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Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) 10% of Europeans. The European Calcified Tissue Society (ECTS) advises that the measurement of serum 25(OH)D be standardized, for example, by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people (especially the institutionalized) and non-Western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-Western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long-term non-skeletal outcomes such as cancer.

Background Genetic factors modify serum 25-hydroxyvitamin D [25(OH)D] concentration and can affect the optimal intake of vitamin D. Objectives We aimed to personalize vitamin D supplementation by applying knowledge of genetic factors affecting serum 25(OH)D concentration. Methods We performed a genome-wide association study of serum 25(OH)D concentration in the Finnish Health 2011 cohort (n = 3339) using linear regression and applied the results to develop a population-matched genetic risk score (GRS) for serum 25(OH)D. This GRS was used to tailor vitamin D supplementation for 96 participants of a longitudinal Digital Health Revolution (DHR) Study. The GRS, serum 25(OH)D concentrations, and personalized supplementation and dietary advice were electronically returned to participants. Serum 25(OH)D concentrations were assessed using immunoassays and vitamin D intake using FFQs. In data analyses, cross-sectional and repeated-measures statistical tests and models were applied as described in detail elsewhere. Results GC vitamin D-binding protein and cytochrome P450 family 2 subfamily R polypeptide 1 genes showed genome-wide significant associations with serum 25(OH)D concentration. One single nucleotide polymorphism from each locus (rs4588 and rs10741657) was used to develop the GRS. After returning data to the DHR Study participants, daily vitamin D supplement users increased from 32.6% to 60.2% (P = 6.5 x 10(-6)) and serum 25(OH)D concentration from 64.4 +/- 20.9 nmol/L to 68.5 +/- 19.2 nmol/L (P = 0.006) between August and November. Notably, the difference in serum 25(OH)D concentrations between participants with no risk alleles and those with 3 or 4 risk alleles decreased from 20.7 nmol/L to 8.0 nmol/L (P = 0.0063). Conclusions We developed and applied a population-matched GRS to identify individuals genetically predisposed to low serum 25(OH)D concentration. We show how the electronic return of individual genetic risk, serum 25(OH)D concentrations, and factors affecting vitamin D status can be used to tailor vitamin D supplementation. This model could be applied to other populations and countries.

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derives dietary reference values (DRVs) for vitamin K. In this Opinion, the Panel considers vitamin K to comprise both phylloquinone and menaquinones. The Panel considers that none of the biomarkers of vitamin K intake or status is suitable by itself to derive DRVs for vitamin K. Several health outcomes possibly associated with vitamin K intake were also considered but data could not be used to establish DRVs. The Panel considers that average requirements and population reference intakes for vitamin K cannot be derived for adults, infants and children, and therefore sets adequate intakes (AIs). The Panel considers that available evidence on occurrence, absorption, function and content in the body or organs of menaquinones is insufficient, and, therefore, sets AIs for phylloquinone only. Having assessed additional evidence available since 1993 in particular related to biomarkers, intake data and the factorial approach, which all are associated with considerable uncertainties, the Panel maintains the reference value proposed by the Scientific Committee for Food (SCF) in 1993. An AI of 1 μg phylloquinone/kg body weight per day is set for all age and sex population groups. Considering the respective reference body weights, AIs for phylloquinone are set at 70 μg/day for all adults including pregnant and lactating women, at 10 μg/day for infants aged 7–11 months, and between 12 μg/day for children aged 1–3 years and 65 μg/day for children aged 15–17 years., This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2017.EN-1220/full

ObjectiveTo investigate serum 25-hydroxyvitamin D (S-25(OH)D) concentration in a multi-ethnic population of northern Norway and determine predictors of S-25(OH)D, including Sami ethnicity.DesignCross-sectional data from the second survey of the Population-based Study on Health and Living Conditions in Regions with Sami and Norwegian Populations (the SAMINOR 2 Clinical Survey, 2012–2014). S-25(OH)D was measured by the IDS-iSYS 25-Hydroxy Vitamin Dˢ assay. Daily dietary intake was assessed using an FFQ. BMI was calculated using weight and height measurements.SettingTen municipalities of northern Norway (latitude 68°–70°N).ParticipantsMales (n 2041) and females (n 2424) aged 40–69 years.ResultsMean S-25(OH)D in the study sample was 64·0 nmol/l and median vitamin D intake was 10·3 µg/d. The prevalence of S-25(OH)DConclusionsThere were many modifiable risk factors related to S-25(OH)D, however no clear ethnic differences were found. Even in winter, the low prevalence of vitamin D deficiency found among participants with non-Sami, multi-ethnic Sami and Sami self-perceived ethnicity was likely due to adequate vitamin D intake.

Objective:We investigated the determinants of serum 25-hydroxyvitamin D [S-25(OH)D] and dietary vitamin D sources among three immigrant groups in Finland and compared their S-25(OH)D to the general Finnish population.Design:Cross-sectional population-based Migrant Health and Wellbeing Study and the nationally representative Finnish Health 2011 Survey. S-25(OH)D was standardised according to the Vitamin D Standardisation Program. Vitamin D sources were assessed by interview.Setting:Six different municipalities in Finland (60°–63°N).Participants:Immigrants aged 18–64 years (446 Russians, 346 Somalis, 500 Kurds), 798 Finns aged 30–64 years.Results:The mean of S-25(OH)D was 64 (95 % CI 62, 66), 44 (95 % CI 41, 46), 35 (95 % CI 34, 37) and 64 (95 % CI 62, 66) nmol/l for Russians, Somalis, Kurds and Finns, respectively. S-25(OH)D among Somalis and Kurds was lower compared with Finns (P < 0·001). The prevalence of vitamin D deficiency (S-25(OH)D P < 0·001). Vitamin D-rich foods differed between the groups; vitamin D-fortified fat spread consumption was higher among Somalis (91 %) than among Russians (73 %) and Kurds (60 %); fish was less consumed among Kurds (17 %) than among Russians (43 %) and Somalis (38 %); and 57 % Russians, 56 % Kurds and 36 % Somalis consumed vitamin D-fortified dairy daily (P < 0·001 for all). Daily smoking, alcohol consumption and winter blood sampling were determinants of vitamin D insufficiency (P ≤ 0·03). Older age, physical activity, fish and vitamin D-fortified dairy consumption were associated with lower odds of insufficiency (P ≤ 0·04).Conclusions:Vitamin D status differed among immigrant groups and the determinants are, to some degree, associated with learned or existing cultural behaviours.

BACKGROUND Plant-based diets may reduce the risk of chronic diseases, but can also lead to low calcium and vitamin D intakes, posing a risk for bone health. OBJECTIVES We investigated whether partial replacement of animal proteins with plant-based proteins using a whole-diet approach affects bone and mineral metabolism in healthy adults in 3 groups fed diets differing in protein composition. METHODS This 12-week clinical trial was comprised of 107 women and 29 men (20-69 years old; BMI mean ± SD, 24.8 ± 3.9) randomly assigned to consume 1 of 3 diets designed to provide 17 energy percent (E%) protein: "animal" (70% animal protein, 30% plant protein of total protein intake), "50/50" (50% animal, 50% plant), and "plant" (30% animal, 70% plant) diets. We examined differences in bone formation [serum intact procollagen type I amino-terminal propeptide (S-iPINP)], bone resorption [serum collagen type 1 cross-linked C-terminal telopeptide (S-CTX)], mineral metabolism markers (primary outcomes), and nutrient intakes (secondary outcomes) by ANOVA/ANCOVA. RESULTS S-CTX was significantly higher in the plant group (mean ± SEM, 0.44 ± 0.02 ng/mL) than in the other groups (P values

Aims: Nordic countries share fairly similar food culture and geographical location as well as common nutrition recommendations. The aim of this paper was to review the latest data on vitamin D status and intake and to describe the national supplementation and food fortification policies to achieve adequate vitamin D intake in the Nordic countries. Methods: The data are based on results derived from a literature search presented in a workshop held in Helsinki in November 2018 and completed by recent studies. Results: Vitamin D policies and the implementation of the recommendations differ among the Nordic countries. Vitamin D fortification policies can be mandatory or voluntary and widespread, moderate or non-existent. Vitamin D supplementation recommendations differ, ranging from all age groups being advised to take supplements to only infants. In the general adult population of the Nordic countries, vitamin D status and intake are better than in the risk groups that are not consuming vitamin D supplements or foods containing vitamin D. Non-Western immigrant populations in all Nordic countries share the problem of vitamin D insufficiency and deficiency. Conclusions: Despite the common nutrition recommendations, there are differences between the Nordic countries in the implementation of the recommendations and policies to achieve adequate vitamin D intake and status. There is a need for wider Nordic collaboration studies as well as strategies to improve vitamin D status, especially in risk groups.

