prevention of vitamin D deficiency. However, despite adopting similar risk assessment protocols, estimates from authoritative agencies over the last 6 years have been diverse. This may have arisen from diverse approaches to data analysis. Modelling strategies for pooling of individual subject data from cognate vitamin D randomized controlled trials (RCTs) are likely to provide the most appropriate DRV estimates. Thus, the objective of the present work was to undertake the first-ever individual participant data (IPD)-level meta-regression, which is increasingly recognized as best practice, from seven winter-based RCTs (with 882 participants ranging in age from 4 to 90 years) of the vitamin D intake–serum 25-hydroxyvitamin D (25(OH)D) dose-response. Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of 25(OH)D concentrations >25, 30, and 50 nmol/L across the population are 10, 13, and 26 µg/day, respectively. In contrast, standard meta-regression analyses with aggregate data (as used by several agencies in recent years) from the same RCTs estimated that a vitamin D intake requirement of 14 µg/day would maintain 97.5% of 25(OH)D >50 nmol/L. These first IPD-derived estimates offer improved dietary recommendations for vitamin D because the underpinning modeling captures the between-person variability in response of serum 25(OH)D to vitamin D intake.
  • ... Thus, four 25(OH)D-vitamin D3 dose-response RCTs were designed and implemented to estimate the dietary requirements for vitamin D to meet 25(OH)D targets of 25/30 to 50 nmol/L in most (97.5%) individuals in these subgroups, under conditions of absent or scarce UVB exposure, providing evidence on which to base dietary allowances for them [22][23][24][25][26]. [14]). ...
    ... Thus, four 25(OH)D-vitamin D 3 dose-response RCTs were designed and implemented to estimate the dietary requirements for vitamin D to meet 25(OH)D targets of 25/30 to 50 nmol/L in most (97.5%) individuals in these subgroups, under conditions of absent or scarce UVB exposure, providing evidence on which to base dietary allowances for them [22][23][24][25][26]. ...
    ... Dietary requirements for vitamin D during childhood and adolescence have been predominantly based on two studies in 8 and 11 year olds (summarised in [5]), leaving large gaps among younger children and teens. Accordingly, two parallel, dose-response RCTs in Denmark (55 • N) and the UK (51 • N) were implemented during winter months to establish the distribution of dietary requirements for vitamin D in 4-8 year olds and 14-18 year olds in the absence of UVB exposure [22,23]. Children and teens were randomised to placebo, 10 or 20 µg/day of vitamin D 3 from October through March. ...
    Article
    Full-text available
    Food-based solutions for optimal vitamin D nutrition and health through the life cycle (ODIN) was a cross-disciplinary, collaborative project, including 30 partners from 19 countries, which aimed to develop evidence-based solutions to prevent low vitamin D status (25-hydroxyvitamin D (25(OH)D) < 30 nmol/L) using a food-first approach. This paper provides a summary overview of some of the important ODIN outcomes and outlines some outstanding data requirements. In a study of almost 56,000 individuals, the first internationally standardised dataset of vitamin D status showed that 13% of EU residents overall, across a latitude gradient of 35° N to 69° N, had serum 25(OH)D < 30 nmol/L and 40% were < 50 nmol/L. The risk of low vitamin D status was several-fold higher among persons of ethnic minority. However, additional data from quality bio-banked sera would be required to improve these estimates. To address the question of dietary requirements for vitamin D among under-researched life-stage and population groups, four dose-response RCTs conducted in Northern Europe showed that vitamin D3 intakes of 8 and 13 μg/day prevented 25(OH)D decreasing below 30 nmol/L in white children and adolescents and 20 and 30 μg/day, respectively, achieved ≥50 nmol/L. Among white women during pregnancy, 30 μg/day is required to prevent umbilical cord 25(OH)D, representing new-born vitamin D status, below 25 nmol/L. While 8 μg/day protected white women in Finland at the 30 nmol/L cut-off, 18 μg/day was needed by women of East African descent to prevent 25(OH)D decreasing below 30 nmol/L during wintertime. Replicate RCTs are needed in young children <5 years and in school-age children, teens and pregnant women of ethnic minority. Using a series of food production studies, food-based RCTs and dietary modelling experiments, ODIN research shows that diverse fortification strategies could safely increase population intakes and prevent low vitamin D status. Building on this solid technological platform, implementation research is now warranted to scale up interventions in real-world settings to eradicate vitamin D deficiency.
  • ... However, Cashman's analysis of his own data indicated that to ensure the 50 nmol/L RDA target for 25(OH)D would require a vitamin D intake 1216 IU/day in winter [12], which is in agreement with the recommendation of the Endocrine Society. Recent dose-finding clinical trials in children and adolescents and blacks confirm Cashman's calculation of a higher dose requirement if the serum 25(OH)D level is targeted to be at least 50 nmol/L [13,30,31]. ...
    ... We went on to show that the approach used to calculate the vitamin D dose needed to deliver a serum level for the population, based on average 25(OH)D levels that had been attained for groups did not ensure that 97.5% of the members of the groups or of the population would sustain 50 nmol/L [29] (Fig. 57B.4). Multiple subsequent clinical trials that have been specifically designed to establish the dosage to deliver that target 25(OH)D level of 50 nmol/L for most of the population and those have concluded that the vitamin D requirements are all well over 1000 IU/day [13,31,32], showing that the IOM vitamin D dosage calculation for the RDA was too low and confirming that the guidance of the Endocrine Society [2] is appropriate. According to the Endocrine Society guidance for musculoskeletal health, the desirable target level of serum 25(OH)D is one that exceeds 75 nmol/L. ...
    Chapter
    There is still controversy about the amount of vitamin D adults need for musculoskeletal health. The Endocrine Society, which made its recommendations for the treatment and prevention of vitamin D deficiency, concluded that to guarantee bone health without any evidence for vitamin D deficiency osteomalacia, a blood level of 25(OH)D of at least 75. nmol/L (30. ng/mL) was required for adults. As a result the Endocrine Society recommended that for adults 1500-2000. IU/day was required for musculoskeletal health and noted that obese adults require 2-3 times more vitamin D to sustain a blood level of 25(OH)D of at least 75. nmol/L. The more conservative recommendation from the Institutes of Medicine (IOM) is the recommended dietary allowance (RDA) for vitamin D, 600. IU/day (15. ?g/day), which the IOM claims sustains 97.5% of the population with serum 25(OH)D above the threshold of 50. nmol/L (20. ng/mL). We show how the IOM made incorrect analyses of the evidence it cited, thereby severely underestimating the serum 25(OH)D threshold. Furthermore, to calculate the intake of vitamin D needed to deliver the threshold serum level, the IOM used group average serum 25(OH)D responses to establish the vitamin D RDA. Because half of a population needs more than the average, the 600. IU/day RDA for vitamin D underestimates the intake needed to assure the threshold for 97.5% of the population. For people who are sun-deprived or with darker skin at temperate latitudes, the 600. IU/day RDA cannot assure the threshold serum level. The IOM specified 4000. IU/day for most children and adults to the safe, upper level for vitamin D, whereas the Endocrine Society specified 4000. IU/day for most children and 10,000. IU/day for adults. Although the IOM did not base its 50. nmol/L (20. ng/mL) threshold for serum 25(OH)D for musculoskeletal health on randomized clinical trials (RCTs), advocates of the IOM position now reject the normal criteria for evidence-based decisions and demand that RCTs are needed for acceptance of any extraskeletal health relationship. We contend that it is unrealistic to ever expect that RCTs can be conducted for vitamin D in the long-term primary prevention of disease events in a healthy adult population under age 50. years. The existing prospective, cross-sectional, and clinical trial evidence for mortality and premature delivery in pregnancy is already enough to warrant further increases in recommendations for vitamin D supplementation.
  • ... Most of the studies evaluated daily vitamin D supple- mentation at doses ranging from 200 to 1000 IU/day [78,[147][148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164]. Supplementation at 400 IU/day for variable length (up to 12 months) was usually insufficient in raising serum 25(OH)D levels > 30 ng/ml [78, 147-149, 151-153, 160-162], particularly in subjects with vitamin D defi- ciency. ...
    ... A recent RCT performed during winter showed that a vitamin D intake up to 800 IU/day was required by white Danish children (4-8 years) to maintain serum 25(OH)D > 20 ng/ml. Particularly, subjects receiving 800 IU/day for 20 weeks increased their 25(OH)D levels from 23.2 ng/ml to 30.3 ng/ml [161]. Another RCT dem- onstrated that white UK adolescents (14-18 years) re- quired higher intake of vitamin D (up to 1200 IU/day) during winter to achieve 25(OH)D concentration > 20 ng/ ml in 97.5% of cases. ...
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    Vitamin D plays a pivotal role in the regulation of calcium-phosphorus metabolism, particularly during pediatric age when nutritional rickets and impaired bone mass acquisition may occur. Besides its historical skeletal functions, in the last years it has been demonstrated that vitamin D directly or indirectly regulates up to 1250 genes, playing so-called extraskeletal actions. Indeed, recent data suggest a possible role of vitamin D in the pathogenesis of several pathological conditions, including infectious, allergic and autoimmune diseases. Thus, vitamin D deficiency may affect not only musculoskeletal health but also a potentially wide range of acute and chronic conditions. At present, the prevalence of vitamin D deficiency is high in Italian children and adolescents, and national recommendations on vitamin D supplementation during pediatric age are lacking. An expert panel of the Italian Society of Preventive and Social Pediatrics reviewed available literature focusing on randomized controlled trials of vitamin D supplementation to provide a practical approach to vitamin D supplementation for infants, children and adolescents.
