Identifying Plasma and Urinary Biomarkers of Fermented Food Intake and Their Associations with Cardiometabolic Health in a Dutch Observational Cohort.

Identification of food intake biomarkers (FIBs) for fermented foods could help improve their dietary assessment and clarify their associations with cardiometabolic health. We aimed to identify novel FIBs for fermented foods in the plasma and urine metabolomes of 246 free-living Dutch adults using nontargeted LC-MS and GC-MS. Furthermore, associations between identified metabolites and several cardiometabolic risk factors were explored. In total, 37 metabolites were identified corresponding to the intakes of coffee, wine, and beer (none were identified for cocoa, bread, cheese, or yoghurt intake). While some of these metabolites appeared to originate from raw food (e.g., niacin and trigonelline for coffee), others overlapped different fermented foods (e.g., 4-hydroxybenzeneacetic acid for both wine and beer). In addition, several fermentation-dependent metabolites were identified (erythritol and citramalate). Associations between these identified metabolites with cardiometabolic parameters were weak and inconclusive. Further evaluation is warranted to confirm their relationships with cardiometabolic disease risk.

Vitamin D status modulates mitochondrial oxidative capacities in skeletal muscle: role in sarcopenia.

Skeletal muscle mitochondrial function is the biggest component of whole-body energy output. Mitochondrial energy production during exercise is impaired in vitamin D-deficient subjects. In cultured myotubes, loss of vitamin D receptor (VDR) function decreases mitochondrial respiration rate and ATP production from oxidative phosphorylation. We aimed to examine the effects of vitamin D deficiency and supplementation on whole-body energy expenditure and muscle mitochondrial function in old rats, old mice, and human subjects. To gain further insight into the mechanisms involved, we used C2C12 and human muscle cells and transgenic mice with muscle-specific VDR tamoxifen-inducible deficiency. We observed that in vivo and in vitro vitamin D fluctuations changed mitochondrial biogenesis and oxidative activity in skeletal muscle. Vitamin D supplementation initiated in older people improved muscle mass and strength. We hypothesize that vitamin D supplementation is likely to help prevent not only sarcopenia but also sarcopenic obesity in vitamin D-deficient subjects.

Eating for 2: A Systematic Review of Dutch App Stores for Apps Promoting a Healthy Diet during Pregnancy.

A healthy diet during pregnancy has been associated with beneficial child and maternal health outcomes but is challenging to achieve. Recent technological advances offer new opportunities to support pregnant women in their food choices-for instance, via apps. This is already reflected by a wide availability of pregnancy-related apps, but health care professionals feel unsure about their potential. Therefore, the Dutch Google Play Store and Apple App Store were reviewed to identify existing apps on diet and pregnancy. App quality was assessed using the 1) Mobile App Rating Scale (MARS; i.e., assessing functionality, aesthetics, engagement, information quality), 2) Dutch dietary guidelines for pregnant women, and 3) App Behavior Change Scale (ABACUS). Fifty-seven unique apps were identified with an average star rating of 4.2 ±  0.6 and MARS quality score of 3.2 ±  0.3, indicating a moderate quality. Most apps scored best in terms of functionality and aesthetics (4.0 ±  0.4 and 3.3 ±  0.6), but lowest in terms of engagement (2.5 ±  0.6). Regarding nutrition information provision, most apps were incomplete or deviated from the Dutch guidelines. Folic acid supplementation (91%), hygiene (81%), caffeine (79%), and alcohol (77%) were the most commonly addressed nutrition aspects, whereas licorice (11%), iodine (19%), and soy (18%) were only addressed in a few apps. Moreover, a median of 2 out of 21 ABACUS behavior change items were identified per app, which were predominantly related to the category "knowledge and information." Thus, despite the abundance of apps supporting a healthy diet during pregnancy in the Dutch app stores, there is an urgent need for apps with complete and scientifically sound dietary information that is supported by effective behavior change techniques.