In Finland the recommendation for the use of vitamin D supplement is a daily supplement throughout the year for all children. It is also recommended that fluid milk products and fat spreads are fortified with vitamin D. The purpose of this study was to provide up-to-date data on children's dietary and supplemental intake of vitamin D. We also examined educational level differences in the intake and sources of vitamin D.A cross-sectional study on the diet in Finnish 3–6-year-old preschool children (the DAGIS Study) was carried out in 2015–2016. Children were recruited in preschools in Southern Finland and in the Southern Ostrobothnia Region (n = 864). The parents reported child's supplement use (brand name, dose, frequency of use) during the last month and their own education level. The highest parental education level (PEL) was used in analysis. Parents and preschool personnel also filled in a 3-day food record for the child. A part of the families also kept an additional 2-day food record, which we sent to capture seasonal variation in the diet. In this analysis we included children (n = 794) with data for supplement use and at least 1-day food record. We calculated dietary intake based on the Fineli food composition database and created a dietary supplement database. We used Kruskal-Wallis test for statistical analysis.Most of the children in all PELs used vitamin D supplements (low 77%, medium 85%, high 85%). Dietary supplements covered almost half of the total intake in all groups (low 42%, medium 48%, high 47%, p = 0,087). The main dietary sources of vitamin D were fortified fluid milk products, fortified fat spreads and fish dishes. A higher proportion of vitamin D was obtained from fish dishes in families with higher PEL (low 4.3%, medium 4.5%, high 6.1%, p = 0.005), but otherwise there were no differences in the proportions of the main sources. The vitamin D intake from diet and supplements was lowest in families with low PEL but the total intake of vitamin D was adequate in all groups (low 18.3, medium 20.7, high 20.7 μg/day, p = 0.001).The use of vitamin D fortified fluid milk products and fat spreads and the vitamin D supplementation seem to ensure adequate vitamin D intake in all children, regardless the level of parental education.

Ultraviolet-irradiated yeast (Saccharomyces cerevisiae) can be used to biofortify bakery products with vitamin D, but in bread, it was not effective in increasing serum 25-hydroxyvitamin D [25(OH)D] in humans, possibly because of the low digestibility of the yeast matrix. We investigated the effects of vitamin D-2-rich intact yeast cells and their separated fraction, yeast cell walls, which we hypothesized to provide vitamin D-2 in a more bioavailable form, on serum 25(OH)D and its metabolites in growing female Sprague-Dawley rats (n = 54) compared to vitamin D-2 and D-3 supplements (8 treatment groups: 300 or 600 IU vitamin D/d, and a control group, 8-week intervention). The D-3 supplement groups had the highest 25(OH)D concentrations, and the vitamin D-2 supplement at the 600-IU dose increased 25(OH)D better than any yeast form (P .05). Serum 24,25-dihydroxyvitamin D (a vitamin D catabolite) concentrations and the trend in the differences between the groups were in line with 25 (OH)D (P .05). These findings do not support the hypothesis: the ability of the different ultraviolet-treated vitamin D-2-containing yeast forms to increase 25(OH)D did not differ, and the poor bioavailability of vitamin D-2 in the yeasts compared D-3 or D-2 supplements could not be explained by the increased vitamin D catabolism in the yeast-treated groups. (C) 2018 Elsevier Inc. All rights reserved.

Insufficient vitamin D status (serum 25-hydroxyvitamin D (S-25(OH)D)3 supplementation, through a 5-month randomised controlled trial, in East African and Finnish women in Southern Finland (60°N) from December 2014 to May 2015. Vitamin D intakes (dietary and supplemental) were also examined. Altogether, 191 subjects were screened and 147 women (East Africans n 72, Finns n 75) aged 21–64 years were randomised to receive placebo or 10 or 20 µg of vitamin D3/d. S-25(OH)D concentrations were assessed by liquid chromatography–tandem MS. At screening, 56 % of East Africans and 9 % of Finns had S-25(OH)Dsd 14·3) v. 15·2 (sd 13·4) µg/d, Psd=16·3) nmol/l) than in East Africans (51·5 (sd 15·4) nmol/l) (P=0·001). In repeated-measures ANCOVA (adjusted for baseline S-25(OH)D), mean S-25(OH)D increased by 8·5 and 10·0 nmol/l with a 10-µg dose and by 10·7 and 17·1 nmol/l with a 20-µg dose for Finns and East Africans, respectively (P>0·05 for differences between ethnic groups). In conclusion, high prevalence of vitamin D insufficiency existed among East African women living in Finland, despite higher vitamin D intake than their Finnish peers. Moderate vitamin D3 supplementation was effective in increasing S-25(OH)D in both groups of women, and no ethnic differences existed in the response to supplementation.

Aims: We evaluated the consumption of healthy foods among Russian, Somali and Kurdish immigrants in Finland, and examined the relationship between socio-demographic factors and food consumption. Methods: We used data from the Migrant Health and Wellbeing Study (Maamu), a population-based health interview and examination survey in six different municipalities in Finland between 2010 and 2012. Altogether, 635 men and 737 women, aged 18–64 years, of Russian ( n = 527), Somali ( n = 337) and Kurdish ( n = 508) origin were included. The important socio-demographic determinants of healthy food consumption – sex, age, education, place of residence and household size – were assessed by logistic regression. Results: Based on the consumption frequencies of recommended healthy foods – fruits, berries, vegetables, fish and rye bread – immigrants of Russian origin had higher consumption of healthy foods than their peers of Kurdish and Somali origin. Low consumption of fresh vegetables, fruits and berries was found among Somali immigrants. Sex and age were the most important determinants of healthy food consumption, as women and older age groups had diets closer to the national nutrition recommendations. High educational level was also positively associated with healthy food consumption. Conclusions: We found ethnic differences in the consumption of healthy foods among the immigrant groups of Russian, Somali and Kurdish origin in Finland. Socio-demographic factors, especially age, sex and education, seem to also play an important role in immigrants’ food consumption. Further studies examining the consumption of fruits, berries and fresh vegetables among Somali immigrants in Finland are needed.

Dear Editor, We read with interest the recently published paper by McClure et al. [1] that reports trends in intake and primary sources of dietary phosphorus in the NHANES data for the period 2001–2014.[...] Non

The human leukocyte antigen (HLA) gene region associates with the risk for several autoimmune diseases, including type 1 diabetes. An association between vitamin D deficiency and several autoimmune diseases has been suggested. We tested the association between serum 25-hydroxyvitamin D (25OHD) concentrations and HLA alleles in pregnant Finnish women.HLA-B (n=395), HLA-DRB1 (n=501) and HLA-DQB1 (n=475) alleles were genotyped in pregnant women (mothers of children who later developed type 1 diabetes and mothers of non-diabetic children). HLA-B alleles were divided into supertypes that share similar peptide-binding specificity. Serum 25OHD concentration had been previously measured in these women from sera collected during the first trimester of pregnancy. Multiple testing was controlled for using the false discovery rate method.An association was found between 25OHD concentration and HLA-B44 supertype (P=0.009); women with HLA-B44 supertype (B*18, B*37, B*40 and B*44 alleles) had lower 25OHD concentrations. No association was found between HLA-DRB1 or -DQB1 alleles and 25OHD concentration.In this study we found for the first time an association between HLA genetic polymorphisms and 25OHD concentration. In future studies, the mechanistic background of this association and the role of vitamin D in the regulation of HLA gene expression should be investigated.