  • ... The downward trend in human semen quality has been attributed to diverse factors [6], and previous studies have shown that biopsychosocial fac- tors, one of the overwhelming issues in modern society, may affect the quality of human semen. [7][8][9][10]. ...
    Article
    Objective: Psychosocial factors have been associated with a decline of the quality of semen. The study was aimed at (i) estimating the association between work stress and semen quality and (ii) exploring the moderating effect of social support in semen parameters among Chinese male workers. Methods: Data were obtained from 384 adult male workers recruited from April 2014 to December 2015 in Chongqing, China. Participants completed a questionnaire assessing demographic and life-style factors. Work stress and social support was measured by the Chinese version of a 22-item Job Content Questionnaire (JCQ). They underwent a physical examination and provided a semen sample. Results: Subjects with high work stress were associated with a higher risk of being classified below WHO's thresholds for “normal,” defined by sperm concentration (OR 2.14, 95% CI 1.24–3.68, p =.006) or total sperm count (OR 1.95, 95% CI 1.13–3.36, p =.02) criteria than subjects with low work stress were. However, these adverse associations were not observed among subjects with high social support (p =.80 for sperm concentration, and p =.39 for total sperm count). Interaction effects between social support and work stress on sperm concentration (p =.002) and total sperm count (p =.02) were detected. Conclusion: Work stress is associated with lower levels of semen quality. Social support attenuates the negative association between work stress and semen quality, which may have implications for reproductive health.
  • ... The dose-response data used to calculate intake rec- ommendations are generally derived from studies of Caucasian adults and elderly individuals, and include limited data from dark-skinned popula- tions, children, and pregnant or lactating women. Recent studies in children 67 and adolescents 68 have aided in our understanding of potential variability in the dose-response in specific age groups, and the working group acknowledged that intake recom- mendations may require revision to align with new data in the future. ...
    Article
    Vitamin D is an essential nutrient for bone health and may influence the risks of respiratory illness, adverse pregnancy outcomes, and chronic diseases of adulthood. Because many countries have a relatively low supply of foods rich in vitamin D and inadequate exposure to natural ultraviolet B (UVB) radiation from sunlight, an important proportion of the global population is at risk of vitamin D deficiency. There is general agreement that the minimum serum/plasma 25-hydroxyvitamin D concentration (25(OH)D) that protects against vitamin D deficiency-related bone disease is approximately 30 nmol/L; therefore, this threshold is suitable to define vitamin D deficiency in population surveys. However, efforts to assess the vitamin D status of populations in low- and middle-income countries have been hampered by limited availability of population-representative 25(OH)D data, particularly among population subgroups most vulnerable to the skeletal and potential extraskeletal consequences of low vitamin D status, namely exclusively breastfed infants, children, adolescents, pregnant and lactating women, and the elderly. In the absence of 25(OH)D data, identification of communities that would benefit from public health interventions to improve vitamin D status may require proxy indicators of the population risk of vitamin D deficiency, such as the prevalence of rickets or metrics of usual UVB exposure. If a high prevalence of vitamin D deficiency is identified (>20% prevalence of 25(OH)D < 30 nmol/L) or the risk for vitamin D deficiency is determined to be high based on proxy indicators (e.g., prevalence of rickets >1%), food fortification and/or targeted vitamin D supplementation policies can be implemented to reduce the burden of vitamin D deficiency-related conditions in vulnerable populations.
  • ... The study was a three-arm, parallel, dose-response, double-blind, placebo-controlled randomised trial of vitamin D 3 supplementation. The power calculation was based on similar dose-response studies of vitamin D nutritional requirements designed by our research group, whereby 31 participants per arm is adequate to detect a 10 nmol/L difference in 25(OH)D concentrations and provide a 90% power to demonstrate a dose-response relation with slope 1.5 and alpha equal to 0.05 [26][27][28][29]. This study was conducted throughout the year because it was a pregnancy study, with three assessment points across gestation, unlike our previous trials in non-pregnant groups which were conducted during winter time. ...
    Article
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    Adverse effects of low vitamin D status and calcium intakes in pregnancy may be mediated through functional effects on the calcium metabolic system. Little explored in pregnancy, we aimed to examine the relative importance of serum 25-hydroxyvitamin D (25(OH)D) and calcium intake on parathyroid hormone (PTH) concentrations in healthy white-skinned pregnant women. This cross-sectional analysis included 142 participants (14 ± 2 weeks’ gestation) at baseline of a vitamin D intervention trial at 51.9 °N. Serum 25(OH)D, PTH, and albumin-corrected calcium were quantified biochemically. Total vitamin D and calcium intakes (diet and supplements) were estimated using a validated food frequency questionnaire. The mean ± SD vitamin D intake was 10.7 ± 5.2 μg/day. With a mean ± SD serum 25(OH)D of 54.9 ± 22.6 nmol/L, 44% of women were <50 nmol/L and 13% <30 nmol/L. Calcium intakes (mean ± SD) were 1182 ± 488 mg/day and 23% of participants consumed <800 mg/day. The mean ± SD serum albumin-adjusted calcium was 2.2 ± 0.1 mmol/L and geometric mean (95% CI) PTH was 9.2 (8.4, 10.2) pg/mL. PTH was inversely correlated with serum 25(OH)D (r = −0.311, p < 0.001), but not with calcium intake or serum calcium (r = −0.087 and 0.057, respectively, both p > 0.05). Analysis of variance showed that while serum 25(OH)D (dichotomised at 50 nmol/L) had a significant effect on PTH (p = 0.025), calcium intake (<800, 800–1000, ≥1000 mg/day) had no effect (p = 0.822). There was no 25(OH)D-calcium intake interaction effect on PTH (p = 0.941). In this group of white-skinned women with largely sufficient calcium intakes, serum 25(OH)D was important for maintaining normal PTH concentration.
  • Article
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    The optimum dose of vitamin D and corresponding serum 25-hydroxyvitamin D (25OHD) concentration for bone health is still debated and some health practitioners are recommending doses well above the Canada/USA recommended Dietary Reference Intake (DRI). We designed a three-year randomized double-blind clinical trial investigating whether there are dose-dependent effects of vitamin D supplementation above the Dietary Reference Intake (DRI) on bone health. The primary aims of this study are to assess, whether supplementation of vitamin D3increases 1) volumetric bone mineral density measured by high-resolution peripheral quantitative computed tomography (HR-pQCT); 2) bone strength assessed by finite element analysis, and 3) areal bone mineral density by dual X-ray absorptiometry (DXA). Secondary aims are to understand whether vitamin D3supplementation improves parameters of bone microarchitecture, balance, physical function and quality of life. Participants are men and women aged 55-70 years, with women at least 5-years post-menopause. The intervention is daily vitamin D3supplementation doses of 400, 4000 or 10,000 IU. Participants not achieving adequate dietary calcium intake are provided with calcium supplementation, up to a maximum supplemental dose of 600 mg elemental calcium per day. Results from this three-year study will provide evidence whether daily vitamin D3supplementation with adequate calcium intake can affect bone density, bone microarchitecture and bone strength in men and women. Furthermore, the safety of high dose daily vitamin D3supplementation will be explored.
  • Article
    PurposeWhile reports of inadequate vitamin D intakes among young children are widespread, data on the prevalence of vitamin D deficiency are inconsistent. We aimed to quantify vitamin D intake and serum 25-hydroxyvitamin D [25(OH)D] concentrations in children aged 2 years in the prospective Cork BASELINE Birth Cohort Study. Methods Serum 25(OH)D was analysed using UPLC-MS/MS in 741 children living in Cork, Ireland (51°N). Two-day weighed food diaries were collected in 467 children, and 294 provided both a blood sample and a food diary. ResultsMean (SD) 25(OH)D concentrations were 63.4 (20.4) nmol/L [winter: 54.5 (19.9), summer: 71.2 (17.5)]. The prevalence of vitamin D deficiency (<30 nmol/L) was 4.6, and 26.7% were <50 nmol/L [45.2% during winter (November–April) and 10.4% in summer (May–October)]. With a mean (SD) vitamin D intake of 3.5 (3.1) µg/day, 96% had intakes below 10 µg/day, the current IOM estimated average requirement and the SACN safe intake value for this age group. After adjustment for season, vitamin D intake (µg/day) was associated with higher 25(OH)D concentrations [adjusted estimate (95% CI) 2.5 (1.9, 3.1) nmol/L]. Children who did not consume vitamin D-fortified foods or supplements had very low vitamin D intakes (1.2 (0.9) µg/day), and during winter, 12 and 77% were <30 and <50 nmol/L, respectively, compared with 6 and 44% of fortified food consumers. Conclusion There was a high prevalence of low vitamin D status during winter, especially among children who did not consume fortified foods or nutritional supplements. Our data indicate the need for dietary strategies to increase vitamin D intakes in this age group. This report provides further evidence that DRVs for vitamin D should be based on experimental data in specific population groups and indicates the need for dose–response RCTs in young children.
  • Article
    Vitamin D is a unique nutrient that has captured the attention of scientific and medical communities, regulatory authorities and the general public over recent years. Low vitamin D status is a worldwide public health concern and occurs across all age, sex and ethnic groups. Dietary requirements for vitamin D have been re-evaluated and revised over recent years by several authoritative bodies, including the Institute of Medicine, the Nordic Council of Ministers, the European Food Safety Authority and, of course, the UK Scientific Advisory Committee on Nutrition. However, a lack of vitamin D dose–response trials in children and adolescents prior to these reports has hindered the development of evidence-based dietary requirements for vitamin D in these population sub-groups. Two recent randomised controlled trials have addressed this significant knowledge gap and estimated that intakes of between 6 and ~30 μg/day are needed during the winter time to avoid vitamin D deficiency and ensure adequacy in healthy White 4–8 year-old children residing in Denmark (55°N) and 14–18 year-old adolescents residing in the UK (51°N). These new data suggest that, while the current vitamin D recommendations of 10–15 μg/day for children and adolescents will help avoid winter-time vitamin D deficiency (25–hydroxyvitamin D concentrations <25–30 nmol/l), they remain inadequate for ensuring vitamin D concentrations are maintained above 40–50 nmol/l, which may be necessary for optimal bone accretion during these rapid growth phases. Such data will allow for the ongoing refinement of evidence-based dietary requirements for children and adolescents.