Midwives' Experiences with and Perspectives on Online (Nutritional) Counselling and mHealth Applications for Pregnant Women; an Explorative Qualitative Study.

Prenatal nutrition is a key predictor of early-life development. However, despite mass campaigns to stimulate healthy nutrition during pregnancy, the diet of Dutch pregnant women is often suboptimal. Innovative technologies offer an opportunity to develop tailored tools, which resulted in the release of various apps on healthy nutrition during pregnancy. As midwives act as primary contact for Dutch pregnant women, the goal was to explore the experiences and perspectives of midwives on (1) nutritional counselling during pregnancy, and (2) nutritional mHealth apps to support midwifery care. Analyses of eleven in-depth interviews indicated that nutritional counselling involved the referral to websites, a brochure, and an app developed by the Dutch Nutrition Centre. Midwives were aware of the existence of other nutritional mHealth apps but felt uncertain about their trustworthiness. Nevertheless, midwives were open towards the implementation of new tools providing that these are trustworthy, accessible, user-friendly, personalised, scientifically sound, and contain easy-digestible information. Midwives stressed the need for guidelines for professionals on the implementation of new tools. Involving midwives early-on in the development of future nutritional mHealth apps may facilitate better alignment with the needs and preferences of end-users and professionals, and thus increase the likelihood of successful implementation in midwifery practice.

The Importance of Maternal Folate Status for Brain Development and Function of Offspring.

The importance of an adequate periconceptional maternal folate status to prevent fetal neural tube defects has been well demonstrated and resulted in the recommendation for women to use folic acid supplements during the periconception period. The importance of maternal folate status for offspring neurodevelopment and brain health is less well described. We reviewed the current evidence linking maternal folate status before conception and during pregnancy with neurodevelopment and cognition of the offspring. We discuss both animal and human studies. Preclinical research revealed the importance of maternal folate status for several key processes required for normal neurodevelopment and brain functioning in the offspring, including DNA synthesis, regulation of gene expression, synthesis of phospholipids and neurotransmitters, and maintenance of healthy plasma homocysteine concentrations. Human observational studies are inconclusive; about half have shown a positive association between maternal folate status and cognitive performance of offspring. Whereas some studies suggest a positive association between maternal folate intake and cognition of offspring during childhood, data from interventional studies are too limited to conclude that there is a direct effect. Future preclinical studies are needed to help us characterize the behavioral effects, understand the underlying mechanisms, and to establish an optimal dosage and time window of folate supplementation. Moreover, more conclusive data from well-designed human observational studies and randomized controlled trials are needed to determine whether current recommendations for folic acid supplementation during pregnancy cover the needs for normal cognitive development in the offspring.

Changes in Micronutrient Intake and Status, Diet Quality and Glucose Tolerance from Preconception to the Second Trimester of Pregnancy.

Data on changes in dietary intake and related blood parameters throughout pregnancy are scarce; moreover, few studies have examined their association with glucose homeostasis. Therefore, we monitored intake of folate, vitamin B6, vitamin B12, vitamin D and iron, their status markers, and diet quality from preconception to the second trimester of pregnancy, and we examined whether these dietary factors were associated with glucose homeostasis during pregnancy. We included 105 women aged 18⁻40 years with a desire to get pregnancy or who were already <24 weeks pregnant. Women at increased gestational diabetes (GDM) risk were oversampled. Measurements were scheduled at preconception (n = 67), and 12 (n =53) and 24 weeks of pregnancy (n =66), including a fasting venipuncture, 75-grams oral glucose tolerance test, and completion of a validated food frequency questionnaire. Changes in micronutrient intake and status, and associations between dietary factors and glucose homeostasis, were examined using adjusted repeated measures mixed models. Micronutrient intake of folate, vitamin B6 and vitamin D and related status markers significantly changed throughout pregnancy, which was predominantly due to changes in the intake of supplements. Micronutrient intake or status levels were not associated with glucose homeostasis, except for iron intake (FE µg/day) with fasting glucose (ß = -0.069 mmol/L, p = 0.013) and HbA1c (ß = -0.4843 mmol, p = 0.002). Diet quality was inversely associated with fasting glucose (ß = -0.006 mmol/L for each DHD15-index point, p = 0.017). It was shown that micronutrient intakes and their status markers significantly changed during pregnancy. Only iron intake and diet quality were inversely associated with glucose homeostasis.