Increased vitamin D fortification of dairy products has increased the supply of vitamin D-containing products with different vitamin D contents on the market in Finland. The authors developed a ninety-eight-item FFQ with eight food groups and with a question on supplementation to assess dietary and supplemental vitamin D and Ca intakes in Finnish women (60ºN). The FFQ was validated in subgroups with different habitual vitamin D supplement use (0–57·5 µg/d) against the biomarker serum 25-hydroxyvitamin D (S-25(OH)D) and against 3-d food records (FR) (n29–67). Median total vitamin D intake among participants was 9·4 (range 1·6–30·5) µg/d. Spearman’s correlations for vitamin D and Ca ranged from 0·28 (P0·146, FFQv. S-25(OH)D, persons not using supplements) to 0·75 (Pv. FR, supplement use included). The correlations between the FFQ and S-25(OH)D concentrations improved within increasing supplement intake. The Bland–Altman analysis showed wide limits of agreement between FFQ and FR: for vitamin D between −7·8 and 8·8 µg/d and for Ca between −938 and 934 mg/d, with mean differences being 0·5 µg/d and 2 mg/d, respectively. The triads method was used to calculate the validity coefficients of the FFQ for vitamin D, resulting in a mean of 1·00 (95 % CI 0·59, 1·00) and a range from 0·33 to 1·00. The perceived variation in the estimates could have been avoided with a longer FR period and larger number of participants. The results are comparable with earlier studies, and the FFQ provides a reasonable estimation of vitamin D and Ca intakes.

The Department of Nutrition for Health and Development of the World Health Organization (WHO) in collaboration with the Executive Committee of the 18th Vitamin D Workshop (VDW), organised a joint symposium on the prevention and consequences of vitamin D deficiency in pregnant women and children, convening experts on vitamin D, clinicians and policy-makers. The overall aim was to identify priority areas for research and to discuss the need for global options for policy, with a focus on the prevention of rickets in infants and children and vitamin D deficiency in pregnant women. The scope and purpose were: (i) to present the WHO research strategy for health, addressing vitamin D-related public health problems and the process for the development of evidence-informed guidelines in general and how vitamin D interventions in diverse populations could be prioritised; (ii) to provide an overview of vitamin D status in children and pregnant and lactating women across the world; (iii) to review the health risks associated with vitamin D deficiency in children and in pregnant women and their offspring; (iv) to understand the aetiology of vitamin D deficiency in pregnant women and children; (v) to identify and interpret biomarkers to assess vitamin D status and to consider possible clinical and biochemical screening tools for determining the prevalence of nutritional rickets in at risk groups or communities; and (vi) to provide an overview of policies and recommendations on vitamin D across the world. The format of the symposium was a composite of comprehensive scientific presentations and a panel debate with international experts on WHO guidelines, nutritional rickets, nutritional policy and consequences of vitamin D deficiency during pregnancy. This paper summarizes the content and outcomes of the panel debate. (C) 2015 Elsevier Ltd. All rights reserved.

Current vitamin D recommendations have been established based on an assumption that there are no differences between Caucasian and other ethnic/racial groups in terms of vitamin D requirements. This assumption, largely made due to the absence of data, is a key knowledge gap identified by a number of authorities. To test whether the distribution of dietary requirements for maintaining winter serum 25-hydroxyvitamin D [25(OH)D] concentrations ≥ 30 nmol/L (a priority threshold linked to vitamin D deficiency prevention) differ between Caucasian and Somali women living at northerly latitude. We used data from a 5-month, winter-based, vitamin D3 dose-related randomized, placebo-controlled trial in Somali (n 47) and Causcian women (n 69), aged 21–64-year old, living in Southern Finland (60°N), to model the vitamin D intake–serum 25(OH)D dose–response relationship. Regression analyses were used to predict the vitamin D intake required to maintain 97.5% (as well as 50, 90, and 95%) of women in both ethnic groups above serum 25(OH)D thresholds of 30, 40 and 50 nmol/L. Using a model which adjusted for baseline 25(OH)D, age, and BMI, the estimated vitamin D intake that maintained serum 25(OH)D ≥ 30 nmol/L in 97.5% of Caucasian and Somali women was 8 and 18 µg/day, respectively. Ethnic differences were also evident at 40 and 50 nmol/L serum 25(OH)D thresholds. The present study adds further evidence that ethnic differences in the dietary requirement for vitamin D do exist and that dose–response vitamin D intervention studies are required in at-risk target populations specified by ethnicity.

Three hundred eighty-seven home-dwelling older women were divided into quartiles based on mean serum 25-hydroxyvitamin D (S-25(OH)D) levels. The rates of falls and fallers were about 40% lower in the highest S-25(OH)D quartile compared to the lowest despite no differences in physical functioning, suggesting that S-25(OH)D levels may modulate individual fall risk. Vitamin D supplementation of 800 IU did not reduce falls in our previous 2-year vitamin D and exercise RCT in 70–80 year old women. Given large individual variation in individual responses, we assessed here effects of S-25(OH)D levels on fall incidence. Irrespective of original group allocation, data from 387 women were explored in quartiles by mean S-25(OH)D levels over 6–24 months; means (SD) were 59.3 (7.2), 74.5 (3.3), 85.7 (3.5), and 105.3 (10.9) nmol/L. Falls were recorded monthly with diaries. Physical functioning and bone density were assessed annually. Negative binomial regression was used to assess incidence rate ratios (IRRs) for falls and Cox-regression to assess hazard ratios (HR) for fallers. Generalized linear models were used to test between-quartile differences in physical functioning and bone density with the lowest quartile as reference. There were 37% fewer falls in the highest quartile, while the two middle quartiles did not differ from reference. The respective IRRs (95% CI) for falls were 0.63 (0.44 to 0.90), 0.78 (0.55 to 1.10), and 0.87 (0.62 to 1.22), indicating lower falls incidence with increasing mean S-25(OH)D levels. There were 42% fewer fallers (HR 0.58; 040 to 0.83) in the highest quartile compared to reference. Physical functioning did not differ between quartiles. Falls and faller rates were about 40% lower in the highest S-25(OH)D quartile despite similar physical functioning in all quartiles. Prevalent S-25(OH)D levels may influence individual fall risk. Individual responses to vitamin D treatment should be considered in falls prevention.

IntroductionOur previous study-level (aggregate data) meta-analysis suggested that vitamin D supplements may be beneficial for bone density specifically in children with vitamin D deficiency. However, the misclassification of vitamin D status inherent in study-level data means that the results are not definitive and cannot provide an accurate assessment of the size of any effect. Therefore, we propose to undertake an individual patient data (IPD) meta-analysis to determine whether the effect of vitamin D supplementation on bone density in children differs according to baseline vitamin D status, and to specifically estimate the effect of vitamin D in children who are vitamin D deficient.Methods and analysisThis study has been designed to adhere to the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement. We will include randomised placebo-controlled trials of vitamin D supplementation reporting bone density outcomes at least 6 months after the study commenced in children and adolescents (aged 2and potential publication bias (small-study effects) and availability bias by funnel plots, Egger’s test and Peter’s test.Ethics and disseminationEthics approval will not be required as the data are to be used for the primary purpose for which they were collected and all original individual studies had ethics approval. Results of the IPD meta-analysis will be submitted for publication in a peer-reviewed journal.PROSPERO registration numberCRD42017068772.