  • Article
    Background: Dark skin and low exposure to sunlight increase the risk of vitamin D insufficiency in children. Objective: The aim of the study was to evaluate the amount of vitamin D needed to ascertain that most children >4 y of age attain sufficient serum 25-hydroxyvitamin D [S-25(OH)D; i.e., ≥50 nmol/L] during winter regardless of latitude and skin color. Design: In a longitudinal, double-blind, randomized, food-based intervention study, 5- to 7-y-old children from northern (63°N) and southern (55°N) Sweden with fair (n = 108) and dark (n = 98) skin were included. Children, stratified by skin color by using Fitzpatrick’s definition, were randomly assigned to receive milk-based vitamin D3 supplements that provided 2 (placebo), 10, or 25 μg/d during 3 winter months. Results: Mean daily vitamin D intake increased from 6 to 17 μg and 26 μg in the intervention groups supplemented with 10 and 25 μg, respectively. In the intention-to-treat analysis, 90.2% (95% CI: 81.1%, 99.3%) of fair-skinned children randomly assigned to supplementation of 10 μg/d attained sufficient concentrations, whereas 25 μg/d was needed in dark-skinned children to reach sufficiency in 95.1% (95% CI: 88.5%, 100%). In children adherent to the study product, 97% (95% CI: 91.3%, 100%) and 87.9% (95% CI: 76.8%, 99%) of fair- and dark-skinned children, respectively, achieved sufficient concentrations if supplemented with 10 μg/d. By using 95% prediction intervals for 30 and 50 nmol S-25(OH)D/L, intakes of 6 and 20 μg/d are required in fair-skinned children, whereas 14 and 28 μg/d are required in children with dark skin. Conclusion: Children with fair and dark skin require vitamin D intakes of 20 and 28 μg/d, respectively, to maintain S-25(OH)D ≥50 nmol/L, whereas intakes of 6 and 14 μg/d, respectively, are required to maintain concentrations ≥30 nmol/L during winter. This trial was registered at clinicaltrials.gov as NCT01741324.
  • Article
    Purpose: The effects of vitamin D supplementation on bone turnover markers (BTMs) have been inconsistent. This study examined the effects of weekly 35,000 IU vitamin D supplementation for 1 month on BTMs. Methods: Sixty-eight vitamin D deficient adolescent females were given 35,000 IU of vitamin D3 for 4 weeks. Pre and post intervention blood samples were taken for 25(OH) D, PTH, osteocalcin and βCTX. Results: There was a significant increase in serum 25 (OH) D in the post intervention period which was accompanied by a significant decrease in PTH, osteocalcin and βCTX (P < 0.001). Conclusions: We concluded that weekly 35,000 IU vitamin D supplementation for 4 weeks results in significant improvement of BTMs.
  • Article
    Purpose: To explore whether muscle strength, the insulin-like growth factor axis (IGF-axis), height, and body composition were associated with serum 25-hydroxyvitamin D [25(OH)D] and affected by winter vitamin D supplementation in healthy children, and furthermore to explore potential sex differences. Methods: We performed a double-blind, placebo-controlled, dose-response winter trial at 55ºN. A total of 117 children aged 4-8 years were randomly assigned to either placebo, 10, or 20 µg/day of vitamin D3for 20 weeks. At baseline and endpoint, we measured muscle strength with handgrip dynamometer, fat mass index (FMI), fat free mass index (FFMI), height, plasma IGF-1, IGF-binding protein 3 (IGFBP-3), and serum 25(OH)D. Results: At baseline, serum 25(OH)D was positively associated with muscle strength, FFMI, and IGFBP-3 in girls only (all p < 0.01). At endpoint, baseline-adjusted muscle strength, FMI and FFMI did not differ between intervention groups. However, baseline-adjusted IGF-1 and IGFBP-3 were higher after 20 µg/day compared to placebo (p = 0.043 and p = 0.006, respectively) and IGFBP-3 was also higher after 20 µg/day compared to 10 µg/day (p = 0.011). Children tended to be taller after 20 µg/day compared to placebo (p = 0.064). No sex interactions were seen at endpoint. Conclusions: Avoiding the winter-related decline in serum 25(OH)D may influence IGF-1 and IGFBP-3 in children. Larger trials are required to confirm these effects, and the long-term implication for linear growth.
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    Associations of underweight and stunting with impaired vitamin D status in Ecuadorian children provides insights into the vitamin’s biology - Noel W Solomons, Eduardo Villamor
  • Article
    Background Most Canadian children do not meet the recommended dietary intake for vitamin D. Objectives The aims were to test how much vitamin D from food is needed to maintain a healthy serum 25-hydroxyvitamin D3 [25(OH)D3] status from fall to spring in young children and to examine musculoskeletal outcomes. Design Healthy children aged 2–8 y (n = 51) living in Montreal, Canada, were randomly assigned to 1 of 2 dietary vitamin D groups (control or intervention to reach 400 IU/d by using vitamin D–fortified foods) for 6 mo, starting October 2014. At baseline and at 3 and 6 mo, anthropometric characteristics, vitamin D metabolites (liquid chromatography–tandem mass spectrometry), and bone biomarkers (IDS-iSYS, Immunodiagnositc Systems; Liaison; Diasorin) were measured and physical activity and food intakes surveyed. At baseline and at 6 mo, bone outcomes and body composition (dual-energy X-ray absorptiometry) were measured. Cross-sectional images of distal tibia geometry and muscle density were conducted with the use of peripheral quantitative computed tomography scans at 6 mo. Results At baseline, participants were aged 5.2 ± 1.9 (mean ± SD) y and had a body mass index z score of 0.65 ± 0.12; 53% of participants were boys. There were no differences between groups in baseline serum 25(OH)D3 (66.4 ± 13.6 nmol/L) or vitamin D intake (225 ± 74 IU/d). Median (IQR) compliance was 96% (89–99%) for yogurt and 84% (71–97%) for cheese. At 3 mo, serum 25(OH)D3 was higher in the intervention group (P < 0.05) but was not different between groups by 6 mo. Although lean mass accretion was higher in the intervention group (P < 0.05), no differences in muscle density or bone outcomes were observed. Conclusions The consumption of 400 IU vitamin D/d from fall to spring did not maintain serum 25(OH)D3 concentration or improve bone outcomes. Further work with lean mass accretion as the primary outcome is needed to confirm if vitamin D enhances lean accretion in healthy young children. This trial was registered at www.clinicaltrials.gov as NCT02387892.
  • Article
    Purpose: We explored the effect of winter cholecalciferol (vitamin D3) supplementation on innate immune markers in healthy Danish children (55°N). Methods: In the double-blind, placebo-controlled trial, ODIN Junior, 119 healthy, white, 4-8 year-olds were randomized to 0 (placebo), 10 or 20 µg/day of vitamin D3for 20 weeks (October-March). Cheek mucosal swabs, blood samples, and questionnaires on acute respiratory infections the previous month were collected at baseline and endpoint. Innate immune markers were measured as secondary outcomes including in vivo oral mucosal gene expression of calprotectin (S100A9), lipocalin-2 (LCN2), beta-defensin-4 (DEFB4), interleukin-8 (IL-8), viperin (RSAD2), and the cathelicidin-antimicrobial-peptide (CAMP); ex vivo whole-blood lipopolysaccharide (LPS)-induced cathelicidin, IL-8, and IL-6; and plasma cathelicidin, together with serum 25-hydroxyvitamin D [25(OH)D]. Results: Serum 25(OH)D was 56.7 ± 12.3 nmol/L at baseline and 31.1 ± 7.5, 61.8 ± 10.6, and 75.8 ± 11.5 nmol/L at endpoint after placebo, 10 and 20 µg/day of vitamin D3(P < 0.0001), respectively. A decreased oral mucosal S100A9 expression with placebo [- 18 (95% CI - 1; - 32)%] was marginally avoided with 20 µg/day [6 (- 13; 28)%] (P = 0.06). Likewise, a decreased LPS-induced IL-8 with placebo [- 438 (95% CI - 693; - 184) ng/L] was marginally avoided with 20 µg/day [- 109 (- 374; 157) ng/L] (P = 0.07). All other immune markers and respiratory infection episodes were unaffected by vitamin D3supplementation (all P > 0.11). Conclusions: Winter vitamin D3supplementation of 10 µg/day did not affect innate immune markers, whereas 20 µg/day tended to maintain the capacity to produce a few markers in healthy children.