Supplement Use and Dietary Sources of Folate, Vitamin D, and n-3 Fatty Acids during Preconception: The GLIMP2 Study.

An adequate nutritional status during the preconception period is important, particularly for folate, vitamin D, and n-3 fatty acids (i.e., EPA+DHA). We aimed to determine supplement intake and the main dietary sources of folate, vitamin D, and EPA+DHA using the data of 66 Dutch women aged 18⁻40 years who wished to become pregnant. Additionally, associations of these intakes with their blood levels were examined. Dietary intake was assessed with a validated food frequency questionnaire, and supplement use with a structured questionnaire. 25-hydroxyvitamin D levels were determined in serum and folate and phospholipid EPA+DHA levels in plasma. Partial Spearman's correlations, restricted cubic splines and trend analyses over tertiles of nutrient intakes were performed to examine intake-status associations. A large proportion of women did not meet the Dutch recommended intakes of folate (50%), vitamin D (67%), and EPA+DHA (52%). Vegetables were the main contributor to dietary folate intake (25%), oils and fats to dietary vitamin D intake (39%), and fish to dietary EPA+DHA intake (69%). Fourteen percent of the women had an inadequate folate status and 23% an inadequate vitamin D status. Supplemental folate intake, supplemental and dietary vitamin D intake and dietary EPA+DHA intake were significantly associated with their blood levels. In conclusion, even in our highly educated population, a large proportion did not achieve recommended folate, vitamin D and n-3 fatty acid intakes. Promotion of folate and vitamin D supplement use and fish consumption is needed to improve intakes and blood levels of these nutrients in women who wish to become pregnant.

Maternal vitamin D concentrations are associated with faster childhood reaction time and response speed, but not with motor fluency and flexibility, at the age of 5-6 years: the Amsterdam Born Children and their Development (ABCD) Study.

About 57 % of the pregnant European women have 25-hydroxyvitamin D (25(OH)D) concentrations below 50 nmol/l. However, as data on the impact of gestational vitamin D deficiency on maternal and fetal health are limited, the WHO does not advocate vitamin D supplementation as part of routine antenatal care. We explored associations between first trimester maternal 25(OH)D status and childhood cognition at 5-6 years of age (n 1854, primarily Caucasian). Median serum 25(OH)D was determined at 13 (interquartile range 12-14) weeks of gestation. Childhood attention, motor fluency and flexibility and executive function were assessed using the Amsterdam Neuropsychological Tasks. Restricted cubic splines and linear regression analyses were used to analyse the data while adjusting for many maternal and child related covariates. Higher 25(OH)D status (nmol/l) was associated with better attention and executive functioning as shown by a faster reaction time (ß -0·30 (sd 0·14) ms, P=0·03), faster response speed (ß -0·58 (sd 0·21) ms, P=0·006), and better response speed stability (ß -0·45 (sd 0·17) ms, P=0·009). No associations were observed of serum 25(OH)D with motor fluency and flexibility. Associations were most pronounced among children of African origin (n 205) as compared with those of Caucasian or another origin, for example attention (reaction time, ß -2·06 (sd 0·70) ms, P=0·004) and executive function (response speed, ß -1·95 (sd 0·94) ms, P=0·04). Concluding, maternal 25(OH)D status was significantly associated with childhood attention and executive function, while no associations were observed for 25(OH)D status with motor fluency and flexibility.

Folate and Vitamin B12-Related Biomarkers in Relation to Brain Volumes.