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to revise the tolerable upper intake level (UL) for vitamin D for infants (≤ 1 year) set in 2012. From its literature review, the Panel concluded that the available evidence on daily vitamin D intake and the risk of adverse health outcomes (hypercalciuria, hypercalcaemia, nephrocalcinosis and abnormal growth patterns) cannot be used alone for deriving the UL for infants. The Panel conducted a meta‐regression analysis of collected data, to derive a dose–response relationship between daily supplemental intake of vitamin D and mean achieved serum 25(OH)D concentrations. Considering that a serum 25(OH)D concentration of 200 nmol/L or below is unlikely to pose a risk of adverse health outcomes in infants, the Panel estimated the percentage of infants reaching a concentration above this value at different intakes of vitamin D. Based on the overall evidence, the Panel kept the UL of 25 μg/day for infants aged up to 6 months and set a UL of 35 μg/day for infants 6–12 months. The Panel was also asked to advise on the safety of the consumption of infant formulae with an increased maximum vitamin D content of 3 μg/100 kcal (Commission Delegated Regulation (EU) 2016/127 repealing Directive 2006/141/EC in 2020). For infants aged up to 4 months, the intake assessment showed that the use of infant formulae containing vitamin D at 3 μg/100 kcal may lead some infants to receive an intake above the UL of 25 μg/day from formulae alone without considering vitamin D supplemental intake. For infants aged 4–12 months, the 95th percentile of vitamin D intake (high consumers) estimated from formulae and foods fortified or not with vitamin D does not exceed the ULs, without considering vitamin D supplemental intake., This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2018.EN-1456/full

BACKGROUND: Vitamin D binding protein (DBP) binds vitamin D and its plasma metabolites, including 25-hydroxyvitamin D (25(OH)D), in the circulation. Only a small fraction circulates free (free 25(OH)D). Genetic variation of the GC gene, encoding DBP, has been associated with 25(OH)D concentrations. The roles of DBP and free 25(OH)D concentrations in the biological actions of vitamin D remain unclear. METHODS: We assessed the relationship between GC gene variants rs4588, rs7041, and rs705124, and serum total 25(OH)D, free and bioavailable 25(OH)D, and serum DBP and parathyroid hormone (PTH) concentrations in 622 Caucasian females (421) and males (201) aged 37–47 years. Concentrations of 25(OH)D, DBP, and PTH were measured from fasting blood samples. Dietary intakes of vitamin D and Ca were evaluated using 1-month food use frequency data, which were collected by a validated Food Frequency Questionnaire on vitamin D and calcium intakes. The subjects filled in the questionnaire covering overall health, medications, use of vitamin D and calcium supplements, and holidays in sunny locations. Three SNPs in the GC gene were genotyped: rs4588, rs7041, and rs705124. The SNPs rs4588 and rs7041 combine to form six common diplotypes. Free and bioavailable 25(OH)D were calculated by using specific binding coefficients. Differences among the diplo- and haplotypes of the GC gene in measures of 25(OH)D, DBP, and PTH were tested by analysis of covariance (ANCOVA) using appropriate covariates. RESULTS: We found significant variation among the SNPs rs4588 and rs7041 variants in DBP, total, free, and bioavailable 25(OH)D, and PTH. DBP concentration was lowest in genotype GC2/2 in both diplotypes and haplotypes (p = 0.039 and 0.039, respectively). The lowest 25(OH)D concentrations were found in diplotype variants GC1S/2, GC1S/F,and GC2/2 (p = 0.033), but free and bioavailable 25(OH)D concentrations were highest in the GC2/2 variant after corrected with a genotype-specific binding coefficient (p

Background Studies have shown altered vitamin D metabolism in obesity. We assessed differences between obese and normal-weight subjects in total, free, and bioavailable 25-hydroxyvitamin D (25(OH)D, 25(OH)DFree, and 25(OH)DBio, respectively), vitamin D binding protein (DBP), parathyroid hormone (PTH) and bone traits. Methods 595 37-47-year-old healthy Finnish men and women stratified by BMI were examined in this cross-sectional study. Background characteristic and intakes of vitamin D and calcium were collected. The concentrations of 25(OH)D, PTH, DBP, albumin and bone turnover markers were determined from blood. 25(OH)DFree and 25(OH)DBio were calculated. pQCT was performed at radius and tibia. Results Mean±SE (ANCOVA) 25(OH)DFree (10.8±0.6 vs 12.9±0.4 nmol/L; P = 0.008) and 25(OH)DBio (4.1±0.3 vs 5.1±0.1 nmol/L; P = 0.003) were lower in obese than in normal-weight women. In men, 25(OH)D (48.0±2.4 vs 56.4±2.0 nmol/L, P = 0.003), 25(OH)DFree (10.3±0.7 vs 12.5±0.6 pmol/L; P = 0.044) and 25(OH)DBio (4.2±0.3 vs 5.1±0.2 nmol/L; P = 0.032) were lower in obese. Similarly in all subjects, 25(OH)D, 25(OH)DFree and 25(OH)DBio were lower in obese (P

Objective The in utero environment plays an important role in shaping development and later life health of the fetus. It has been shown that maternal genetic factors in the metabolic pathway of vitamin D associate with type 1 diabetes in the child. In this study we analyzed the genetic determinants of serum 25-hydroxyvitamin D (25OHD) concentration during pregnancy in mothers whose children later developed type 1 diabetes and in control mothers. Study design 474 mothers of type 1 diabetic children and 348 mothers of non-diabetic children were included in the study. We previously selected 7 single nucleotide polymorphisms (SNPs) in four genes in the metabolic pathway of vitamin D vitamin based on our previously published data demonstrating an association between genotype and serum 25OHD concentration. In this re-analysis, possible differences in strength in the association between the SNPs and serum 25OHD concentration in mothers of type 1 diabetic and non-diabetic children were investigated. Serum 25OHD concentrations were previously shown to be similar between the mothers of type 1 diabetic and non-diabetic children and vitamin D deficiency prevalent in both groups. Results Associations between serum 25OHD concentration and 2 SNPs, one in the vitamin D receptor (VDR) gene (rs4516035) and one in the group-specific component (GC) gene (rs12512631), were stronger during pregnancy in mothers whose children later developed type 1 diabetes than in mothers whose children did not (p(interaction) = 0.03, 0.02, respectively). Conclusions We show for the first time that there are differences in the strength of genetic determinants of serum 25OHD concentration during pregnancy between the mothers of type 1 diabetic and non-diabetic children. Our results emphasize that the in utero environment including maternal vitamin D metabolism should be important lines of investigation when searching for factors that lead to early programming of type 1 diabetes.

Background: Both exercise and vitamin D are recommended means to prevent falls among older adults, but their combined effects on fallinduced injuries are scarcely studied. Methods: A 2-year follow-up of a previous 2-year randomized controlled trial with vitamin D and exercise (Ex) of 409 older home-dwelling women using a factorial 2 x 2 design (D(-)Ex(-), D(+)Ex(-), D(-)Ex(+), D(+)Ex(+)). Besides monthly fall diaries, femoral neck bone mineral density (fn-BMD), and physical functioning were assessed at 1 and 2 years after the intervention. Results: After the intervention, S-25OHD concentrations declined to baseline levels in both supplement groups. The groups did not differ for change in fn-BMD or physical functioning, except for leg extensor muscle strength, which remained about 10% greater in the exercise groups compared with the reference group (D(-)Ex(-)). There were no between-group differences in the rate of all falls, but medically attended injurious falls reduced in D+ Ex-and D(-)Ex(+) groups compared with D(-)Ex(-). However, all former treatment groups had less medically attended injured fallers, HRs (95% CI) being 0.62 (0.39-1.00) for D+ Ex-, 0.46 (0.28-0.76) for D(-)Ex(+), and 0.55 (0.34-0.88) for D(+)Ex(+), compared with D(-)Ex(-). Conclusions: Exercise-induced benefits in physical functioning partly remained 2 years after cessation of supervised training. Although there was no difference in the rate of all falls, former exercise groups continued to have lower rate of medically attended injured fallers compared with referents even 2 years after the intervention. Vitamin D without exercise was associated with less injurious falls with no difference in physical functioning.