  • Article
    Full-text available
    Background: In the absence of dose-response data, Dietary Reference Values for vitamin D in nonpregnant adults are extended to pregnancy. Objective: The aim was to estimate vitamin D intake needed to maintain maternal 25-hydroxyvitamin D [25(OH)D] in late gestation at a concentration sufficient to prevent newborn 25(OH)D <25-30 nmol/L, a threshold indicative of increased risk of nutritional rickets. Design: We conducted a 3-arm, dose-response, double-blind, randomized placebo-controlled trial in Cork, Ireland (51.9oN). A total of 144 white-skinned pregnant women were assigned to receive 0, 10 (400 IU), or 20 (800 IU) µg vitamin D3/d from ≤18 wk of gestation. Vitamin D metabolites at 14, 24, and 36 wk of gestation and in cord sera, including 25(OH)D3, 3-epi-25(OH)D3, 24,25(OH)2D3, and 25(OH)D2 were quantified by liquid chromatography-tandem mass spectrometry. A curvilinear regression model predicted the total vitamin D intake (from diet and antenatal supplements plus treatment dose) that maintained maternal 25(OH)D in late gestation at a concentration sufficient to maintain cord 25(OH)D at ≥25-30 nmol/L. Results: Mean ± SD baseline 25(OH)D was 54.9 ± 10.7 nmol/L. Total vitamin D intakes at the study endpoint (36 wk of gestation) were 12.1 ± 8.0, 21.9 ± 5.3, and 33.7 ± 5.1 µg/d in the placebo and 10-µg and 20-µg vitamin D3 groups, respectively; and 25(OH)D was 24.3 ± 5.8 and 29.2 ± 5.6 nmol/L higher in the 10- and 20-µg groups, respectively, compared with placebo (P < 0.001). For maternal 25(OH)D concentrations ≥50 nmol/L, 95% of cord sera were ≥30 nmol/L and 99% were >25 nmol/L. The estimated vitamin D intake required to maintain serum 25(OH)D at ≥50 nmol/L in 97.5% of women was 28.9 µg/d. Conclusions: Thirty micrograms of vitamin D per day safely maintained serum 25(OH)D concentrations at ≥50 nmol/L in almost all white-skinned women during pregnancy at a northern latitude, which kept 25(OH)D at >25 nmol/L in 99% and ≥30 nmol/L in 95% of umbilical cord sera. This trial was registered at www.clinicaltrials.gov as NCT02506439.
  • Article
    Background: Epidemiologic studies have supported inverse associations between low serum 25-hydroxyvitamin D [25(OH)D] and cardiometabolic risk markers, but few randomized trials have investigated the effect of vitamin D supplementation on these markers in adolescents. Objective: The objective of this study was to investigate the effect of winter-time cholecalciferol (vitamin D3) supplementation on cardiometabolic risk markers in white, healthy 14- to 18-y-old adolescents in the UK (51°N) as part of the ODIN Project. Methods: In a dose-response trial, 110 adolescents (mean ± SD age: 15.9 ± 1.4 y; 43% male; 81% normal weight) were randomly assigned to receive 0, 10 or 20 μg/d vitamin D3 for 20 wk (October-March). Cardiometabolic risk markers including BMI-for-age z score (BMIz), waist circumference, systolic and diastolic blood pressure, fasting plasma triglycerides, cholesterol (total, HDL, LDL, and total:HDL), and glucose were measured at baseline and endpoint as secondary outcomes, together with serum 25(OH)D. Intervention effects were evaluated in linear regression models as between-group differences at endpoint, adjusted for the baseline value of the outcome variable and additionally for age, sex, Tanner stage, BMIz, and baseline serum 25(OH)D. Results: Mean ± SD baseline serum 25(OH)D was 49.1 ± 12.3 nmol/L and differed between groups at endpoint with concentrations of 30.7 ± 8.6, 56.6 ± 12.4, and 63.9 ± 10.6 nmol/L in the 0, 10, and 20 μg/d groups, respectively (P ≤ 0.001). Vitamin D3 supplementation had no effect on any of the cardiometabolic risk markers (all P > 0.05), except for lower HDL (-0.12 mmol/L; 95% CI: -0.21, 0.04 mmol/L; P = 0.003) and total cholesterol (-0.21 mmol/L; 95% CI: -0.42, 0.00 mmol/L; P = 0.05) in the 20 μg/d than in the 10 μg/d group, which disappeared in the fully adjusted analysis (P = 0.27 and P = 0.30, respectively). Conclusions: Supplementation with vitamin D3 at 10 and 20 μg/d, which increased serum 25(OH)D concentrations during the winter-time, had no effect on markers of cardiometabolic risk in healthy 14- to 18-y-old adolescents. This trial was registered at clinicaltrials.gov as NCT02150122.
  • Article
    Background: Low serum 25-hydroxyvitamin D [25(OH)D] has been associated with unfavorable cardiometabolic risk profles in many observational studies in children, but very few randomized controlled trials have investigated this. Objective: We explored the effect of winter-time cholecalciferol (vitamin D3) supplementation on cardiometabolic risk markers in young, white, 4-to 8-y-old healthy Danish children (55°N) as part of the pan-European ODIN project. Methods: In the ODIN Junior double-blind, placebo-controlled, dose-response trial, 119 children (mean ± SD age: 6.7 ± 1.5 y; 36% male; 82% normal weight) were randomly allocated to 0, 10 or 20 μ g/d of vitamin D3 for 20 wk (October-March). Cardiometabolic risk markers including BMI-for-age z score (BMIz), waist circumference, systolic and diastolic blood pressure, serum triglycerides and cholesterol (total, LDL, HDL, and total:HDL), plasma glucose and insulin, and whole-blood glycated hemoglobin were measured at baseline and endpoint as secondary outcomes together with serum 25(OH)D. Intervention effects were evaluated in linear regression models as between-group differences at endpoint adjusted for baseline value of the outcome, and additionally for age, sex, baseline serum 25(OH)D, BMIz, time since breakfast, and breakfast content. Results: Mean ± SD serum 25(OH)D was 56.7 ± 12.3 nmol/L at baseline and differed between groups at endpoint with concentrations of 31.1 ± 7.5, 61.8 ± 10.6, and 75.8 ± 11.5 nmol/L in the 0-, 10-, and 20 μ g/d groups, respectively (P < 0.0001). Vitamin D3 supplementation had no effect on any of the cardiometabolic risk markers in analyses adjusted for baseline value of the outcome (all P = 0.05), and additional covariate adjustment did not change the results notably. Conclusions: Preventing the winter decline in serum 25(OH)D with daily vitamin D3 supplementation of 10 or 20 μ g had no cardiometabolic effects in healthy 4-to 8-y-old Danish children.
  • Article
    Meta-analyses on the effect of vitamin D intake on status in children are lacking, especially those focused on vitamin D-fortified foods. The objective of this meta-analysis was to investigate the effect of vitamin D interventions (fortified foods, supplements, bolus injections) on vitamin D status in children 2-18 y of age. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, literature searches were conducted up to December 2016. Randomized placebo-controlled vitamin D interventions in healthy children aged 2-18 y were included. A random-effects model was used with I2 assessing heterogeneity. We included 26 trials (5403 children) with interventions (n = 9 fortified foods, n = 15 supplements, n = 2 bolus injections) from 100-4000 IU vitamin D/d over 4 wk to 2 y. The serum 25-hydroxyvitamin D [25(OH)D] weighted mean difference for all 26 trials (23.5 nmol/L; 95% CI: 20.7, 26.3 nmol/L; I2 = 99.9%) resulted in a mean increase of 1.0 nmol/L (95% CI: 0.3, 1.7 nmol/L) for each increase of 100 IU vitamin D/d (per 1 µg/d : 0.4 nmol/L; 95% CI: 0.1, 0.7 nmol/L). The response per 100 IU vitamin D/d was greater in trials with a mean baseline serum 25(OH)D <30 nmol/L, with the use of fortified foods and with baseline vitamin D intakes <100 IU/d. In conclusion, the serum 25(OH)D response to vitamin D intake differs on the basis of baseline status, intakes, and delivery mode, but not age, sex, or latitude.
  • Article
    Objective To explore determinants of serum 25-hydroxyvitamin D (s-25(OH)D) during autumn in young, Caucasian children not consuming vitamin D-fortified foods or supplements, and explore differences in sun behaviours between pre-school and school children. Design In September–October, s-25(OH)D was measured by LC–MS/MS; physical activity, sun behaviours and vitamin D intake were assessed with questionnaires. Setting Baseline data from the ODIN Junior trial at 55°N. Subjects Children aged 4–8 years ( n 130), of whom 96% gave blood samples. Results Mean s-25(OH)D was 56·8 ( sd 12·5) nmol/l and positively associated with fat-free mass index ( P =0·014). Children being active 6–7 h/week had 5·6 (95% CI 1·1, 10·0) nmol/l higher s-25(OH)D than less active children ( P =0·014). Children seeking shade sometimes or rarely/never had 7·0 (95% CI 1·2, 12·9; P =0·018) and 7·2 (95% CI 0·8, 13·6; P =0·028) nmol/l higher s-25(OH)D, respectively, than children always/often seeking shade. Pre-school children had more sun-safe behaviour than school children in terms of use of a hat, sunscreen and sunscreen sun protection factor ( P <0·05). In school but not pre-school children, using a hat rarely/never was associated with 12·1 (95% CI 2·5, 21·7; P =0·014) nmol/l higher s-25(OH)D v . always/often ( Pinteraction =0·019). Vitamin D intake was not associated with s-25(OH)D ( P =0·241). Conclusions Physical activity and sun behaviours are associated with s-25(OH)D in young children. Identifying factors influencing autumn s-25(OH)D is relevant to optimize levels before sun exposure diminishes. Strategies to reduce risk of inadequacy should consider risk of skin cancer and sunburn, and could include fortification and/or vitamin D supplementation.
  • Article
    Objective To develop an internationally acceptable definition of child overweight and obesity, specifying the measurement, the reference population, and the age and sex specific cut off points. Design International survey of six large nationally representative cross sectional growth studies. Setting Brazil, Great Britain, Hong Kong, the Netherlands, Singapore, and the United States. Subjects 97 876 males and 94 851 females from birth to 25 years of age. Main outcome measure Body mass index (weight/height 2 ). Results For each of the surveys, centile curves were drawn that at age 18 years passed through the widely used cut off points of 25 and 30 kg/m 2 for adult overweight and obesity. The resulting curves were averaged to provide age and sex specific cut off points from 2›18 years. Conclusions The proposed cut off points, which are less arbitrary and more internationally based than current alternatives, should help to provide internationally comparable prevalence rates of overweight and obesity in children.