AIM: We investigated cross-sectional associations between circulating homocysteine, folate, biomarkers of vitamin B12 status and brain volumes. We furthermore compared brain volumes of participants who received daily folic acid and vitamin B12 supplementation with participants who did not. METHODS: Participants of the B-PROOF study (n = 2919) were assigned to 400 µg folic acid and 500 µg vitamin B12, or a placebo. After two years of intervention, T1-weighted magnetic resonance imaging (MRI) scans were made in a random subsample (n = 218) to obtain grey and white matter volume, and total brain volume (TBV). Plasma homocysteine, serum folate, vitamin B12, holotranscobalamin, and methylmalonic acid concentrations were measured. RESULTS: Multiple linear regression analyses showed inverse associations between plasma homocysteine with TBV (ß = -0.91, 95% CI -1.85-0.03; p = 0.06) and between serum folate and TBV (ß = -0.20, 95% CI -0.38, -0.02; p = 0.03). No significant associations were observed for serum vitamin B12 and holotranscobalamin. Fully adjusted ANCOVA models showed that the group that received B-vitamins had a lower TBV (adjusted mean 1064, 95% CI 1058-1069 mL) than the non-supplemented group (1072, 95% CI 1067-1078 mL, p = 0.03). CONCLUSIONS: Results were contradictory, with higher Hcy levels associated with lower TBV, but also with higher folate levels associated with lower TBV. In addition, the lack of a baseline measurement withholds us from giving recommendations on whether folic acid and vitamin B12 supplementation will be beneficial above and beyond normal dietary intake for brain health.

Effects of Two-Year Vitamin B12 and Folic Acid Supplementation on Depressive Symptoms and Quality of Life in Older Adults with Elevated Homocysteine Concentrations: Additional Results from the B-PROOF Study, an RCT.

Lowering elevated plasma homocysteine (Hcy) concentrations by supplementing vitamin B12 and folic acid may reduce depressive symptoms and improve health-related quality of life (HR-QoL) in older adults. This study aimed to test this hypothesis in a randomized controlled trial. Participants (N = 2919, ≥65 years, Hcy concentrations ≥12 µmol/L) received either 500 µg vitamin B12 and 400 µg folic acid daily or placebo for two years. Both tablets contained 15 µg vitamin D3. Depressive symptoms were measured with the Geriatric Depression Scale-15 (GDS-15). HR-QoL was assessed with the SF-12 Mental and Physical component summary scores and the EQ-5D Index score and Visual Analogue Scale. Differences in two-year change scores were analyzed with Analysis of Covariance (ANCOVA). Hcy concentrations decreased more in the intervention group, but two-year change scores of the GDS-15 and three of four HR-QoL measures did not differ between groups. The EQ-5D Index score declined less in the intervention group than in the placebo group (mean change 0.00 vs. -0.02, p = 0.004). In conclusion, two-year supplementation with vitamin B12 and folic acid in older adults with hyperhomocysteinemia showed that lowering Hcy concentrations does not reduce depressive symptoms, but it may have a small positive effect on HR-QoL.

The Impact of Maternal Vitamin D Status on Offspring Brain Development and Function: a Systematic Review.

Various studies have examined associations between maternal vitamin D (VD) deficiency and offspring health, including offspring brain health. The purpose of this review was to summarize current evidence concerning the impact of maternal VD deficiency on brain development and function in offspring. A systematic search was conducted within Medline (on Ovid) for studies published through 7 May 2015. Animal and human studies that examined associations between maternal VD status or developmental VD deficiency and offspring brain development and function were included. A total of 26 animal studies and 10 human studies met the inclusion criteria. Several animal studies confirmed the hypothesis that low prenatal VD status may affect brain morphology and physiology as well as behavioral outcomes. In humans, subtle cognitive and psychological impairments in offspring of VD-deficient mothers were observed. However, data obtained from animal and human studies provide inconclusive evidence, and results seem to depend on strain or race and age of offspring. To conclude, prenatal VD status is thought to play an important role in brain development, cognitive function, and psychological function. However, results are inconclusive; validation of these findings and investigation of underlying mechanisms are required. Thus, more investigation is needed before recommending supplementation of VD during pregnancy to promote brain health of offspring.