Measurement of serum 25-hydroxyvitamin D [25(OH)D] is considered the best indicator of vitamin D status. Two minor vitamin D metabolites are common interferences encountered in 25(OH)D assays. The first is 3-epi-25-hydroxyvitamin D3 [3-epi-25(OH)D3], which if not chromatographically resolved from 25-hydroxyvitamin D3 [25(OH)D3], can overestimate 25(OH)D concentrations. The second is 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], which can cross-react with the antibodies in 25(OH)D immunoassays. Our aim was to develop an LCâ MS/MS method capable of detecting both 3-epi-25(OH)D3 and 24R,25(OH)2D3 in serum without the use of a derivatization agent. We report an isotope dilution LCâ MS/MS method, with electrospray ionization in the positive mode, that can simultaneously detect 24R,25(OH)2D3, 25(OH)D3, 3-epi-25(OH)D3, and 25-hydroxyvitamin D2. The method employs a cost-effective liquidâ liquid extraction using only 150 μL of sera and a total run time of 10 min. Method performance was assessed by using quality controls made from pooled sera as an alternative to sera spiked with analytes. Biobanked samples, originally analyzed by chemiluminescent microparticle immunoassay (CMIA), were re-analyzed with this method to determine the contribution of 24R,25(OH)2D3 cross-reactivity to 25(OH)D measurement bias. The CMIA over-estimation of 25(OH)D measurements relative to LCâ MS/MS was found to depend on both 25(OH)D and 24R,25(OH)2D3 concentrations.

Calcium and phosphorus metabolism are interconnected with effects on parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25 (OH)2D), serum, and urinary concentrations of both calcium and phosphorus including intestinal absorption, urinary excretion, and skeletal actions. Many studies have shown that an increased phosphorus (P) intake may have negative effects on the skeleton, whereas calcium (Ca) intake may have a protective effect on it. As there may be an optimal balance between the nutrients in relation to bone health, interest has been focused on the dietary Ca:P ratio. Both animal and human research data indicate that a low Ca:P ratio has a negative impact on the skeleton, but there is also suggestive evidence that if P intake is high, a high Ca intake does not completely counteract the adverse effect of a high P intake, especially if it derives from food additives.

Background: A systematic vitamin D fortification of fluid milk products and fat spreads was started in 2003 in Finland to improve vitamin D status. Objective: We investigated the effects of the vitamin D fortification policy on vitamin D status in Finland between 2000 and 2011.Design: Serum 25-hydroxyvitamin D [S-25(OH)D] concentrations of a nationally representative sample comprising 6134 and 4051 adults aged ≥30 y from the Health 2000 and Health 2011 surveys, respectively, were standardized according to the Vitamin D Standardization Program with the use of liquid chromatography-tandem mass spectrometry. Linear and logistic regression models were used to assess the change in S-25(OH)D concentrations.Results: Between 2000 and 2011, the mean S-25(OH)D increased from 48 nmol/L (95% CI: 47, 48 nmol/L) to 65 nmol/L (95% CI: 65, 66 nmol/L) (P 50 nmol/L in 2011.Conclusions: The vitamin D status of the Finnish adult population has improved considerably during the time period studied. The increase is mainly explained by food fortification, especially of fluid milk products, and augmented vitamin D supplement use. Other factors, such as the difference in the ultraviolet radiation index between 2000 and 2011, may partly explain the results. When consuming vitamin D sources based on the nutritional recommendations, vitamin D status is sufficient [S-25(OH)D ≥50 nmol/L], and supplementation is generally not needed.

Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derived dietary reference values (DRVs) for thiamin (vitamin B1). The Panel considers that data from depletion–repletion studies in adults on the amount of dietary thiamin intake associated with the erythrocyte transketolase activity coefficient (αETK)

There is a need for food-based solutions for preventing vitamin D deficiency. Vitamin D3(D3) is mainly used in fortified food products, although the production of vitamin D2(D2) is more cost-effective, and thus may hold opportunities. We investigated the bioavailability of D2from UV-irradiated yeast present in bread in an 8-week randomised-controlled trial in healthy 20–37-year-old women (n33) in Helsinki (60°N) during winter (February–April) 2014. Four study groups were given different study products (placebo pill and regular bread=0 µg D2or D3/d; D2supplement and regular bread=25 µg D2/d; D3supplement and regular bread=25 µg D3/d; and placebo pill and D2-biofortified bread=25 µg D2/d). Serum 25-hydroxyvitamin D2(S-25(OH)D2) and serum 25-hydroxyvitamin D3(S-25(OH)D3) concentrations were measured at baseline, midpoint and end point. The mean baseline total serum 25-hydroxyvitamin D (S-25(OH)D=S-25(OH)D2+S-25(OH)D3) concentration was 65·1 nmol/l. In repeated-measures ANCOVA (adjusted for baseline S-25(OH)D as total/D2/D3), D2-bread did not affect total S-25(OH)D (P=0·707) or S-25(OH)D3(P=0·490), but increased S-25(OH)D2compared with placebo (P2supplement was more effective than bread in increasing S-25(OH)D2(P2and D3supplementation increased total S-25(OH)D compared with placebo (P=0·030 andP=0·001, respectively), but D2supplementation resulted in lower S-25(OH)D3(P2from UV-irradiated yeast in bread was not bioavailable in humans. Our results support the evidence that D2is less potent in increasing total S-25(OH)D concentrations than D3, also indicating a decrease in the percentage contribution of S-25(OH)D3to the total vitamin D pool.

Targeted exercise training and sufficient vitamin D intake may significantly improve muscle performance and balance and thus reduce the risk of falling among older people.

Context: Guidelines in Finland recommend 10 μg of vitamin D3 daily for all infants. Recent observations suggest that this may be insufficient to maintain optimal serum 25-hydroxyvitamin D (S-25-OHD). Objective: The aim of the study was to evaluate effects of various vitamin D doses and determine a dose ensuring S-25-OHD of at least 80 nmol/liter in infants without signs of vitamin D excess. Design: We conducted a randomized double-blind intervention study. Cord blood was obtained at birth for S-25-OHD; 113 infants were randomized to receive vitamin D3 10, 30, or 40 μg/d from age 2 wk to 3 months. Setting: An investigator-initiated study was performed in a single maternity hospital in Helsinki, Finland. Main Outcome Measures: S-25-OHD, calcium homeostasis, and skeletal characteristics were evaluated with peripheral quantitative computed tomography at age 3 months. Results: Baseline S-25-OHD was similar in all three groups (median, 53 nmol/liter). At 3 months, the mean S-25-OHD values were 88, 124, and 153 nmol/liter, and the minimum values were 46, 57, and 86 nmol/liter in the groups receiving 10, 30, and 40 μg (ANOVA; P < 0.001). No hypercalcemia occurred; plasma calcium, serum PTH, and urine calcium excretion was similar between the groups. Peripheral quantitative computed tomography showed a trend toward larger tibial total bone and cortical bone area with higher vitamin D doses. Conclusion: Vitamin D3 supplementation with up to 40 μg/d from age 2 wk to 3 months was safe and caused no hypercalcemia or hypercalciuria. The 40-μg dose maintained S-25-OHD above 80 nmol/liter in all infants. More extensive and longer intervention studies are necessary to assess long-term effects.

