Long-term effects of folic acid and vitamin-B12 supplementation on fracture risk and cardiovascular disease: extended follow-up of the B-PROOF trial

Background & aims: In the initial B-proof, we found inconsistent results of B vitamin supplementation. However, the debate regarding the effects of B vitamins on age-related diseases continues. Therefore, our aim was to investigate the long-term effects (5-7 years follow-up) of an intervention with folic acid and vitamin-B12 supplementation on fracture and cardiovascular disease risk.Methods: Extended follow-up of the B-PROOF trial, a multi-center, double-blind randomized placebo controlled trial designed to assess the effect of 2-3 years daily supplementation with folic acid (400 mg) and vitamin-B12 (500 mg) versus placebo (n = 2,919). Primary outcome was verified self reported fracture incidence and secondary outcomes were self-reported cardiovascular endpoints, which were collected through a follow-up questionnaires Proportional hazard analyses was used for the effect of the intervention on risk of fracture(s) and logistic regression for the effect of the intervention on risk of cardiovascular disease.Results: A total of 1,298 individuals (4 4.5%) participated in the second follow-up round with median of 54 months [51-58], (n = 662 and n = 636, treatment versus placebo group). Median age at baseline was 71.0 years [68.0-76.0] for both groups. No effect was observed of the intervention on osteoporotic fracture or any fracture risk after a follow-up (HR: 0.99, 95% CI: 0.62-1.59 and HR: 0.77; 95% CI: 0.50-1.19, respectively), nor on cardiovascular or cerebrovascular disease risk (OR: 1.05; 95%CI: 0.80-1.44 and OR: 0.85; 95%CI: 0.50-1.45, respectively). Potential interaction by baseline homocysteine concentration was observed for osteoporotic-and any fracture (p = 0.10 and 0.06 respectively), which indicated a significantly lower risk of any fracture in the treatment group with higher total homocysteine concentrations (>15.1 mmol/l). No age-dependent effects were present.Conclusions: This study supports and extends previous null -findings of the B-PROOF trial and shows that supplementation of folic acid and vitamin-B12 has no effect on fracture risk, nor on cardiovascular disease in older individuals over a longer follow-up period. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with high total homocysteine concentrations, a finding which needs to be replicated. (c) 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.Prevention, Population and Disease management (PrePoD)Public Health and primary car

Low vitamin D status is associated with more depressive symptoms in Dutch older adults

Purpose: The existence of vitamin D receptors in the brain points to a possible role of vitamin D in brain function. We examined the association of vitamin D status and vitamin D-related genetic make-up with depressive symptoms amongst 2839 Dutch older adults aged ≥65 years. Methods: 25-Hydroxyvitamin D (25(OH)D) was measured, and five ‘vitamin D-related genes’ were selected. Depressive symptoms were measured with the 15-point Geriatric Depression Scale. Results were expressed as the relative risk of the score of depressive symptoms by quartiles of 25(OH)D concentration or number of affected alleles, using the lowest quartile or minor allele group as reference. Results: A clear cross-sectional and pr

Discovery of predictors of sudden cardiac arrest in diabetes: rationale and outline of the RESCUED (REcognition of Sudden Cardiac arrest vUlnErability in Diabetes) project

Introduction Early recognition of individuals with increased risk of sudden cardiac arrest (SCA) remains challenging. SCA research so far has used data from cardiologist care, but missed most SCA victims, since they were only in general practitioner (GP) care prior to SCA. Studying individuals with type 2 diabetes (T2D) in GP care may help solve this problem, as they have increased risk for SCA, and rich clinical datasets, since they regularly visit their GP for check-up measurements. This information can be further enriched with extensive genetic and metabolic information. Aim To describe the study protocol of the REcognition of Sudden Cardiac arrest vUlnErability in Diabetes (RESCUED) project, which aims at identifying clinical, genetic and metabolic factors contributing to SCA risk in individuals with T2D, and to develop a prognostic model for the risk of SCA. Methods The RESCUED project combines data from dedicated SCA and T2D cohorts, and GP data, from the same region in the Netherlands. Clinical data, genetic data (common and rare variant analysis) and metabolic data (metabolomics) will be analysed (using classical analysis techniques and machine learning methods) and combined into a prognostic model for risk of SCA. Conclusion The RESCUED project is designed to increase our ability at early recognition of elevated SCA risk through an innovative strategy of focusing on GP data and a multidimensional methodology including clinical, genetic and metabolic analyses.Molecular Epidemiolog

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 I

Cognitive performance: a cross-sectional study on serum vitamin D and its interplay with glucose homeostasis in Dutch older adults