Relative importance of summer sun exposure, vitamin D intake, and genes to vitamin D status in Dutch older adults: The B-PROOF study.

BACKGROUND/OBJECTIVES: The prevalence of vitamin D deficiency among seniors is high. Whereas sun exposure, vitamin D intake, genes, demographics, and lifestyle have been identified as being important determinants of vitamin D status, the impact of these factors is expected to differ across populations. To improve current prevention and treatment strategies, this study aimed to explore the main determinants of vitamin D status and its relative importance in a population of community-dwelling Dutch older adults. METHODS/SUBJECTS: Serum 25-hydroxyvitamin D (25(OH)D) was measured in 2857 adults aged ≥65 years. Sun exposure was assessed with a structured questionnaire (n=1012), vitamin D intake using a Food Frequency Questionnaire (n=596), and data on genetic variation that may affect 25(OH)D status was obtained for 4 genes, DHCR7 (rs12785878), CYP2R1 (rs10741657), GC (rs2282679), and CYP24A1 (rs6013897) (n=2530). RESULTS: Serum 25(OH)D concentrations <50nmol/L were observed in 45% of the population; only 6% of these participants used vitamin D supplements. Sun exposure (being outside daily during summer: 66±25nmol/L vs not being outside daily during summer: 58±27nmol/L, P=0.02) and vitamin D intake (per unit µg/day during winter/spring: 3.1±0.75nmol/L, P<0.0001) were associated with higher 25(OH)D concentrations. Major allele carriers of SNPs related to DHCR7, CYP24A1, and GC, as well as CYP2R1 minor allele carriers had the highest 25(OH)D concentrations. Together, sun (R2=0.29), vitamin D intake (R2=0.24), and genes (R2=0.28) explained 35% (R2=0.35) of the variation in 25(OH)D concentrations during summer/autumn period, when adjusted for age, sex, BMI, education, alcohol consumption, smoking, physical activity, and self-rated health status (n=185). CONCLUSION: The investigated determinants explained 35% of 25(OH)D status. Of the three main determinants under study, sun exposure still appeared to be an important determinant of serum 25(OH)D in older individuals, closely followed by genes, and vitamin D intake. Given the low frequency of vitamin D supplement use in this population, promoting supplement use may be an inexpensive, easy, and effective strategy to fight vitamin D deficiency.

A Randomized Controlled Trial to Examine the Effect of 2-Year Vitamin B12 and Folic Acid Supplementation on Physical Performance, Strength, and Falling: Additional Findings from the B-PROOF Study.

Elevated homocysteine concentrations are associated with a decline in physical function in elderly persons. Homocysteine-lowering therapy may slow down this decline. This study aimed to examine the effect of a 2-year intervention of vitamin B12 and folic acid supplementation on physical performance, handgrip strength, and risk of falling in elderly subjects in a double-blind, randomized placebo-controlled trial. Participants aged ≥65 years with elevated plasma homocysteine concentrations [12-50 µmol/L (n = 2919)] were randomly assigned to daily supplementation of 500 µg vitamin B12, 400 µg folic acid, and 600 IU vitamin D3, or to placebo with 600 IU vitamin D3. Physical performance (range 0-12) and handgrip strength (kg) were measured at baseline and after 2 years. Falls were reported prospectively on a research calendar. Intention-to-treat (primary) and per-protocol (secondary) analyses were performed. Physical performance level and handgrip strength significantly decreased during the follow-up period, but this decline did not differ between groups. Moreover, time to first fall was not significantly different (HR: 1.0, 95% CI 0.9-1.2). Secondary analyses on a per-protocol base identified an interaction effect with age on physical performance. In addition, the treatment was associated with higher follow-up scores on the walking test (cumulative OR: 1.3, 95% CI 1.1-1.5). Two-year supplementation of vitamin B12 and folic acid was neither effective in reducing the age-related decline in physical performance and handgrip strength, nor in the prevention of falling in elderly persons. Despite the overall null-effect, the results provide indications for a positive effect of the intervention on gait, as well as on physical performance among compliant persons >80 years. These effects should be further tested in future studies.

Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial.

INTRODUCTION: Hyperhomocysteinemia is an important cardiovascular risk indicator in the oldest old, and is associated with elevated arterial stiffness in this age group. Since several intervention trials reported a lack of benefit of B-vitamin supplementation on cardiovascular outcomes, we aimed to investigate the effect of B-vitamin supplementation on arterial stiffness and atherosclerosis in hyperhomocysteinemic elderly patients. METHODS: The B-PROOF study is a double-blind, randomized controlled trial, including 2919 elderly aged at least 65 years, with hyperhomocysteinemia (12-50  µmol/l), treated with B-vitamins (500  µg vitamin B12 and 400  µg folic acid) or placebo for 2 years. In a subgroup (n = 569), the effect of B-vitamins on pulse wave velocity (PWV) was investigated as a measurement of arterial stiffness. To measure atherosclerosis, carotid intima-media thickness (IMT) measures had been used. Incidents of cardiovascular and cerebrovascular events were determined via structured questionnaires, and blood pressure was also measured. RESULTS: Compared to placebo, B-vitamin supplementation lowered serum homocysteine by 3.6  µmol/l (P < 0.001). Analysis of covariance showed no effect of supplementation on PWV levels, and this was not different for patients without increased arterial stiffness at baseline. Furthermore, no effect on carotid IMT was observed. DISCUSSION: Vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly patients have no effect on PWV or carotid IMT. Further research will still be necessary to unravel the effects and pathways of homocysteine-lowering treatment on cardiovascular outcomes.

Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial.

High plasma homocysteine (Hcy) levels are associated with increased osteoporotic fracture incidence. However, the mechanism remains unclear. We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) parameters. This randomized, double-blind, placebo-controlled trial included participants aged ≥65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12, 400 µg folic acid, and 600 IU vitamin D or placebo with 600 IU vitamin D only. In total, 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS. Femoral neck (FN) BMD, lumbar spine (LS) BMD, calcaneal broadband ultrasound attenuation (BUA), and calcaneal speed of sound (SOS) were assessed. After 2 years, FN-BMD and BUA had significantly decreased, while LS-BMD significantly increased (all p < 0.01) and SOS did not change in either treatment arm. No statistically significant differences between the intervention and placebo group were present for FN-BMD (p = 0.24), LS-BMD (p = 0.16), SOS (p = 0.67), and BUA (p = 0.96). However, exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons >80 years (estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group, p = 0.04 for difference). In conclusion, this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly, mildly hyperhomocysteinemic persons, but suggests a small beneficial effect on BUA in persons >80 years who were compliant in taking the supplement.

Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial.

BACKGROUND: Elevated plasma homocysteine concentrations are a risk factor for osteoporotic fractures. Lowering homocysteine with combined vitamin B-12 and folic acid supplementation may reduce fracture risk. OBJECTIVE: This study [B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF)] aimed to determine whether vitamin B-12 and folic acid supplementation reduces osteoporotic fracture incidence in hyperhomocysteinemic elderly individuals. DESIGN: This was a double-blind, randomized, placebo-controlled trial in 2919 participants aged ≥65 y with elevated homocysteine concentrations (12-50 µmol/L). Participants were assigned to receive daily 500 µg vitamin B-12 plus 400 µg folic acid or placebo supplementation for 2 y. Both intervention and placebo tablets also contained 600 IU vitamin D3. The primary endpoint was time to first osteoporotic fracture. Exploratory prespecified subgroup analyses were performed in men and women and in individuals younger than and older than age 80 y. Data were analyzed according to intention-to-treat and per-protocol principles. RESULTS: Osteoporotic fractures occurred in 61 persons (4.2%) in the intervention group and 75 persons (5.1%) in the placebo group. Osteoporotic fracture risk was not significantly different between groups in the intention-to-treat analyses (HR: 0.84; 95% CI: 0.58, 1.21) or per-protocol analyses (HR: 0.81; 95% CI: 0.54, 1.21). For persons aged >80 y, in per-protocol analyses, osteoporotic fracture risk was lower in the intervention group than in the placebo group (HR: 0.27; 95% CI: 0.10, 0.74). The total number of adverse events (including mortality) did not differ between groups. However, 63 and 42 participants in the intervention and placebo groups, respectively, reported incident cancer (HR: 1.56; 95% CI: 1.04, 2.31). CONCLUSIONS: These data show that combined vitamin B-12 and folic acid supplementation had no effect on osteoporotic fracture incidence in this elderly population. Exploratory subgroup analyses suggest a beneficial effect on osteoporotic fracture prevention in compliant persons aged >80 y. However, treatment was also associated with increased incidence of cancer, although the study was not designed for assessing cancer outcomes. Therefore, vitamin B-12 plus folic acid supplementation cannot be recommended at present for fracture prevention in elderly people. The B-PROOF study was registered with the Netherlands Trial Register (trialregister.nl) as NTR1333 and at clinicaltrials.gov as NCT00696414.