  • Article
    Full-text available
    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.
  • Article
    Background: A well-designed, validated quantitative food frequency questionnaire (FFQ) could offer an efficient and cost-effective method for assessing habitual vitamin D intake. The present study aimed to describe the development, validation and implementation of a vitamin D FFQ. Methods: National food consumption survey data obtained from Irish adults (18-64 years) were used to identify foods that contribute 95% of vitamin D intake. A winter-based validation study was carried out for the resulting FFQ in 120 females, including 98 women [mean (SD) 65.0 (7.3) years] and 22 girls [12.2 (0.8) years], using a 14-day diet history (DH) as a comparator. Serum 25(OH)D concentrations were analysed. Validity coefficients were calculated using the method of triads. Cross-classification and Bland-Altman analysis were also performed. Results: Median (interquartile range) vitamin D intakes (including the contribution from nutritional supplements) were 5.4 (3.7) and 3.7 (5.9) μg day(-1) from the FFQ and DH, respectively and intakes of vitamin D from food sources were 3.6 (3.1) and 2.4 (2.2) μg day(-1) . The FFQ and DH classified 86% and 87% of individuals into the same and adjacent thirds of wintertime serum 25(OH)D status, respectively. There was a strong association (r = 0.71, P < 0.0001) and no significant systematic or proportional bias observed for the difference between estimates from the FFQ and DH. The validity coefficient for the FFQ was 0.92 (95% confidence interval = 0.80-0.97). Repeatability analysis (n = 56) performed 6-12 months later showed no significant difference in estimates of vitamin D between administrations. Conclusions: The data obtained in the present study indicate high validity and good reproducibility of a short, interviewer-administered FFQ for vitamin D.
  • Article
    In recent years, reports suggesting a resurgence of vitamin D deficiency in the Western world, combined with various proposed health benefits for vitamin D supplementation, have resulted in increased interest from health care professionals, the media, and the public. The aim of this position paper is to summarise the published data on vitamin D intake and prevalence of vitamin D deficiency in the healthy European paediatric population, to discuss the health benefits of vitamin D and to provide recommendations for the prevention of vitamin D deficiency in this population. Vitamin D plays a key role in calcium and phosphate metabolism and is essential for bone health. There is insufficient evidence from interventional studies to support vitamin D supplementation for other health benefits in infants, children, and adolescents. The pragmatic use of a serum concentration >50 nmol/L to indicate sufficiency and a serum concentration <25 nmol/L to indicate severe deficiency is recommended. Vitamin D deficiency occurs commonly among healthy European infants, children, and adolescents, especially in certain risk groups, including breast-fed infants, not adhering to the present recommendation for vitamin D supplementation, children and adolescents with dark skin living in northern countries, children and adolescents without adequate sun exposure, and obese children. Infants should receive an oral supplementation of 400 IU/day of vitamin D. The implementation should be promoted and supervised by paediatricians and other health care professionals. Healthy children and adolescents should be encouraged to follow a healthy lifestyle associated with a normal body mass index, including a varied diet with vitamin D-containing foods (fish, eggs, dairy products) and adequate outdoor activities with associated sun exposure. For children in risk groups identified above, an oral supplementation of vitamin D must be considered beyond 1 year of age. National authorities should adopt policies aimed at improving vitamin D status using measures such as dietary recommendations, food fortification, vitamin D supplementation, and judicious sun exposure, depending on local circumstances.
  • Article
    Requests for vitamin D testing have increased considerably over the past few years, due in part to recent studies that show its association with protecting against skeletal and nonskeletal disorders such as malignancies and metabolic diseases. The Institute of Medicine recently created a consensus report of recommended reference rages and recommended dietary allowances for this vitamin. Two basic categories of laboratory methods exist for analysis of vitamin D; however, their differing methodologies measure a variety of forms and metabolites of vitamin D that may create confusion in interpretation of results. This review of methods considers that total 25-hydroxyvitamin D is the recommended test for vitamin D status and compares methods from published studies and recent findings of proficiency testing surveys.
  • Article
    Beyond the well-accepted effects on the skeleton, low vitamin D status has been linked to increased risk of several non-skeletal disease, including CVD. If low serum 25-hydroxyvitamin D (25(OH)D) concentration is causally linked to risk of CVD then this is important not only because low vitamin D status is quite common particularly in winter in countries above 40°N, but also of key relevance is the fact that such low vitamin D status can be improved by food-based strategies. The overarching aim of the present paper is to review the current evidence-base to support a link between low vitamin D status and CVD risk. The review initially briefly overviews how mechanistically vitamin D may play a role in CVD and then reviews the current available evidence-base to support a link between low vitamin D status and CVD risk, with particular emphasis on data from the randomised control trials, cohort studies and recent meta-analysis data as well as to the conclusions of a number of authoritative agencies/bodies. Finally, the review summarises current serum 25(OH)D concentrations within a select number of adult populations in the context of different definitions of vitamin D status proposed recently, and then briefly highlights food-based strategies for increasing vitamin D intake and status. In conclusion, at present the data for a causal link between low vitamin D status and CVD are mixed and ambiguous; however, should causality be affirmed by ongoing and future studies, there are food-based strategies for enhanced vitamin D status in the population which could ultimately lower risk of CVD.
  • Article
    Full-text available
    Context:Changes in serum vitamin D metabolites and calcium absorption with varying doses of oral vitamin D3 in healthy children are unknown.Objective:Our objective was to examine the dose-response effects of supplemental vitamin D3 on serum vitamin D metabolites and calcium absorption in children living at two U.S. latitudes.Design:Black and white children (n = 323) participated in a multisite (U.S. latitudes 34° N and 40° N), triple-masked trial. Children were randomized to receive oral vitamin D3 (0, 400, 1000, 2000, and 4000 IU/d) and were sampled over 12 weeks in winter. Serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured using RIA and intact PTH (iPTH) by immunoradiometric assay. Fractional calcium absorption was determined from an oral stable isotope (44)Ca (5 mg) in a 150-mg calcium meal. Nonlinear and linear regression models were fit for vitamin D metabolites, iPTH, and calcium absorption.Results:The mean baseline 25(OH)D value for the entire sample was 70.0 nmol/L. Increases in 25(OH)D depended on dose with 12-week changes ranging from -10 nmol/L for placebo to 76 nmol/L for 4000 IU. Larger 25(OH)D gains were observed for whites vs blacks at the highest dose (P < .01). Gains for 1,25(OH)2D were not significant (P = .07), and decreases in iPTH were not dose-dependent. There was no dose effect of vitamin D on fractional calcium absorption when adjusted for pill compliance, race, sex, or baseline 25(OH)D.Conclusion:Large increases in serum 25(OH)D with vitamin D3 supplementation did not increase calcium absorption in healthy children living at 2 different latitudes. Supplementation with 400 IU/d was sufficient to maintain wintertime 25(OH)D concentrations in healthy black, but not white, children.
  • Article
    BACKGROUND: The Vitamin D Standardization Program (VDSP) has developed protocols for standardizing procedures of 25-hydroxyvitamin D [25(OH)D] measurement in National Health/Nutrition Surveys to promote 25(OH)D measurements that are accurate and comparable over time, location, and laboratory procedure to improve public health practice. OBJECTIVE: We applied VDSP protocols to existing ELISA-derived serum 25(OH)D data from the Irish National Adult Nutrition Survey (NANS) as a case-study survey and evaluated their effectiveness by comparison of the protocol-projected estimates with those from a reanalysis of survey serums by using liquid chromatography-tandem mass spectrometry (LC-tandem MS). DESIGN: The VDSP reference system and protocols were applied to ELISA-based serum 25(OH)D data from the representative NANS sample (n = 1118). A reanalysis of 99 stored serums by using standardized LC-tandem MS and resulting regression equations yielded predicted standardized serum 25(OH)D values, which were then compared with LC-tandem MS reanalyzed values for all serums. RESULTS: Year-round prevalence rates for serum 25(OH)D concentrations <30, <40, and <50 nmol/L were 6.5%, 21.9%, and 40.0%, respectively, via original ELISA measurements and 11.4%, 25.3%, and 43.7%, respectively, when VDSP protocols were applied. Differences in estimates at <30- and <40-nmol/L thresholds, but not at the <50-nmol/L threshold, were significant (P < 0.05). A reanalysis of all serums by using LC-tandem MS confirmed prevalence estimates as 11.2%, 27.2%, and 45.0%, respectively. Prevalences of serum 25(OH)D concentrations >125 nmol/L were 1.2%, 0.3%, and 0.6% by means of ELISA, VDSP protocols, and LC-tandem MS, respectively. CONCLUSION: VDSP protocols hold a major potential for national nutrition and health surveys in terms of the standardization of serum 25(OH)D data.
  • Article
    In recent years, reports suggesting a resurgence of vitamin D deficiency in the Western world, combined with various proposed health benefits for vitamin D supplementation have resulted in increased interest from healthcare professionals, the media and the public. The aim of this position paper is to summarize the published data on vitamin D intake and prevalence of vitamin D deficiency in the healthy European paediatric population, to discuss health benefits of vitamin D and to provide recommendations for the prevention of vitamin D deficiency in this population. Vitamin D plays a key role in calcium and phosphate metabolism and is essential for bone health. There is insufficient evidence from interventional studies to support vitamin D supplementation for other health benefits in infants, children and adolescents. The pragmatic use of a serum concentration above 50 nmol/l to indicate sufficiency and a serum concentration below 25 nmol/l to indicate severe deficiency is recommended. Vitamin D deficiency occurs quite commonly among healthy European infants, children and adolescents, especially in certain risk groups including breast-fed infants not adhering to the current recommendation for vitamin D supplementation, children and adolescents with dark skin living in Northern countries, as well as children and adolescents without adequate sun exposure, and obese children. Infants should receive an oral supplementation of 400 IU/day of vitamin D. The implementation should be promoted and supervised by paediatricians and other healthcare professionals. Healthy children and adolescents should be encouraged to follow a healthy lifestyle associated with a normal body mass index and including a varied diet with vitamin D containing foods (fish, eggs, dairy products) and adequate outdoor activities with associated sun exposure. For children in risk groups identified above an oral supplementation of vitamin D must be considered beyond one year of age. National Authorities should adopt policies aimed at improving vitamin D status using measures such as dietary recommendations, food fortification, vitamin D supplementation and judicious sun exposure, depending on local circumstances.
  • Article
    OBJECTIVE: To describe vitamin D intakes in children and teenagers and the contribution from supplements and fortified foods in addition to the base diet. DESIGN: Analysis of 7 d weighed food records collected during the Children's and Teens' National Nutrition Surveys in Ireland. Food composition data for vitamin D were updated from international analytical sources. SETTING: Nationally representative cross-sectional dietary surveys. SUBJECTS: Children (n 594; 5-12 years) and teenagers (n 441; 13-17 years). RESULTS: Median vitamin D intakes were 1·9, 2·1 and 2·4 μg/d in 5-8-, 9-12- and 13-17-year-olds, respectively. The prevalence of vitamin D-containing supplement use was 21, 16 and 15 % in 5-8-, 9-12- and 13-17-year-olds and median intakes in users ranged from 6·0 to 6·7 μg/d. The prevalence of inadequate intakes, defined as the percentage with mean daily intakes below the Estimated Average Requirement of 10 μg/d, ranged from 88 to 96 % in supplement users. Foods fortified with vitamin D, mainly breakfast cereals, fat spreads and milk, were consumed by 71, 70 and 63 % of 5-8-, 9-12- and 13-17-year-olds. Non-supplement users who consumed vitamin D-fortified foods had median intakes of 1·9-2·5 μg/d, compared with 1·2-1·4 μg/d in those who did not consume fortified foods. CONCLUSIONS: It is currently not possible for children consuming the habitual diet to meet the US Institute of Medicine dietary reference intake for vitamin D. In the absence of nationally representative 25-hydroxyvitamin D data in children, the implications of this observation for prevalence of vitamin D deficiency and health consequences are speculative.
  • The importance of vitamin D intake to nutritional status is a corollary of sunshine deficit. There is a dose-response of serum 25-hydroxyvitamin D (25(OH)D) concentrations to total vitamin D intake in persons who do not receive UVB exposure. This updated summary of vitamin D intakes and sources in adults and children focuses on data from North America and Europe. We explore the evidence that intakes of vitamin D are inadequate with reference to the Institute of Medicine (IOM) Dietary Reference Intakes. Due to mandatory fortification, usual vitamin D intakes are higher in the US and Canada than most of Europe, with the exception of the Nordic countries. Intakes of vitamin D in national surveys are typically below 5 μg/d in most European countries and vary according to country-specific fortification practices, sex and age. The main source of variation is the contribution from nutritional supplements. Usual vitamin D intake estimates need to capture data on the contributions from fortified and supplemental sources as well as the base diet. The current dietary supply of vitamin D makes it unfeasible for most adults to meet the IOM Estimated Average Requirement of 10 μg/d. While supplements are an effective method for individuals to increase their intake, food fortification represents the best opportunity to increase the vitamin D supply to the population. Well-designed sustainable fortification strategies, which use a range of foods to accommodate diversity, have potential to increase vitamin D intakes across the population distribution and minimize the prevalence of low 25(OH)D concentrations.
  • Article
    Full-text available
    In this review, we define hypercalcemia levels, common causes for hypercalcemia in children, and treatment in order to aid the practicing pediatrician. One rare cause of hypercalcemia in the child is familial hypocalciuric hypercalcemia (also termed familial benign hypercalcemia). Mutations that inactivate the Ca-sensing receptor gene FHH have been described as an autosomal dominant disorder, but recently milder mutations in the CASR have been shown to cause hypercalcemia when homozygous. Normal serum levels of calcium are maintained through the interplay of parathyroid, renal, and skeletal factors. In this review, we have distinguished the neonate and infant from the older child and adolescent because the causes and clinical features of hypercalcemia can differ in these two age groups. However, the initial approach to the medical treatment of severe or symptomatic hypercalcemia is to increase the urinary excretion of calcium in both groups. In most cases, hypercalcemia is due to osteoclastic bone resorption, and agents that inhibit or destroy osteoclasts are, therefore, effective treatments. Parathyroid surgery, the conventional treatment for adults with symptomatic primary hyperparathyroidism, is recommended for all children with primary hyperparathyroidism.
  • Article
    Full-text available
    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.
  • Article
    Full-text available
    Knowledge gaps have contributed to considerable variation (between 0 and 15 μg/d) in international dietary recommendations for vitamin D in adolescents. 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 (25, 37.5, 40, and 50 nmol/L) during wintertime in adolescent white girls. Data (baseline and 6 mo) from 2 randomized, placebo-controlled, double-blind, 12-mo intervention studies in Danish (55°N) and Finnish (60°N) girls (n = 144; mean age: 11.3 y; mean vitamin D intake: 3.7 μg/d) at vitamin D(3) supplementation amounts of 0, 5, and 10 μg/d were used. Serum 25(OH)D was measured with an HPLC assay in a centralized laboratory. Clear dose-related increments (P < 0.0001) in serum 25(OH)D with increasing supplemental vitamin D(3) were observed. The slope of the relation between vitamin D intake and serum 25(OH)D at the end of winter was 2.43 nmol ⋅ L(-1) ⋅ μg intake(-1), and no difference in the slopes between Finnish and Danish girls was observed. The vitamin D intakes that maintained serum 25(OH)D concentrations at >25, >37.5, and >50 nmol/L in 97.5% of the sample were 8.3, 13.5, and 18.6 μg/d, respectively, whereas an intake of 6.3 μg/d maintained a serum 25(OH)D concentration >40 nmol/L in 50% of the sample. The vitamin D intakes required to ensure that adequate vitamin D status [defined variably as serum 25(OH)D >25 and >50 nmol/L] is maintained during winter in the vast majority (>97.5%) of adolescent girls (mean age: 11.3 y) at northern latitudes (>55°N) are 8.3 and 18.6 μg/d, respectively. This trial was registered at clinicaltrials.gov as NCT00267540.
  • Article
    In the 1990s, the American population-based study NHANES III renewed the focus on possible secular trends in male puberty. However, no conclusions could be made on pubertal onset due to the lack of compatible data. The aim of the study was to evaluate secular trends in pubertal onset during the recent 15 yr and their relation to body mass index (BMI) in boys. We conducted a cross-sectional study in 1991-1993 and a combined cross-sectional and longitudinal study in 2006-2008 (The Copenhagen Puberty Study) at a tertiary center for pediatric endocrinology. A total of 1528 boys aged 5.8 to 19.9 yr participated (n = 824 in 1991-1993, and n = 704 in 2006-2008). Genital and pubic hair stages as well as testicular volume by orchidometry were evaluated. Blood samples were analyzed for LH, FSH, testosterone, and SHBG. We measured age at onset of pubertal markers. Onset of puberty, defined as age at attainment of testicular volume above 3 ml, occurred significantly earlier in 2006-2008 [11.66 yr (11.49-11.82); mean (95% confidence interval)] than in 1991-1993 [11.92 yr (11.76-12.08); P = 0.025]. Significantly higher LH, but not testosterone, levels were found in the 11- to 16-yr-old boys from 2006-2008 compared to 1991-1993 (P = 0.020). BMI Z-score increased significantly from 1991-1993 [0.044 (-0.016 to 0.104)] to 2006-2008 [0.290 (0.219-0.361); P < 0.001]. Interestingly, pubertal onset and LH levels were no longer significantly different between study periods after adjustment for BMI. Estimated mean age at onset of puberty has declined significantly during the recent 15 yr. This decline was associated with the coincident increase in BMI.
  • Article
    Recent publications showing unexpectedly early breast development in American girls created debate worldwide. However, secular trend analyses are often limited by poor data comparability among studies performed by different researchers in different time periods and populations. Here we present new European data systematically collected from the same region and by 1 research group at the beginning and end of the recent 15-year period. Girls (N = 2095) aged 5.6 to 20.0 years were studied in 1991-1993 (1991 cohort; n = 1100) and 2006-2008 (2006 cohort; n = 995). All girls were evaluated by palpation of glandular breast, measurement of height and weight, and blood sampling (for estradiol, luteinizing hormone, and follicle-stimulating hormone). Age distribution at entering pubertal breast stages 2 through 5, pubic hair stages 2 through 5, and menarche was estimated for the 2 cohorts. Onset of puberty, defined as mean estimated age at attainment of glandular breast tissue (Tanner breast stage 2+), occurred significantly earlier in the 2006 cohort (estimated mean age: 9.86 years) when compared with the 1991 cohort (estimated mean age: 10.88 years). The difference remained significant after adjustment for BMI. Estimated ages at menarche were 13.42 and 13.13 years in the 1991 and 2006 cohorts, respectively. Serum follicle-stimulating hormone and luteinizing hormone did not differ between the 2 cohorts at any age interval, whereas significantly lower estradiol levels were found in 8- to 10-year-old girls from the 2006 cohort compared with similarly aged girls from the 1991 cohort. We found significantly earlier breast development among girls born more recently. Alterations in reproductive hormones and BMI did not explain these marked changes, which suggests that other factors yet to be identified may be involved.