Objective Among plant foods, grain products, legumes, and seeds are important sources of phosphorus (P). Current data on P content and absorbability of P from these foods are lacking. Measurement of in vitro digestible P (DP) content of foods may reflect absorbability of P. The objective of this study was to measure both total phosphorus (TP) and DP contents of selected foods and to compare the amounts of TP and DP and the proportion of DP to TP among different foods. Methods TP and DP content of 21 foods and drinks of plant origin were measured by inductively coupled plasma optical emission spectrometry. In DP analysis, samples were digested enzymatically in principle in the same way as in the alimentary canal before P analyses. The most popular national brands were chosen for analysis. Results The highest amount of TP (667 mg/100 g) was found in sesame seeds with hull, which also had the lowest percentage of DP (6%) to TP. Instead, in cola drinks and beer, the percentage of DP to TP was 87 to 100% (13 to 22 mg/100 g). In cereal products, the highest TP content (216 mg/100 g) and DP proportion (100%) were present in industrial muffins, which contain sodium phosphate as a leavening agent. Legumes contained an average DP content of 83 mg/100 g (38% of TP). Conclusion Absorbability of P may differ substantially among different plant foods. Despite high TP content, legumes may be a relatively poor P source. In foods containing phosphate additives, the proportion of DP is high, which supports previous conclusions of the effective absorbability of P from P additives.

Objective Meat and milk products are important sources of dietary phosphorus (P) and protein. The use of P additives is common both in processed cheese and meat products. Measurement of in vitro digestible phosphorus (DP) content of foods may reflect absorbability of P. The objective of this study was to measure both total phosphorus (TP) and DP contents of selected meat and milk products and to compare amounts of TP and DP and the proportion of DP to TP among different foods. Methods TP and DP contents of 21 meat and milk products were measured by inductively coupled plasma optical emission spectrometry (ICP-OES). In DP analysis, samples were digested enzymatically, in principle, in the same way as in the alimentary canal before the analyses. The most popular national brands of meat and milk products were chosen for analysis. Results The highest TP and DP contents were found in processed and hard cheeses; the lowest, in milk and cottage cheese. TP and DP contents in sausages and cold cuts were lower than those in cheeses. Chicken, pork, beef, and rainbow trout contained similar amounts of TP, but slightly more variation was found in their DP contents. Conclusions Foods containing P additives have a high content of DP. Our study confirms that cottage cheese and unenhanced meats are better choices than processed or hard cheeses, sausages, and cold cuts for chronic kidney disease patients, based on their lower P-to-protein ratios and sodium contents. The results support previous findings of better P absorbability in foods of animal origin than in, for example, legumes.

The bioavailability of phosphorus (P) in foodstuffs is mostly unknown. The aim of this study was to test a method for in vitro digestible phosphorus (DP) analysis and analyse the DP content in variously processed cereal products by an in vitro method combined with inductively coupled plasma–mass spectrometry (ICP–MS). For DP analysis the samples were treated as chyme by adding alpha-amylase and proteases. The samples were dialysed, using equilibrium dialysis, and the DP was analysed by ICP–MS. The amount of total phosphorus (TP) was also analysed by ICP–MS. In soured wheat and rye breads, the proportion of DP/TP was higher (DP/TP: rye 83%, wheat 78%) than in flours (DP/TP: rye 45%; wheat 43%) or non-soured breads (DP/TP: wheat 46%). This indicates that, during processing, phytic acid degrades and releases soluble inorganic P, which increases the DP content. The DP content in the cereals was significantly lower than the TP content, which indicates that not all dietary P may be absorbed in the human body.

Fluid milk products are systematically, either mandatorily or voluntarily, fortified with vitamin D in some countries but their overall contribution to vitamin D intake and status worldwide is not fully understood. We searched the PubMed database to evaluate the contribution of vitamin D-fortified fluid milk products (regular milk and fermented products) to vitamin D intake and serum or plasma 25-hydroxyvitamin D (25(OH)D) status in observational studies during 1993–2017. Twenty studies provided data on 25(OH)D status (n = 19,744), and 22 provided data on vitamin D intake (n = 99,023). Studies showed positive associations between the consumption of vitamin D-fortified milk and 25(OH)D status in different population groups. In countries with a national vitamin D fortification policy covering various fluid milk products (Finland, Canada, United States), milk products contributed 28–63% to vitamin D intake, while in countries without a fortification policy, or when the fortification covered only some dairy products (Sweden, Norway), the contribution was much lower or negligible. To conclude, based on the reviewed observational studies, vitamin D-fortified fluid milk products contribute to vitamin D intake and 25(OH)D status. However, their impact on vitamin D intake at the population level depends on whether vitamin D fortification is systematic and policy-based.

Due to little outdoor activity and low dietary intake of vitamin D (VD), Bangladeshi low-income women are at risk for osteoporosis at an early age. The present study assessed the effect of VD, Ca and multiple micronutrient supplementation on VD and bone status in Bangladeshi young female garment factory workers. This placebo-controlled 1-year intervention randomly assigned 200 apparently healthy subjects (aged 16–36 years) to four groups: VD group, daily 10 μg VD; VD and Ca (VD-Ca) group, daily 10 μg VD+600 mg Ca; multiple micronutrient and Ca (MMN-Ca) group, 10 μg VD and other micronutrients+600 mg Ca; a placebo group. Serum 25-hydroxyvitamin D (S-25OHD), intact parathyroid hormone (S-iPTH), Ca, phosphate and alkaline phosphatase were measured. Bone mineral density and bone mineral content were measured by dual-energy X-ray absorptiometry. All measurements were made at baseline and at 12 months. Significantly (P P

Summary Background Vitamin D insufficiency is common in winter in the Nordic countries. Objectives To examine whether a short course of narrowband ultraviolet B (NB-UVB) improves vitamin D balance. Methods Fifty-six healthy, white women (mean age 41 years) volunteered and 53 completed the study. NB-UVB exposures were given on seven consecutive days either on the whole body (n = 19), on the head and arms (n = 9) or on the abdomen (n = 14). Similarly, seven solar simulator exposures were given on the face and arms (n = 11). The cumulative UVB dose was 13 standard erythema doses in all regimens. Serum calcidiol (25-hydroxyvitamin D) concentration was measured by radioimmunoassay before and after the NB-UVB exposures. Follow-up samples were taken from the whole-body NB-UVB group at 2 months. Results At onset 41 women (77%) had vitamin D insufficiency (calcidiol

Vitamin D and calcium insufficiencies are risk factors for multiple chronic diseases. Data from 46 recent studies from Europe, North America, South-East Asia and the South Pacific area clearly indicate that a low vitamin D status and inadequate calcium nutrition are highly prevalent in the general population (30–80%), affecting both genders. The extent of insufficiencies is particularly high in older populations, and in some geographical areas, also in children and in young women of child-bearing age, in ethnic minorities and immigrants, as well as in people of low socio-economic status. Enrichment of cereal grain products with vitamin D and calcium would be a viable approach to increase consumption and improve health outcomes in the general population worldwide.

ObjectiveFoods can contain natural phosphorus (NP) and phosphate-containing food additives (AP). The main objective of the present study was to investigate whether NP and AP of habitual diets differ in their effects on markers of Ca metabolism. We also investigated the impact of total habitual dietary P intake on markers of Ca metabolism.DesignCross-sectional study. Fasting blood samples were collected and participants kept a 4 d food record, from which dietary intake of total P and the consumption of NP (milk and cheese, excluding processed cheese) and AP (processed cheese) sources were calculated. Participants were divided into groups according to their NP- and AP-containing food consumption and into quartiles according to their total P intake.SettingSouthern Finland.SubjectsOne hundred and forty-seven healthy premenopausal women aged 31–43 years.ResultsRelative to the lowest total dietary P quartile, mean serum parathyroid hormone (S-PTH) concentration was higher (P = 0·048, analysis of covariance (ANCOVA)) and the mean serum ionized Ca concentration lower (P = 0·016, ANCOVA) in the highest P intake quartile. Mean S-PTH concentrations were higher among participants who consumed processed cheese (P = 0·027, ANCOVA) and less milk and other cheese than processed cheese (P = 0·030, ANCOVA).ConclusionsHigh total habitual dietary P intake affected S-PTH unfavourably. Furthermore, phosphate additives may have more harmful effects on bone than other P sources, as indicated by higher mean S-PTH concentration among participants who consumed AP-containing foods. Because of the high dietary P intake and current upward trend in consumption of processed foods in Western countries, these findings may have important public health implications.

Both K and Ca supplementation may have beneficial effects on bone through separate mechanisms. K in the form of citrate or bicarbonate affects bone by neutralising the acid load caused by a high protein intake or a low intake of alkalising foods, i.e. fruits and vegetables. Ca is known to decrease serum parathyroid hormone (S-PTH) concentration and bone resorption. We compared the effects of calcium carbonate, calcium citrate and potassium citrate on markers of Ca and bone metabolism in young women. Twelve healthy women aged 22–30 years were randomised into four controlled 24 h study sessions, each subject serving as her own control. At the beginning of each session, subjects received a single dose of calcium carbonate, calcium citrate, potassium citrate or a placebo in randomised order. The diet during each session was identical, containing 300 mg Ca. Both the calcium carbonate and calcium citrate supplement contained 1000 mg Ca; the potassium citrate supplement contained 2250 mg K. Markers of Ca and bone metabolism were followed. Potassium citrate decreased the bone resorption marker (N-terminal telopeptide of type I collagen) and increased Ca retention relative to the control session. Both Ca supplements decreased S-PTH concentration. Ca supplements also decreased bone resorption relative to the control session, but this was significant only for calcium carbonate. No differences in bone formation marker (bone-specific alkaline phosphatase) were seen among the study sessions. The results suggest that potassium citrate has a positive effect on the resorption marker despite low Ca intake. Both Ca supplements were absorbed well and decreased S-PTH efficiently.

Parathyroid hormone-related protein (PTHrP) has been shown to have anabolic effects in women with postmenopausal osteoporosis. PTHrP promotes the recruitment of osteogenic cells and prevents apoptotic death of osteoblasts and osteocytes. The receptor responsible for the effects of PTHrP is the common PTH/PTHrP receptor (PTH1R). Glucocorticoids (GC) are commonly used as drugs to treat inflammatory diseases. Long-term GC treatments are often associated with bone loss which can lead to GC-induced osteoporosis. The aim of this work was to study the effects of the glucocorticoid dexamethasone (Dex) on the expression of PTHrP and PTH1R in adult human mesenchymal stem cells, the progenitor cells of osteoblasts. Adult human mesenchymal stem cells (hMSC) were cultured and differentiated by standard methods. The expression of PTHrP and PTH1R mRNA was assayed by real-time qPCR. The PTHrP release into the culture media was measured by an immunoradiometric assay. Treatment with Dex (10 nM) resulted in an 80% drop in the PTHrP release within 6 h. A 24 h Dex treatment also reduced the expression of PTHrP mRNA by up to 90%. The expression of PTH1R receptor mRNA was simultaneously increased up to 20-fold by 10 nM Dex. The effects of Dex on PTHrP and PTH1R were dose-dependent and experiments with the GC-receptor antagonist mifepristone showed an involvement of GC-receptors in these effects. In addition to the Dex-induced effects on PTHrP and PTH1R, Dex also increased mineralization and the expression of the osteoblast markers Runx2 and alkaline phosphatase. In our studies, we show that dexamethasone decreases the expression of PTHrP and increases the expression of the PTH1R receptor. This could have an impact on PTHrP-mediated anabolic actions on bone and could also affect the responsiveness of circulating PTH. The results indicate that glucocorticoids affect the signalling pathway of PTHrP by regulating both PTHrP and PTH1R expression and these mechanisms could be involved in glucocorticoid-induced osteoporosis.

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.

Background: Thus far the search for osteoporosis candidate genes has focused less attention on the regulation of calcium homeostasis. Associations of vitamin D receptor (VDR) FokI, calcium-sensing receptor (CaSR) A986S and parathyroid hormone (PTH) BstBI polymorphisms with calcium homeostasis and peripheral bone density were investigated in adult Finns. Methods: The subgroup of the population-based FINRISK survey consists of 339 healthy adults aged 31–43 years. Lifestyle data were assessed with questionnaires and food diaries. DNA was isolated from blood, and biochemical determinants of calcium metabolism were measured from blood and 24-hour urine samples. Bone mineral density (BMD) was measured using the DXA method at the distal forearm and by quantitative ultrasound (broadband ultrasound attenuation and speed of sound) at the calcaneus. Subjects were genotyped for VDR FokI, CaSR A986S and PTH BstBI polymorphisms. Results: The CaSR 986S allele was associated with higher serum ionized calcium (p = 0.014). Forearm BMD was lowest for the PTH BstBI genotype bb in males (p = 0.023). VDR FokI and PTH BstBI polymorphisms showed a significant interaction on serum PTH (p = 0.010). The other gene–gene or diet–gene interactions studied showed no significant results. Conclusions: VDR, CaSR and PTH contribute to the genetic regulation of calcium homeostasis and peripheral bone density.

The second messenger molecule cyclic adenosine monophosphate (cAMP) plays an important role in the hormonal regulation of bone metabolism. cAMP is inactivated by the cyclic nucleotide phosphodiesterases (PDEs), a superfamily of enzymes divided into 11 known families designated PDE 1–11. The aim of this study was to investigate the effect of PDE7 and PDE8 inhibition on the gene expression and differentiation of human osteoblasts. Osteoblasts differentiated from human mesenchymal stem cells (hMSC) were cultured and treated with short interfering RNAs (siRNAs) generated from PDE7 and PDE8 PCR products. Total RNA was isolated from the cells, and gene expression was assayed with cDNA microarray and quantitative real-time PCR. bALP measurements were assayed during differentiation, and mineralization was determined by quantitative Alizarin red S staining. PDE7 and PDE8 inhibition by RNA interference decreased the gene expression of PDE7A by 60–70%, PDE7B by 40–50%, and PDE8A by 30%. PDE7 silencing increased the expression of β-catenin, osteocalcin, caspase-8, and cAMP-responsive element-binding protein 5 (CREB-5) genes and decreased the expression of the 1, 25-dihydroxyvitamin D3 receptor gene. PDE8A silencing increased the expression of anti-apoptotic genes, but decreased the expression of osteoglycin (osteoinductive factor) and bone morphogenetic protein 1 (BMP-1). PDE7 silencing increased bALP and mineralization up to three-fold compared to controls. Treatment with the PDE7-selective PDE inhibitor BRL-50481 had similar effects on mineralization as the gene silencing. The PDE7 silencing also increased forskolin stimulated cAMP response, but had no effect on the proliferation rate. Furthermore, osteocalcin expression was increased by PDE7 silencing by a mechanism dependent on protein kinase A. Our results show that specific gene silencing with the RNAi method is a useful tool for inhibiting the gene expression of specific PDEs and that PDE7 silencing upregulates several osteogenic genes and increases mineralization. PDE7 may play an important role in the regulation of osteoblastic differentiation.

Severe vitamin D deficiency is common among Muslim immigrants. The dose necessary to correct the deficiency and its consequence for bone health are not known for immigrants. The aim was to assess the effect of relatively low dosages of supplemental vitamin D on vitamin D and bone status in Pakistani immigrants. This 1-year-long randomised double-blinded placebo-controlled intervention with vitamin D3 (10 and 20mg/d) included girls (10·1 – 14·7 years), women (18·1 – 52·7 years) and men (17·9 – 63·5 years) of Pakistani origin living in Denmark. The main endpoints were serum 25-hydroxyvitamin D (S-25OHD), parathyroid hormone, bone turnover markers and bone mass. The study showed that supplementation with 10 and 20mg vitamin D3 per d increased S-25OHD concentrations similarly in vitamin D-deficient Pakistani women (4-fold), and that 10mg increased S-25OHD concentrations 2-fold and 20mg 3-fold in Pakistani men. S-25OHD concentrations increased at 6 months and were stable thereafter. Baseline S-25OHD concentrations tended to be lower in girls and women than in men; females achieved about 46 nmol/l and men 55 nmol/l after supplementation. Serum intact parathyroid hormone concentrations decreased at 6 months, but there was no significant effect of the intervention on bone turnover markers and dual-energy X-ray absorptiometry measurements of the whole body and lumbar spine. Randomised controlled trials: Vitamin D intervention: Pakistani immigrants: Bone turnover: Bone mass

The manufacture of garments is the main industry in Bangladesh and employs 1·6 million female workers. Due to the indoor lifestyle and low dietary intake of calcium, we hypothesised that they are at risk of low vitamin D and bone mineral status. Two hundred female garment workers (aged 18– 36 years) were randomly selected. Serum 25-hydroxyvitamin D (S-25OHD), serum intact parathyroid hormone (S-iPTH), serum calcium (S-Ca), serum phosphate (S-P) concentration and serum alkaline phosphatase activity (S-ALP) were measured from fasting samples. Bone indexes of hip and spine were measured by dual-energy X-ray absorptiometry. The mean S-25OHD (36·7 nmol/l) was low compared to that recommended for vitamin D sufficiency. About 16 % of the subjects were found to be vitamin D-deficient (S-25OHD , 25 nmol/l). We observed a high prevalence (88·5 %) of vitamin D insufficiency (S-25OHD , 50 nmol/l) as well as a significant inverse relationship between S-25OHD and S-iPTH (r 20·25, P# 0·001). A decrease in S-25OHD (,38 nmol/l) and an increase in S-iPTH (. 21 ng/l) was associated with progressive reduction in bone mineral density at the femoral neck and lumbar spine. According to the WHO criteria, the mean T-score of the femoral neck and lumbar spine of the subjects were within osteopenic range. We observed that subjects with a bone mineral density T-score ,2 2·5 had a trend of lower values of BMI, waist – hip circumference, mid-upper-arm circumference, S-25OHD and higher S-iPTH and S-ALP. The high prevalence of hypovitaminosis D and low bone mineral density among these subjects are indicative of higher risk for osteomalacia or osteoporosis and fracture. 25-Hydroxyvitamin D: Bone mineral density: Vitamin D status: Female garment workers: Bangladesh Osteoporosis is a disease in which the density of bone is decreased with a consequent increase in bone fragility and susceptibility to fracture risk. Women are four times more likely than men to develop this disease. Osteoporosis has profound implications for an individual and for the economics of society. Although the exact mechanisms that lead to osteoporosis are not fully understood, two major determinants are known: peak bone mass during childhood and adolescence

Summary Background Vitamin D insufficiency during winter is common in the Nordic countries. Heliotherapy (HT) may heal atopic dermatitis (AD) but its effect on vitamin D balance has not been examined. Objectives To study the effect of HT on serum calcidiol (25-hydroxyvitamin D) concentration and on healing of AD. Methods Twenty-three adult patients with AD received a 2-week course of HT in the Canary Islands in either January or March 2005. Daily solar ultraviolet (UV) radiation was measured and personal UV exposure calculated as standard erythema doses (SED). Blood samples were taken during HT and during a 1–2 month follow-up. Serum calcidiol concentration was measured by radioimmunoassay. Healing of AD was examined by SCORAD index. Results Before HT 17 (74%) AD patients had vitamin D insufficiency (calcidiol 80 nmol L−1) serum calcidiol values. The median personal UV dose during the 2-week HT course was 60 SED in the January group and 109 SED in the March group. Serum calcidiol concentration increased significantly in both groups, by 13·4 and 24·0 nmol/L−1, respectively, and after HT only four (17%) patients had vitamin D insufficiency. SCORAD improved from 34 to 9 in the January HT group and from 30 to 9 in the March group. Conclusions A 2-week course of HT significantly improved vitamin D balance by increasing serum calcidiol concentration, and caused a marked healing of AD. These parallel positive responses should be taken into account when the benefits of HT are considered.

Parathyroid hormone-related peptide (PTHrP) has been shown to have anabolic effects on bone in women with postmenopausal osteoporosis. On the cellular level PTHrP promotes the recruitment of osteogenic cells and prevents apoptotic death of osteoblasts and osteocytes. The calcium concentration is considerably higher in the vicinity of resorbing osteoclasts than in the plasma. Therefore the osteoblasts are likely to be confronted by elevated extracellular calcium concentrations in the areas of resorptive activity. The present study was designed to assess the possibility that extracellular calcium could regulate PTHrP expression in osteoblastic cells. Adult human mesenchymal stem cells (hMSC) were cultured and differentiated by standard methods. The PTHrP release into the culture media was measured by an immunoradiometric assay and the expression of PTHrP, osteocalcin and Runx2 mRNA was assayed by real-time PCR. Increasing the extracellular calcium from 1 mM to 5 mM for 24 h resulted in a 4-6-fold increase in the PTHrP release. PTHrP mRNA was also increased by elevated calcium levels. The effect of calcium stimulation on PTHrP release could be seen within 60 min of treatment. The extracellular calcium sensing receptor (CaR) agonist neomycin mimicked the effects of calcium and the MEK/MAPK inhibitor PD98059 abolished the effect of calcium and neomycin. High extracellular calcium increased the mineralization of hMSC and the expression of osteocalcin, but this effect was not mimicked by neomycin. Our results show that in hMSC, elevated extracellular calcium levels increases both released PTHrP and PTHrP mRNA expression. The effect of calcium on PTHrP can be mimicked by activation of the CaR and can be diminished by inhibition of the MAPK signalling pathway.

A high dietary P intake is suggested to have negative effects on bone through increased parathyroid hormone secretion, as high serum parathyroid hormone (S-PTH) concentration increases bone resorption. In many countries the P intake is 2- to 3-fold above dietary guidelines, whereas Ca intake is too low. This combination may not be optimal for bone health. In a previous controlled study, we found that dietary P dose-dependently increased S-PTH and bone resorption and decreased bone formation. The aim of the present study was to investigate the dose–response effects of Ca intake on Ca and bone metabolism with a dietary P intake higher than recommended. Each of the twelve healthy female subjects aged 21–40 years attended three 24-h study sessions, which were randomized with regard to a Ca dose of 0 (control day), 600 or 1200 mg, and each subject served as her own control. The meals on each study day provided 1850 mg P and 480 mg Ca. S-PTH concentration decreased (P P P = 0·4). By contrast, the bone resorption marker, urinary N-terminal telopeptide of collagen type I, decreased significantly with both Ca doses (P = 0·008). When P intake was above current recommendations, increased Ca intake was beneficial for bone, as indicated by decreased S-PTH concentration and bone resorption. However, not even a high Ca intake could affect bone formation when P intake was excessive.

To determine vitamin D and bone status in adolescent girls, pre-menopausal women and men of Pakistani origin, to single out determinants of vitamin D status and to determine the association between vitamin D status, bone metabolism and bone status.Cross-sectional study, Copenhagen (55 degrees N), January-November. Serum 25-hydroxyvitamin D (S-25OHD), serum intact parathyroid hormone (S-iPTH), bone turnover markers and whole body and lumbar spine bone mineral density were measured. Sun, smoking and clothing habits, age, body mass index (BMI), and vitamin D and calcium from food and from supplements were recorded. Thirty-seven girls (median age, range: 12.2 years, 10.1-14.7), 115 women (36.2 years, 18.1-52.7) and 95 men (38.3 years, 17.9-63.5) of Pakistani origin (immigrants or descendants with Pakistani parents) took part in the study.Median concentration of S-25OHD was 10.9, 12.0 and 20.7 nmol/l for girls, women and men, respectively. Forty-seven per cent of the girls, 37% of the women and 24% of the men had elevated S-iPTH, and there was a negative relationship between S-iPTH and S-25OHD. Use of vitamin D-containing supplements had a positive association with S-25OHD for men (P=0.04) and women (P=0.0008). Twenty-one per cent of the women and 34% of the men had osteopenia. Neither S-25OHD nor S-iPTH was associated with lumbar spine or whole body bone mineral content.Severely low vitamin D status and elevated S-iPTH is common among Pakistani immigrants in Denmark. The low vitamin D status is not associated with bone markers or bone mass among relatively young Pakistanis.