Results of 2-year vitamin B treatment on cognitive performance: secondary data from an RCT.

OBJECTIVE: We investigated the effects of 2-year folic acid and vitamin B12 supplementation on cognitive performance in elderly people with elevated homocysteine (Hcy) levels. METHODS: This multicenter, double-blind, randomized, placebo-controlled trial included 2,919 elderly participants (65 years and older) with Hcy levels between 12 and 50 µmol/L. Participants received daily either a tablet with 400 µg folic acid and 500 µg vitamin B12 (B-vitamin group) or a placebo tablet. Both tablets contained 15 µg vitamin D3. Data were available for global cognitive functioning assessed by Mini-Mental State Examination (n = 2,556), episodic memory (n = 2,467), attention and working memory (n = 759), information processing speed (n = 731), and executive function (n = 721). RESULTS: Mean age was 74.1 (SD 6.5) years. Hcy concentrations decreased 5.0 (95% confidence interval -5.3 to -4.7) µmol/L in the B-vitamin group and 1.3 (-1.6 to -0.9) µmol/L in the placebo group. Cognitive domain scores did not differ over time between the 2 groups, as determined by analysis of covariance. Mini-Mental State Examination score decreased with 0.1 (-0.2 to 0.0) in the B-vitamin group and 0.3 (-0.4 to -0.2) in the placebo group (p = 0.05), as determined by an independent t test. CONCLUSIONS: Two-year folic acid and vitamin B12 supplementation did not beneficially affect performance on 4 cognitive domains in elderly people with elevated Hcy levels. It may slightly slow the rate of decline of global cognition, but the reported small difference may be attributable to chance. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 2-year supplementation with folic acid and vitamin B12 in hyperhomocysteinemic elderly people does not affect cognitive performance.

Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence.

BACKGROUND: Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk. As vitamin B12 and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration. METHODS/DESIGN: The B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration (≥ 12 µmol/L). One group receives daily a tablet with 500 µg vitamin B12 and 400 µg folic acid and the other group receives a placebo tablet. In both tablets 15 µg (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers, physical performance and physical activity including falls, nutritional intake and status, cognitive function, depression, genetics and quality of life. This large multi-center project is carried out by a consortium from the Erasmus MC (Rotterdam, the Netherlands), VUmc (Amsterdam, the Netherlands) and Wageningen University, (Wageningen, the Netherlands), the latter acting as coordinator. DISCUSSION: To our best knowledge, the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population. We expect the first longitudinal results of the B-PROOF intervention in the second semester of 2013. The results of this intervention will provide evidence on the efficacy of vitamin B12 and folate supplementation in the prevention of osteoporotic fractures. TRIAL REGISTRATION: The B-PROOF study is registered with the Netherlands Trial (NTR NTR1333) and with ClinicalTrials.gov (NCT00696514).