  • Article
    Full-text available
    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. 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. 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. 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. 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.
  • Article
    Full-text available
    Knowledge gaps have contributed to considerable variation among international dietary recommendations for vitamin D. 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. 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). 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. 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.
  • Article
    Vitamin D is suggested to have a role in the coupling of bone resorption and formation. Compared with women, men are believed to have more stable bone remodeling, and thus, are considered less susceptible to the seasonal variation of calcitropic hormones. We examined whether seasonal variation exists in calcitropic hormones, bone remodeling markers, and BMD in healthy men. Furthermore, we determined which vitamin D intake is required to prevent this variation. Subjects (N = 48) were healthy white men 21-49 yr of age from the Helsinki area with a mean habitual dietary intake of vitamin D of 6.6 +/- 5.1 (SD) microg/d. This was a 6-mo double-blinded vitamin D intervention study, in which subjects were allocated to three groups of 20 microg (800 IU), 10 microg (400 IU), or placebo. Fasting blood samplings were collected six times for analyses of serum (S-)25(OH)D, iPTH, bone-specific alkaline phosphatase (BALP), and TRACP. Radial volumetric BMD (vBMD) was measured at the beginning and end of the study with pQCT. Wintertime variation was noted in S-25(OH)D, S-PTH, and S-TRACP (p < 0.001, p = 0.012, and p < 0.05, respectively) but not in S-BALP or vBMD in the placebo group. Supplementation inhibited the winter elevation of PTH (p = 0.035), decreased the S-BALP concentration (p < 0.05), but benefited cortical BMD (p = 0.09) only slightly. Healthy men are exposed to wintertime decrease in vitamin D status that impacts PTH concentration. Vitamin D supplementation improved vitamin D status and inhibited the winter elevation of PTH and also decreased BALP concentration. The ratio of TRACP to BALP shows the coupling of bone remodeling in a robust way. A stable ratio was observed among those retaining a stable PTH throughout the study. A daily intake of vitamin D in the range of 17.5-20 microg (700-800 IU) seems to be required to prevent winter seasonal increases in PTH and maintain stable bone turnover in young, healthy white men.
  • Article
    Sunlight has long been recognized as a major provider of vitamin D for humans; radiation in the UVB (290-315 nm) portion of the solar spectrum photolyzes 7-dehydrocholesterol in the skin to previtamin D3, which, in turn, is converted by a thermal process to vitamin D3. Latitude and season affect both the quantity and quality of solar radiation reaching the earth's surface, especially in the UVB region of the spectrum, but little is known about how these influence the ability of sunlight to synthesize vitamin D3 in skin. A model has been developed to evaluate the effect of seasonal and latitudinal changes on the potential of sunlight to initiate cutaneous production of vitamin D3. Human skin or [3 alpha-3H]7-dehydrocholesterol exposed to sunlight on cloudless days in Boston (42.2 degrees N) from November through February produced no previtamin D3. In Edmonton (52 degrees N) this ineffective winter period extended from October through March. Further south (34 degrees N and 18 degrees N), sunlight effectively photoconverted 7-dehydrocholesterol to previtamin D3 in the middle of winter. These results quantify the dramatic influence of changes in solar UVB radiation on cutaneous vitamin D3 synthesis and indicate the latitudinal increase in the length of the "vitamin D winter" during which dietary supplementation of the vitamin may be advisable.
  • Article
    Fifty-one healthy prepubertal schoolchildren were followed for 13 months in a double blind study. Twenty-four of them were supplemented with 400 IU of vitamin D2 5-7 times weekly, while 27 received a placebo. The children were examined in winter both at the beginning and at the end of the study, and in the middle of the study in autumn. Mean 25-hydroxyvitamin D levels in the supplemented group were significantly higher than those in the placebo group both in autumn and in winter, when the study ended. The vitamin D supplementation did not, however, affect other vitamin D metabolites, serum calcium, albumin, inorganic phosphorus, parathyroid hormone concentrations or alkaline phosphatase activity. Moreover, the supplementation caused no alterations in the weight or height gain or bone mineral content of the distal radius of the children, and thus subclinical rickets could not be shown.
  • Article
    Full-text available
    To develop an internationally acceptable definition of child overweight and obesity, specifying the measurement, the reference population, and the age and sex specific cut off points. International survey of six large nationally representative cross sectional growth studies. Brazil, Great Britain, Hong Kong, the Netherlands, Singapore, and the United States. 97 876 males and 94 851 females from birth to 25 years of age. Body mass index (weight/height(2)). For each of the surveys, centile curves were drawn that at age 18 years passed through the widely used cut off points of 25 and 30 kg/m(2) for adult overweight and obesity. The resulting curves were averaged to provide age and sex specific cut off points from 2-18 years. The proposed cut off points, which are less arbitrary and more internationally based than current alternatives, should help to provide internationally comparable prevalence rates of overweight and obesity in children.
  • Article
    Full-text available
    The deceleration of longitudinal growth in children during winter occurs simultaneously with a decrease in the number of daylight hours and a reduction in vitamin D status. Due to worries about deleterious effects on bone of a relative insufficiency, vitamin D supplementation to healthy children has been suggested. To see whether supplementation of vitamin D to healthy children during winter affects seasonal growth. Twelve girls and eight boys aged 6.2-13.7 (mean 9.8) years, all healthy, were enrolled in a double-blind, randomized, placebo-controlled cross-over study with two 4-week treatment periods and 2-week run-in and wash-out periods. Vitamin D(3) 600 IU was given in one tablet ABCDin daily. Knemometry of the right lower leg was performed on the first and last day of each period. Lower leg growth rates (mean +/- SEM) during placebo and vitamin D(3) administration were identical: 0.28 +/- 0.04 mm per week (p = 0.94, t = 0.1, 95% CI: - 0.12-0.13 mm per week). Supplementation with vitamin D(3) 600 IU day(-1) to healthy children during winter may not improve seasonal growth. Therefore, supplementation may not be recommended on the grounds of concerns about growth; however firm conclusions await randomized long-term studies.
  • Article
    Full-text available
    Very few studies have evaluated both parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D] and their effects on bone mass in children. We studied the associations of serum 25(OH)D and intact PTH (iPTH) with bone mineral content (BMC) and bone mineral density (BMD) at different bone sites and the relation between serum 25(OH)D and iPTH in early pubertal and prepubertal Finnish girls. The subjects were 10-12-y-old girls (n = 193) at Tanner stage 1 or 2, who reported a mean (+/- SD) dietary calcium intake of 733 +/- 288 mg/d. 25(OH)D, iPTH, tartrate-resistant acid phosphatase 5b (TRAP 5b), urinary calcium excretion, BMC, areal BMD, and volumetric BMD were assessed by using different methods. Thirty-two percent of the girls were vitamin D deficient [serum 25(OH)D < or = 25 nmol/L], and 46% of the girls had an insufficient concentration (26-40 nmol/L). iPTH and TRAP 5b concentrations were significantly higher in the deficient group than in the insufficient and sufficient groups [iPTH: 43.9 +/- 15.7 compared with 38.6 +/- 11.2 pg/L (P = 0.049) and 32.7 +/- 12.1 pg/L (P < 0.001), respectively; TRAP 5b: 12.2 +/- 2.9 compared with 11.0 +/- 2.8 U/L (P = 0.009) and 10.9 +/- 1.9 U/L (P = 0.006), respectively]. The girls in the deficient group also had significantly lower cortical volumetric BMD of the distal radius (P < 0.001) and tibia shaft (P = 0.002). High iPTH concentrations were also associated with low total-body apparent mineral density and urinary calcium excretion (P < 0.007). Vitamin D-deficient girls have low cortical BMD and high iPTH concentrations, which are consistent with secondary hyperparathyroidism. A low vitamin D concentration accompanied by high bone resorption (TRAP 5b) may limit the accretion of bone mass in young girls.
  • Article
    Rickets, once thought vanquished, is reappearing. In some less developed countries it hardly went away. This seminar reviews the effects of genes, stage of development, and environment on clinical expression of the disease. Rickets can be secondary to disorders of the gut, pancreas, liver, kidney, or metabolism; however, it is mostly due to nutrient deficiency and we concentrate on this form. Although calcium deficiency contributes in communities where little cows' milk is consumed, deficiency of vitamin D is the main cause. There are three major problems: the promotion of exclusive breastfeeding for long periods without vitamin D supplementation, particularly for babies whose mothers are vitamin D deficient; reduced opportunities for production of the vitamin in the skin because of female modesty and fear of skin cancer; and the high prevalence of rickets in immigrant groups in more temperate regions. A safety net of extra dietary vitamin D should be re-emphasised, not only for children but also for pregnant women. The reason why many immigrant children in temperate zones have vitamin D deficiency is unclear. We speculate that in addition to differences in genetic factors, sun exposure, and skin pigmentation, iron deficiency may affect vitamin D handling in the skin or gut or its intermediary metabolism.