Objectives First, the association between serum 25-hydroxyvitamin D (25[OH]D) and cognitive performance was examined. Second, we assessed whether there was evidence for an interplay between 25(OH)D and glucose homeostasis in the association with cognitive performance. Design, Setting, and Participants Associations were studied using cross-sectional data of 776 (3 domains) up to 2722 (1 domain) Dutch community-dwelling older adults, aged 65 years or older. Measurements Serum 25(OH)D, plasma glucose, and insulin concentrations were obtained. Cognitive performance was assessed with an extensive cognitive test battery. Prevalence ratios (PRs) were calculated to quantify the association between 25(OH)D and cognition; poor performance was defined as the worst 10% of the distribution of the cognitive scores. Results The overall median MMSE score was 29 (IQR 28–30). Higher serum 25(OH)D was associated with better attention and working memory, PR 0.50 (95% CI 0.29–0.84) for the third serum 25(OH)D tertile, indicating a 50% lower probability of being a poor performer than participants in the lowest tertile. Beneficial trends were shown for 25(OH)D with executive function and episodic memory. Serum 25(OH)D was not associated with plasma glucose or insulin. Plasma insulin only modified the association between serum 25(OH)D and executive function (P for interaction: .001), suggesting that the improvement in executive function with high 25(OH)D concentrations is stronger in participants with high plasma insulin concentrations compared with those with low plasma insulin concentrations. Conclusion Higher 25(OH)D concentrations significantly associated with better attention and working memory performance. This study does not demonstrate an interplay between serum 25(OH)D and glucose homeostasis in the association with cognitive performance

Effect of Vitamin B<inf>12</inf> 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 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

Folate and vitamin B12-related biomarkers in relation to brain volumes

Contains fulltext : 162573.pdf (publisher's version ) (Open Access)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 mu-g folic acid and 500 mu-g 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 (beta = -0.91, 95% CI -1.85-0.03; p = 0.06) and between serum folate and TBV (beta = -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.12 p

Vitamin D status is associated with physical performance: the results of three independent cohorts

This study, on the association between vitamin D status and physical performance and its decline, shows that vitamin D status is associated with physical performance in several older age groups. However, vitamin D status does not predict a decline in physical performance in individuals aged 55-65 years. Previous research in the Longitudinal Aging Study Amsterdam (LASA) showed an association of vitamin D status with physical performance and its decline in persons aged 65 years and older. The current study aims to determine these associations in younger individuals and to replicate previous research of LASA. Data from three independent cohorts were used: two cohorts of LASA (LASA-II with measurements in 2002 (n = 707) and 2009 (n = 491), LASA-I-2009 (n = 355)) and the baseline measurement of the B-Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) study (n = 2,813). Participants performed three tests (walking test, chair stands, and tandem stand; range total score 0-12), except in LASA-II-2002 (only walking and chair stands tests; range total score 0-8). Multiple linear and logistic regression were used to assess whether vitamin D status was associated with total physical performance and its decline, respectively. The mean age of the participants was 60.0 (SD 3.0), 65.9 (2.9), 78.4 (5.3), and 74.4 (6.8) years for LASA-II-2002, LASA-II-2009, LASA-I-2009, and B-PROOF, respectively. Vitamin D status was not predictive of a clinical decline in total physical performance score in the LASA-II-2002 cohort (aged 55-65 years). After adjustment for confounding, participants with serum 25(OH)D <50 nmol/L scored 0.8 (95 % confidence interval 0.4-1.2), 0.9 (0.3-1.5), 1.5 (0.8-2.3), and 0.6 (0.3-0.9) points lower on total physical performance than participants with serum 25(OH)D a parts per thousand yenaEuro parts per thousand 75 nmol/L. Our study confirmed that serum 25(OH)D is associated with physical performance. However, vitamin D status did not predict a clinical decline in physical performance in individuals aged 55-65 years

BMI and body fat mass is inversely associated with vitamin D levels in older individuals

Objectives: To assess the association between obesity (measured by Body Mass Index (BMI) and fat percentage) and serum 25(OH)D levels in older persons. Design: Cross-sectional analysis of data from ‘the B-PROOF study’ (B-vitamins for the Prevention Of Osteoporotic Fractures). Participants: 2842 participants aged 65 years and older. Measurements: BMI and fat percentage, measured by Dual Energy X-ray, and serum 25(OH) D levels. Results: Mean age was 74 years (6.5 SD), with 50% women. Mean serum 25(OH)D levels were 55.8 nmol/L (25 SD). BMI and total body fat percentage were significant inversely associated with serum 25(OH)D levels after adjustment for confouders (β−0.93; 95%CI [−1.15; −0.71],

Are higher antidepressant plasma concentrations associated with fall risk in older antidepressant users?

Antidepressants are well-established fall-risk increasing drugs (FRIDs) and therefore falls should be considered an important adverse drug event (ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. Methods: For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry (LC–MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. Results: In total 93 selective serotonin reuptake inhibitor (SSRI) and 41 antidepressant (TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07–5.87, crude model). In the adjusted model, there were no significant associations between concentrations of SSRIs and fall risk. Conclusion: There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, these novel findings need to replicated in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed