Vitamin D supplementation for improving bone density in vitamin D-deficient children and adolescents: systematic review and individual participant data meta-analysis of randomized controlled trials.

BACKGROUND: Vitamin D supplements are widely used for improving bone health in children and adolescents, but their effects in vitamin D-deficient children are unclear. OBJECTIVES: This study aimed to examine whether the effect of vitamin D supplementation on bone mineral density (BMD) in children and adolescents differs by baseline vitamin D status and estimate the effect in vitamin D-deficient individuals. METHODS: This is a systematic review and individual participant data (IPD) meta-analysis. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, MBASE, CINAHL, AMED, and ISI Web of Science (until May 27, 2020) for randomized controlled trials (RCTs) of vitamin D supplementation reporting bone density outcomes after ≥6 mo in healthy individuals aged 1-19 y. We used two-stage IPD meta-analysis to determine treatment effects on total body bone mineral content and BMD at the hip, femoral neck, lumbar spine, and proximal and distal forearm after 1 y; examine whether effects varied by baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, and estimate treatment effects for each 25(OH)D subgroup. RESULTS: Eleven RCTs were included. Nine comprising 1439 participants provided IPD (86% females, mean baseline 25(OH)D = 36.3 nmol/L). Vitamin D supplementation had a small overall effect on total hip areal BMD (weighted mean difference = 6.8; 95% confidence interval: 0.7, 12.9 mg/cm2; I2 = 7.2%), but no effects on other outcomes. There was no clear evidence of linear or nonlinear interactions between baseline 25(OH)D and treatment; effects were similar in baseline 25(OH)D subgroups (cutoff of 35 or 50 nmol/L). The evidence was of high certainty. CONCLUSIONS: Clinically important benefits for bone density from 1-y vitamin D supplementation in healthy children and adolescents, regardless of baseline vitamin D status, are unlikely. However, our findings are mostly generalizable to White postpubertal girls and do not apply to those with baseline 25(OH)D outside the studied range or with symptomatic vitamin D deficiency (e.g., rickets). This study was preregistered at PROSPERO as CRD42017068772. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017068772.

Intake of vitamin B12 in relation to vitamin B12 status in groups susceptible to deficiency: a systematic review.

Objective: To systematically review the evidence for whether habitual or different levels of experimental intake of vitamin B12 from diet and supplements is sufficient to ensure adequate B12 status in groups most susceptible to vitamin B12 deficiency. Methods: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Scopus up to 21 May 2021, for intervention studies, prospective cohort studies and case-control studies assessing B12 intake from diet and/or supplements in relation to B12 status (s/p-B12, holotranscobalamin, methylmalonic acid, homocysteine or breastmilk B12). Cross-sectional studies were eligible for studies conducted during pregnancy and lactation. Included populations were children (0-18 years), young adults (18-35 years), pregnant or lactating women, older adults (≥65 years) and vegans or vegetarians. Study selection, data extraction and risk of bias assessment were conducted by two assessors independently. The evidence was synthesized qualitatively and classified according to the World Cancer Research Fund. Results: The searches yielded 4855 articles of which 89 were assessed in full text and 18 included. Three studies were conducted during pregnancy and three during lactation or infancy - all observational. Eight studies were conducted among older adults; most were interventions among B12-deficient participants. Four studies were eligible for vegetarian and vegans, all interventions. The strength of evidence that habitual B12 intake or an intake in line with the current Nordic recommended intake (RI) is sufficient to ensure adequate status was considered Limited - no conclusion for all included populations. Conclusion: Evidence is insufficient to assess if or which level of B12 intake is sufficient to maintain adequate status for all included populations. Population-based cohort studies and low-to-moderate dose interventions that address this question are highly warranted.

Legume consumption in adults and risk of cardiovascular disease and type 2 diabetes: a systematic review and meta-analysis.

Objectives: This study aimed to systematically review the evidence for associations between consumption of legumes and cardiovascular disease (CVD), type 2 diabetes (T2D) and their risk factors among healthy adults. Methods: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus up to 16 May 2022 for ≥4 weeks long randomized (RCT) and non-randomized controlled trials and prospective cohort studies with follow-up ≥12 months, assessing legume intake (beans/lentils/peas/soybeans, excluding peanuts and legume-products/protein/powder/flour) as the intervention or exposure. Outcomes were CVD, coronary heart disease (CHD), stroke, T2D and in intervention trials only: changes in blood lipids, glycemic markers, and blood pressure. Risk of bias (RoB) was evaluated with Cochrane's RoB2, ROBINS-I, and US Department of Agriculture (USDA)'s RoB-NObS. Effect sizes were pooled using random-effects meta-analyses and expressed as relative risk or weighed mean differences with 95% confidence intervals, heterogeneity quantified as I2. The evidence was appraised according to World Cancer Research Fund's criteria. Results: Of the 181 full-text articles assessed for eligibility, 47 were included: 31 cohort studies (2,081,432 participants with generally low legume consumption), 14 crossover RCTs (448 participants), one parallel RCT and one non-randomized trial. Meta-analyses of cohort studies were suggestive of null associations for CVD, CHD, stroke and T2D. Meta-analyses of RCTs suggested a protective effect on total cholesterol (mean difference -0.22 mmol/L), low density lipoprotein (LDL)-cholesterol (-0.19 mmol/L), fasting glucose (-0.19 mmol/L), and HOMA-IR (-0.30). Heterogeneity was high (I2 = 52% for LDL-cholesterol, >75% for others). The overall evidence for associations between consumption of legumes and risk of CVD and T2D was considered limited - no conclusion. Conclusion: Legume consumption was not found to influence risk of CVD and T2D in healthy adult populations with generally low legume consumption. However, protective effects on risk factors, seen in RCTs, lend some support for recommending legume consumption as part of diverse and healthy dietary patterns for prevention of CVD and T2D.

The effect of vitamin D3 supplementation on atrial fibrillation in generally healthy men and women: The Finnish Vitamin D Trial.

Atrial fibrillation is a common cardiac arrhythmia with high morbidity risk. Observational studies suggest that vitamin D deficiency is associated with higher atrial fibrillation risk but there is limited evidence whether vitamin D supplementation could affect the risk. In these post hoc analyses from the Finnish Vitamin D Trial, we compared the incidence of atrial fibrillation with 5-year supplementation of vitamin D3 (1600 IU/d or 3200 IU/d) vs placebo. CLINICAL TRIAL REGISTRY NUMBER: ClinicalTrials.gov: NCT01463813, https://clinicaltrials.gov/ct2/show/NCT01463813.

Dietary fiber and growth, iron status and bowel function in children 0-5 years old: a systematic review.

Background: While dietary fiber intake is low in many children, the current trend to plant-based diets is associated with higher fiber intake in children raised on these diets. As older reports indicate that diets providing high fiber intake in children 0-5 years may affect growth, iron status and bowel function, we summarized the available evidence in this systematic review. Objective: To identify, critically appraise, and synthesize evidence on the effect of high fiber intake on growth, iron and bowel function in children 0-5 years, with relevance to the Nordic and Baltic countries. Methods: Following a pre-registered protocol, we searched MEDLINE, EMBASE, Cochrane Central of Controlled Trials, and Scopus for clinical trials and prospective cohort studies published until November 2021. Two reviewers independently screened retrieved literature, extracted relevant data, and performed risk of bias assessment. Outcomes were growth, iron metabolism and bowel function in children 0-5 years. We narratively described findings from studies that met inclusion criteria. Results: From 5,644 identified records, five articles met the inclusion criteria. Two RCTs had an overall moderate risk of bias, while the three observational studies had serious risk. Overall, we found no robust association between high intake of dietary fiber and growth. In the RCTs, higher intake of fiber had a positive effect on bowel movements and constipation. No studies on fiber intake and iron status were identified.The certainty of the overall evidence was inconclusive for growth and bowel function, while no assessment was made for iron status. Conclusion: We found no clear association between high intake of dietary fiber and growth or bowel function in young children living in affluent countries, albeit with only a limited number of studies. There is a lack of studies investigating health effects of high fiber intake in small children.

Animal versus plant-based protein and risk of cardiovascular disease and type 2 diabetes: a systematic review of randomized controlled trials and prospective cohort studies.

Objectives: To systematically review the evidence on the effect of replacing the intake of animal protein with plant protein on cardiovascular disease (CVD) and type 2 diabetes (T2D) and their intermediate risk factors. Methods: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus up to 12th May 2022 for randomized controlled trials (RCTs) or prospective cohort studies that investigated replacement of animal protein with plant protein from foods. Outcomes were CVDs, T2D, and in RCTs also the effects on blood lipids, glycemic markers, and blood pressure. Risk of bias was evaluated with the Cochrane's RoB2, ROBINS-I, and USDA's RoB-NObS tools. Random-effects meta-analyses assessed the effects of plant vs. animal proteins on blood lipids in RCTs. The evidence was appraised according to the World Cancer Research Fund's criteria. Results: After screening 15,090 titles/abstracts, full text of 124 papers was scrutinized in detail, from which 13 RCTs and seven cohort studies were included. Eight of the RCTs had either some concern or high risk of bias, while the corresponding evaluation of cohort studies resulted in moderate risk of bias for all seven. Meta-analyses of RCTs suggested a protective effect on total cholesterol (mean difference -0.11 mmol/L; 95% CI -0.22, -0.01) and low-density lipoprotein cholesterol (-0.14 mmol/L; 95% CI -0.25, -0.02) by replacing animal protein with plant protein. The substitution of animal protein with plant protein (percentage of energy intake) in cohort studies was associated with lower CVD mortality (n = 4) and lower T2D incidence (n = 2). The evidence was considered limited-suggestive for both outcomes. Conclusion: Evidence that the substitution of animal protein with plant protein reduces risk of both CVD mortality and T2D incidence is limited-suggestive. Replacing animal protein with plant protein for aspects of sustainability may also be a public health strategy to lower the risk of CVD mortality and T2D.

Nuts and seeds consumption and risk of cardiovascular disease, type 2 diabetes and their risk factors: a systematic review and meta-analysis.

Objectives: We aimed to systematically review studies and evaluate the strength of the evidence on nuts/seeds consumption and cardiometabolic diseases and their risk factors among adults. Methods: A protocol was pre-registered in PROSPERO (CRD42021270554). We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Scopus up to September 20, 2021 for prospective cohort studies and ≥12-week randomized controlled trials (RCTs). Main outcomes were cardiovascular disease (CVD), coronary heart disease (CHD), stroke and type 2 diabetes (T2D), secondary total-/low density lipoprotein (LDL)-cholesterol, blood pressure and glycaemic markers. Data extraction and risk of bias (RoB) assessments (using RoB 2.0 and RoB-NObS) were performed in duplicate. Effect sizes were pooled using random-effects meta-analyses and expressed as relative risk (RR) or weighted mean differences with 95% confidence intervals (CI); heterogeneity quantified as I 2. One-stage dose-response analyses assessed the linear and non-linear associations with CVD, CHD, stroke and T2D. The strength of evidence was classified per the World Cancer Research Fund criteria. Results: After screening 23,244 references, we included 42 papers from cohort studies (28 unique cohorts, 1,890,573 participants) and 18 RCTs (2,266 participants). In the cohorts, mainly populations with low consumption, high versus low total nuts/seeds consumption was inversely associated with total CVD (RR 0.81; 95% CI 0.75, 0.86; I 2 = 67%), CVD mortality (0.77; 0.72, 0.82; I 2 = 59.3%), CHD (0.82; 0.76, 0.89; I 2 = 64%), CHD mortality (0.75; 0.65, 0.87; I 2 = 66.9%) and non-fatal CHD (0.85; 0.75, 0.96; I 2 = 62.2%). According to the non-linear dose-response analyses, consumption of 30 g/day of total nuts/seeds was associated with RRs of similar magnitude. For stroke and T2D the summary RR for high versus low intake was 0.91 (95% CI 0.85, 0.97; I 2 = 24.8%) and 0.95 (0.75, 1.21; I 2 = 82.2%). Intake of nuts (median ~50 g/day) lowered total (-0.15 mmol/L; -0.22, -0.08; I 2 = 31.2%) and LDL-cholesterol (-0.13 mmol/L; -0.21, -0.05; I 2 = 68.6%), but not blood pressure. Findings on fasting glucose, HbA1c and insulin resistance were conflicting. The results were robust to sensitivity and subgroup analyses. We rated the associations between nuts/seeds and both CVD and CHD as probable. There was limited but suggestive evidence for no association with stroke. No conclusion could be made for T2D. Conclusion: There is a probable relationship between consumption of nuts/seeds and lower risk of CVD, mostly driven by CHD, possibly in part through effects on blood lipids. More research on stroke and T2D may affect the conclusions. The evidence of specific nuts should be further investigated.

White meat consumption and risk of cardiovascular disease and type 2 diabetes: a systematic review and meta-analysis.

Objectives: The aim was to systematically review the associations among white meat consumption, cardiovascular diseases (CVD), and type 2 diabetes (T2D). Methods: Databases MEDLINE, Embase, and Cochrane Central Register of Controlled Trials and Scopus were searched (15th October 2021) for randomized intervention trials (RCTs, ≥ 4 weeks of duration) and prospective cohort studies (≥12 month of follow-up) assessing the consumption of white meat as the intervention/exposure. Eligible outcomes for RCTs were cardiometabolic risk factors and for cohorts, fatal and non-fatal CVD and incident T2D. Risk of bias was estimated using the Cochrane's RoB2 and Risk of Bias for Nutrition Observational Studies. Meta-analysis was conducted in case of ≥3 relevant intervention studies or ≥5 cohort studies using random-effects models. The strength of evidence was evaluated using the World Cancer Research Fund's criteria. Results: The literature search yielded 5,795 scientific articles, and after screening 43 full-text articles, 23 cohort studies and three intervention studies were included. All included intervention studies matched fat content of intervention and control diets, and none of them showed any significant effects on the selected outcomes of white meat when compared to red meat. Findings from the cohort studies generally did not support any associations between white meat intake and outcomes. Meta-analyses were conducted for CVD mortality (RR: 0.95, 95% CI: 0.87-1.02, P = 0.23, I2 = 25%) and T2D incidence (RR: 0.98, 95% CI: 0.87-1.11, P = 0.81, I2 = 82%). Conclusion: The currently available evidence does not indicate a role, beneficial or detrimental, of white meat consumption for CVD and T2D. Future studies investigating potentially different health effects of processed versus unprocessed white meat and substitution of red meat with white meat are warranted.Registration: Prospero registration CRD42022295915.

Phosphorus - a scoping review for Nordic Nutrition Recommendations 2023.

This scoping review aims to describe the totality of evidence for the role of phosphorus for health-related outcomes as a basis for setting and updating dietary reference values (DRVs). Phosphorus is needed in many biological processes, such as cellular metabolism and bone mineralization. Dietary phosphorus intake exceeds the previous Nordic Nutrition Recommendations (NNR2012) 2-3-fold in the Nordic countries. Intake from food additives is unknown but may play a significant role because the use of phosphate additives is common in the food industry. Bioavailability of phosphorus in plant-based products is lower than animal-based products. Nevertheless, bioavailability of phosphorus additives is higher. The main phosphorus-related health outcomes concern high phosphorus intake mainly from food additives with potential adverse effects on kidney, bone, and cardiovascular health.

Supplementation with long chain n-3 fatty acids during pregnancy, lactation, or infancy in relation to risk of asthma and atopic disease during childhood: a systematic review and meta-analysis of randomized controlled clinical trials.

Objective: To assess whether supplementation with long chain n-3 fatty acids during pregnancy, lactation, or infancy reduces the risk of developing asthma or atopic disease during childhood. Methods: Searches were performed in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus up to 2021-09-20, for randomized controlled trials (RCTs) that investigated the effect of supplemental long chain n-3 fatty acids during pregnancy, lactation, or infancy for the prevention of childhood asthma or allergy. Article selection, data extraction, and risk of bias assessment (Cochrane's Risk of Bias 2.0) were independently conducted by two assessors. The evidence was synthesized qualitatively according to the criteria of the World Cancer Research Fund and meta-analyzed. Results: A total of nine RCTs met inclusion criteria; six were conducted during pregnancy, two during infancy, and one during both pregnancy and infancy. Meta-analysis showed that long chain n-3 fatty acid supplementation during pregnancy significantly reduced the risk of asthma/wheeze in the child (RR 0.62 [95% confidence interval 0.34-0.91], P = 0.005, I 2 = 67.4%), but not other outcomes. Supplementation during lactation of infancy showed no effects on any outcome. The strength of evidence that long chain n-3 fatty acid supplementation during pregnancy reduces risk of asthma/wheeze in the offspring was considered limited - suggestive. No conclusion could be made for the effects of long chain n-3 fatty acid supplementation during pregnancy for other atopic diseases, or for supplementation during lactation or infancy for any outcome. Conclusion: The intake of long chain n-3 fatty acid supplements during pregnancy may reduce the risk of asthma and/or wheeze in the offspring, but the strength of evidence is low. There is inconclusive evidence for the effects of long chain n-3 fatty acid supplements during pregnancy for other outcomes, as well as for supplementation during lactation or infancy.

Quality of dietary fat and risk of Alzheimer's disease and dementia in adults aged ≥50 years: a systematic review.

Objective: To identify, critically appraise, and synthesize evidence on the effect of quality of dietary fat intake and different classes of fatty acids on the risk of Alzheimer's disease (AD) and dementia in adults aged ≥50 years. Methods: We searched MEDLINE, EMBASE, Cochrane Central of Controlled Trials, and Scopus for clinical trials and prospective cohort studies published until May 2021. Two reviewers independently screened retrieved literature, extracted relevant data, and performed risk of bias assessment. Classes of fatty acids included were saturated fatty acids (SFAs), trans fatty acids (TFAs), monounsaturated fatty acids (MUFAs), poly-unsaturated fatty acids (PUFAs), and their subtypes and sources. Given between-study heterogeneity, we did not perform meta-analyses but narratively described findings from the studies. Results: From 4,491 identified records, five articles (based on four prospective cohort studies) met the inclusion criteria. Three studies had an overall serious risk of bias, while one study had a moderate risk. Overall, we found no robust association between intake of any fatty acids type and the development of AD and dementia. For example, for SFA and TFA, there was contradictory associations reported on AD: one study found that each unit increase in energy-adjusted intake of SFA (risk ratio [RR] 0.83, 95%CI 0.70-0.98) and TFA (RR 0.80, 95%CI 0.65-0.97) was associated with a decreased risk of AD, but not dementia. For PUFA, one study found that higher quintile intake of marine-based n-3 PUFA was associated with a decreased risk of AD. The intake of other fatty acids was not associated with the outcomes. The certainty of the overall evidence was inconclusive. Conclusion: We found no clear association between the intake of various classes of fatty acids and the risk of AD and dementia in adults. More well-designed prospective studies are required to clarify these findings.

Protein intake in children and growth and risk of overweight or obesity: A systematic review and meta-analysis.

Objectives: The aim of this study was to examine the evidence for an association between the dietary protein intake in children and the growth and risk of overweight or obesity up to 18 years of age in settings relevant for the Nordic countries. Methods: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Scopus up to February 26, 2021 for randomized controlled trials (RCTs) or prospective cohort studies assessing for protein intake from foods (total and from different sources) in children. The outcomes include weight, height/length, adiposity indices, and/or risk of overweight and/or obesity. The risk of bias was evaluated with instruments for each respective design (Cochrane's Risk of Bias 2.0 and RoB-NObS). A meta-analysis of five cohort studies was performed. The evidence was classified according to the criteria of the World Cancer Research Fund. Results: The literature search resulted in 9,132 abstracts, of which 55 papers were identified as potentially relevant. In total, 21 studies from 27 publications were included, of which five were RCTs and 16 were cohort studies. The RCTs found generally null effects of high-protein intake in infants on weight gain, nor that lower protein diets negatively affected growth. All included RCTs had some concern regarding the risk of bias and were limited by small sample sizes. Total protein intake and BMI were assessed in 12 cohorts, of which 11 found positive associations. The meta-analysis revealed a pooled effect estimate of 0.06 (95% CI 0.03, 0.1) kg/m2 BMI per one E% increment in total protein (I 2 = 15.5). Therefore, the evidence for a positive relationship between total protein intake and BMI was considered probable. Furthermore, there was probable evidence for an association between higher intake of animal protein and increased BMI. There was limited, suggestive evidence for an effect of total protein intake and higher risk of overweight and/or obesity, while no conclusions could be made on the associations between animal vs. plant protein intake and risk of overweight and/or obesity. Discussion: In healthy, well-nourished children of Western populations, there is probably a causal relationship between a high-protein intake in early childhood (≤ 18 months) - particularly protein of animal origin - and higher BMI later in childhood, with consistent findings across cohort studies. A lack of RCTs precluded a stronger grading of the evidence.

Vitamin D supplementation and prevention of cardiovascular disease and cancer in the Finnish Vitamin D Trial: a randomized controlled trial.