  • Article
    Full-text available
    Nutritional rickets remains a public health problem in many countries, despite dramatic declines in the prevalence of the condition in many developed countries since the discoveries of vitamin D and the role of ultraviolet light in prevention. The disease continues to be problematic among infants in many communities, especially among infants who are exclusively breast-fed, infants and children of dark-skinned immigrants living in temperate climates, infants and their mothers in the Middle East, and infants and children in many developing countries in the tropics and subtropics, such as Nigeria, Ethiopia, Yemen, and Bangladesh. Vitamin D deficiency remains the major cause of rickets among young infants in most countries, because breast milk is low in vitamin D and its metabolites and social and religious customs and/or climatic conditions often prevent adequate ultraviolet light exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh, such factors do not apply. Studies indicated that the disease occurs among older toddlers and children and probably is attributable to low dietary calcium intakes, which are characteristic of cereal-based diets with limited variety and little access to dairy products. In such situations, calcium supplements alone result in healing of the bone disease. Studies among Asian children and African American toddlers suggested that low dietary calcium intakes result in increased catabolism of vitamin D and the development of vitamin D deficiency and rickets. Dietary calcium deficiency and vitamin D deficiency represent 2 ends of the spectrum for the pathogenesis of nutritional rickets, with a combination of the 2 in the middle.
  • Article
    Full-text available
    Nutritional rickets has been described from at least 59 countries in the last 20 years. Its spectrum of causes differs in different regions of the world. We conducted a systematic review of articles on nutritional rickets from various geographical regions published in the last 20 years. We extracted information about the prevalence and causes of rickets. Calcium deficiency is the major cause of rickets in Africa and some parts of tropical Asia, but is being recognised increasingly in other parts of the world. A resurgence of vitamin D deficiency has been observed in North America and Europe. Vitamin D-deficiency rickets usually presents in the 1st 18 months of life, whereas calcium deficiency typically presents after weaning and often after the 2nd year. Few studies of rickets in developing countries report values of 25(OH)D to permit distinguishing vitamin D from calcium deficiency. Rickets exists along a spectrum ranging from isolated vitamin D deficiency to isolated calcium deficiency. Along the spectrum, it is likely that relative deficiencies of calcium and vitamin D interact with genetic and/or environmental factors to stimulate the development of rickets. Vitamin D supplementation alone might not prevent or treat rickets in populations with limited calcium intake.
  • Article
    The effect of vitamin D supplementation on bone mineral augmentation in 212 adolescent girls with adequate calcium intake was studied in a randomized placebo-controlled setting. Bone mineral augmentation determined by DXA increased with supplementation both in the femur and the lumbar vertebrae in a dose-responsive manner. Supplementation decreased the urinary excretion of resorption markers, but had no impact on formation markers. Adequate vitamin D intake protects the elderly against osteoporosis, but there exists no indisputable evidence that vitamin D supplementation would benefit bone mineral augmentation. The aim of this 1-year study was to determine in a randomized double-blinded trial the effect of 5 and 10 microg vitamin D3 supplementation on bone mineral augmentation in adolescent girls with adequate dietary calcium intake. Altogether, 228 girls (mean age, 11.4 +/- 0.4 years) participated. Their BMC was measured by DXA from the femur and lumbar spine. Serum 25-hydroxyvitamin D [S-25(OH)D], intact PTH (S-iPTH), osteocalcin (S-OC), and urinary pyridinoline (U-Pyr) and deoxypyridinoline (U-Dpyr) were measured. Statistical analysis was performed both with the intention-to-treat (IT) and compliance-based (CB) method. In the CB analysis, vitamin D supplementation increased femoral BMC augmentation by 14.3% with 5 microg and by 17.2% with 10 microg compared with the placebo group (ANCOVA, p = 0.012). A dose-response effect was observed in the vertebrae (ANCOVA, p = 0.039), although only with the highest dose. The mean concentration of S-25(OH)D increased (p < 0.001) in the 5-microg group by 5.7 +/- 15.7 nM and in the 10-microg group by 12.4 +/- 13.7 nM, whereas it decreased by 6.7 +/- 11.3 nM in the placebo group. Supplementation had no effect on S-iPTH or S-OC, but it decreased U-DPyr (p = 0.042). Bone mineral augmentation in the femur was 14.3% and 17.2% higher in the groups receiving 5 and 10 microg of vitamin D, respectively, compared with the placebo group, but only 10 mug increased lumbar spine BMC augmentation significantly. Vitamin D supplementation decreased the concentration of bone resorption markers, but had no impact on bone formation markers, thus explaining increased bone mineral augmentation. However, the positive effects were noted with the CB method but not with IT.
  • Article
    Full-text available
    To determine cut offs to define thinness in children and adolescents, based on body mass index at age 18 years. International survey of six large nationally representative cross sectional studies on growth. Brazil, Great Britain, Hong Kong, the Netherlands, Singapore, and the United States. 97 876 males and 94 851 females from birth to 25 years. Body mass index (BMI, weight/height(2)). The World Health Organization defines grade 2 thinness in adults as BMI <17. This same cut off, applied to the six datasets at age 18 years, gave mean BMI close to a z score of -2 and 80% of the median. Thus it matches existing criteria for wasting in children based on weight for height. For each dataset, centile curves were drawn to pass through the cut off of BMI 17 at 18 years. The resulting curves were averaged to provide age and sex specific cut-off points from 2-18 years. Similar cut offs were derived based on BMI 16 and 18.5 at 18 years, together providing definitions of thinness grades 1, 2, and 3 in children and adolescents consistent with the WHO adult definitions. The proposed cut-off points should help to provide internationally comparable prevalence rates of thinness in children and adolescents.
  • Article
    Full-text available
    The objective of this study was to evaluate the role of serum levels of 25(OH)D and PTH on the accumulation of whole body bone mass in a cohort of children. This was a longitudinal study (1.98 +/- 0.07 y) of sixty-nine children (89% Caucasian, 44% male) enrolled in a calcium supplementation trial. Bone area, bone mineral content (BMC) and density (BMD) of the whole body and radius were assessed using a QDR 2000 (Hologic, Inc) dual energy x-ray absorptiometer. Serum PTH and 25(OH)D were measured using radioimmunoassays. Vitamin D stores were inversely related gain in bone area (p < 0.002), BMC (p < 0.002) BMD (p < 0.027), as well as to PTH levels (p < 0.0001). Compared to those with adequate vitamin D stores (>34 ng/ml), those who had consistently low vitamin D stores (18 ng/ml) had a 8% larger gain in bone area (p < 0.05); 11% in BMC (p < 0.05) and no differences in gain in BMD; after adjusting for baseline bone measurements, race, gender, season measured, Tanner stage, and calcium intake. High normal PTH with low-normal 25(OH)D stores and moderate to high calcium intake may be beneficial to accruing larger bone size and BMC during puberty.
  • Article
    Serum 25-hydroxyvitamin D (25(OH)D) is low in obese adults. To examine serum 25(OH)D in obese (BMI >95th percentile for age) vs. non-obese (BMI = 5th-75th percentile for age) 6-10-year-old African American children and compare their differences in therapeutic response to vitamin D supplementation. In an open label non-randomized pre-post comparison 21 obese (OB) and 20 non-obese (non-OB) subjects matched for age, sex, skin color, and pubertal maturation were treated with 400 IU of vitamin D(3) daily for 1 month. Serum 25(OH)D, 1,25-dihydroxyvitamin D (1,25(OH)(2)D), parathyroid hormone (PTH), leptin, and markers of bone turnover (serum bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and urine n -telopeptide cross-links of type 1 collagen (urine NTX)) were measured. Vitamin D deficiency was defined as serum 25(OH)D < or =20 ng/ml and insufficiency as 21-29 ng/ml respectively. Vitamin D deficiency occurred in 12/21 (57%) OB vs. 8/20 (40%) non-OB at baseline (P = 0.35) and persisted in 5/21 (24%) OB vs. 2/18 (11%) non-OB (P = 0.42) after treatment. When the cohort was stratified by the baseline levels of 25(OH)D, there were differences in the response to treatment in the obese and non-obese cohorts. Vitamin D deficiency was common among OB and non-OB preadolescent African American children, and 400 IU of vitamin D(3) (2x the recommended adequate intake) daily for 1 month was inadequate to raise their blood levels of 25(OH)D to > or =30 ng/ml.
  • Article
    Neither the efficiency of the 25-hydroxylation of vitamin D nor the steady state relation between vitamin D(3) and 25-hydroxyvitamin D [25(OH)D] has been studied in humans. We aimed to examine the relation between serum vitamin D(3) and 25(OH)D in normal subjects after either oral administration of vitamin D(3) or ultraviolet-B radiation across a broad range of inputs. Values for serum vitamin D(3) and (OH)D(3) were aggregated from 6 studies--1 acute and 5 near-steady state--at various vitamin D(3) inputs. In 3 of the steady state studies, vitamin D(3) had been administered for 18-26 wk in doses of 0 to 11000 IU/d; in 2 studies, subjects had received solar or ultraviolet-B irradiation. In the acute study, subjects receiving a single 100000-IU dose of vitamin D(3) had a rise in serum cholecalciferol to a mean of 521 nmol/L at 1 d and then a fall to near-baseline values by 7-14 d. Serum 25(OH)D peaked at 103 nmol/L on day 7 and fell slowly to baseline by day 112. In the 5 steady state studies, the relation of serum 25(OH)D to serum vitamin D(3) was biphasic and was well described by a combined exponential and linear function: Y = 0.433X + 87.81[1-exp (-0.468X)], with R(2) = 0.448. At physiologic inputs, there is rapid conversion of precursor to product at low vitamin D(3) concentrations and a much slower rate of conversion at higher concentrations. These data suggest that, at typical vitamin D(3) inputs and serum concentrations, there is very little native cholecalciferol in the body, and 25(OH)D constitutes the bulk of vitamin D reserves. However, at supraphysiologic inputs, large quantities of vitamin D(3) are stored as the native compound, presumably in body fat, and are slowly released to be converted to 25(OH)D.
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  • Growth at adolescence
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  • Danskernes kostvaner 2011-2013. Hovedresultater. DTU Fødevareinstituttet
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  • New reference values for vitamin D
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