BACKGROUND: Vitamin D insufficiency is associated with risks of cardiovascular diseases (CVD) and cancer in observational studies, but evidence for benefits with vitamin D supplementation is limited. OBJECTIVES: To investigate the effects of vitamin D3 supplementation on CVD and cancer incidences. METHODS: The study was a 5-year, randomized, placebo-controlled trial among 2495 male participants ≥60 years and post-menopausal female participants ≥65 years from a general Finnish population who were free of prior CVD or cancer. The study had 3 arms: placebo, 1600 IU/day, or 3200 IU/day vitamin D3. Follow-up was by annual study questionnaires and national registry data. A representative subcohort of 551 participants had more detailed in-person investigations. The primary endpoints were incident major CVD and invasive cancer. Secondary endpoints included the individual components of the primary CVD endpoint (myocardial infarction, stroke, and CVD mortality), site-specific cancers, and cancer death. RESULTS: During the follow-up, there were 41 (4.9%), 42 (5.0%), and 36 (4.3%) major CVD events in the placebo, 1600 IU/d (compared with placebo: HR: 0.97; 95% CI: 0.63-1.49; P = 0.89), and 3200 IU/d (HR: 0.84; 95% CI: 0.54-1.31; P = 0.44) arms, respectively. Invasive cancer was diagnosed in 41 (4.9%), 48 (5.8%), and 40 (4.8%) participants in the placebo, 1600 IU/d (HR: 1.14; 95% CI: 0.75-1.72; P = 0.55), and 3200 IU/d (HR: 0.95; 95% CI: 0.61-1.47; P = 0.81) arms, respectively. There were no significant differences in the secondary endpoints or total mortality. In the subcohort, the mean baseline serum 25-hydroxyvitamin D concentration was 75 nmol/L (SD, 18 nmol/L). After 12 months, the concentrations were 73 nmol/L (SD, 18 nmol/L), 100 nmol/L (SD, 21 nmol/L), and 120 nmol/L (SD, 22 nmol/L) in the placebo, 1600 IU/d, and 3200 IU/d arms, respectively. CONCLUSIONS: Vitamin D3 supplementation did not lower the incidences of major CVD events or invasive cancer among older adults, possibly due to sufficient vitamin D status in most participants at baseline.

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

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

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

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

Vitamin D status and current policies to achieve adequate vitamin D intake in the Nordic countries.

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.

Partial Replacement of Animal Proteins with Plant Proteins for 12 Weeks Accelerates Bone Turnover Among Healthy Adults: A Randomized Clinical Trial.

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 < 0.001 for both), and differed also between the animal (mean ± SEM, 0.29 ± 0.02 ng/mL) and 50/50 groups (mean ± SEM, 0.34 ± 0.02 ng/mL; P = 0.018). S-iPINP was significantly higher in the plant group (mean ± SEM, 63.9 ± 1.91 ng/mL) than in the animal group (mean ± SEM, 55.0 ± 1.82 ng/mL; P = 0.006). In a subgroup without a history of vitamin D supplement use, plasma parathyroid hormone was significantly higher in the plant than in the animal group (P = 0.018). Vitamin D and calcium intakes were below recommended levels in the plant group (mean ± SEM, 6.2 ± 3.7 µg/d and 733 ± 164 mg/d, respectively). CONCLUSIONS: Partial replacement of animal proteins with plant-based proteins for 12 weeks increased the markers of bone resorption and formation among healthy adults, indicating a possible risk for bone health. This is probably caused by lower vitamin D and calcium intakes from diets containing more plant-based proteins, but it is unclear whether differences in protein intake or quality play a major role. This trial was registered at clinicaltrials.gov as NCT03206827.

Genetic Risk Score for Serum 25-Hydroxyvitamin D Concentration Helps to Guide Personalized Vitamin D Supplementation in Healthy Finnish Adults.

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 × 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.

Prevalence and determinants of vitamin D deficiency and insufficiency among three immigrant groups in Finland: evidence from a population-based study using standardised 25-hydroxyvitamin D data.

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 <30 nmol/l) and insufficiency (S-25(OH)D <50 nmol/l) was higher among immigrants than Finns (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.

Vitamin D status in a multi-ethnic population of northern Norway: the SAMINOR 2 Clinical Survey.

OBJECTIVE: To 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. DESIGN: Cross-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 DË¢ assay. Daily dietary intake was assessed using an FFQ. BMI was calculated using weight and height measurements. SETTING: Ten municipalities of northern Norway (latitude 68°-70°N). PARTICIPANTS: Males (n 2041) and females (n 2424) aged 40-69 years. RESULTS: Mean 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)D<30 nmol/l was 1·9 % and <50 nmol/l was 24·7 %. In sex-specific multivariable linear regression models, older age, blood sample collection in September-October, solarium use, sunbathing holiday, higher alcohol intake (in females), use of cod-liver oil/fish oil supplements, use of vitamin/mineral supplements and higher intakes of vitamin D were significantly associated with higher S-25(OH)D, whereas being a current smoker and obesity were associated with lower S-25(OH)D. These factors explained 21-23 % of the variation in S-25(OH)D. CONCLUSIONS: There 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.