R.A.M. Dhonukshe-Rutten

Vitamin B12, Folate, Homocysteine, and Bone Health in Adults and Elderly People: A Systematic Review with Meta-Analyses

Elevated homocysteine levels and low vitamin B12 and folate levels have been associated with deteriorated bone health. This systematic literature review with dose-response meta-analyses summarizes the available scientific evidence on associations of vitamin B12, folate, and homocysteine status with fractures and bone mineral density (BMD). Twenty-seven eligible cross-sectional (n = 14) and prospective (n = 13) observational studies and one RCT were identified. Meta-analysis on four prospective studies including 7475 people showed a modest decrease in fracture risk of 4% per 50 pmol/L increase in vitamin B12 levels, which was borderline significant (RR = 0.96, 95% CI = 0.92 to 1.00). Meta-analysis of eight studies including 11511 people showed an increased fracture risk of 4% per μmol/L increase in homocysteine concentration (RR = 1.04, 95% CI = 1.02 to 1.07). We could not draw a conclusion regarding folate levels and fracture risk, as too few studies investigated this association. Meta-analyses regarding vitamin B12, folate and homocysteine levels, and BMD were possible in female populations only and showed no associations. Results from studies regarding BMD that could not be included in the meta-analyses were not univocal.

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.

Prioritizing micronutrients for the purpose of reviewing their requirements: a protocol developed by EURRECA

Background:The EURRECA (EURopean micronutrient RECommendations Aligned) Network of Excellence (http://www.eurreca.org) is working towards the development of aligned recommendations. A protocol was required to assign resources to those micronutrients for which recommendations are most in need of alignment.Methods:Three important ‘a priori’ criteria were the basis for ranking micronutrients: (A) the amount of new scientific evidence, particularly from randomized controlled trials; (B) the public health relevance of micronutrients; (C) variations in current micronutrient recommendations. A total of 28 micronutrients were included in the protocol, which was initially undertaken centrally by one person for each of the different population groups defined in EURRECA: infants, children and adolescents, adults, elderly, pregnant and lactating women, and low income and immigrant populations. The results were then reviewed and refined by EURRECAs population group experts. The rankings of the different population groups were combined to give an overall average ranking of micronutrients.Results:The 10 highest ranked micronutrients were vitamin D, iron, folate, vitamin B12, zinc, calcium, vitamin C, selenium, iodine and copper.Conclusions:Micronutrient recommendations should be regularly updated to reflect new scientific nutrition and public health evidence. The strategy of priority setting described in this paper will be a helpful procedure for policy makers and scientific advisory bodies.

Effect of a nutrient-enriched drink on dietary intake and nutritional status in institutionalised elderly

Objective:(1) To determine whether nutritional supplementation (energy and micronutrients) in institutionalised elderly has a positive effect on dietary intake and nutritional status. (2) To investigate whether individuals tend to compensate for the energy content of the intervention product by decreasing their habitual food consumption.Methods:A 24-week, randomised, double-blind, placebo-controlled, intervention trial in homes for the elderly (n=3), in nursing homes (n=3) and ‘mixed’ homes (n=3) in The Netherlands. Institutionalised elderly people (n=176) older than 60 years of age, with a body mass index ⩽30 kg/m2 and a Mini-Mental State Examination score of 10 points or higher, randomly received a nutrient-enriched drink or a placebo drink twice a day during 24 weeks in addition to their usual diet. Allocation to treatment took into account of sex, the Mini-Mental State Examination score and the plasma homocysteine level. Body weight and several nutrition-related analyses in fasting blood samples were measured in all participants. Data on dietary intake were collected in a subsample (n=66).Results:A significantly favourable effect (P<0.001) of the intervention drink was observed on vitamin intake, mineral intake and vitamin status in blood (for example, homocysteine decreased from 14.7 to 9.5 μmol/l in the intervention group as compared with that in the placebo group (17.2–15.9)). The difference in change in total energy intake between the two treatment groups was 0.8 MJ/day (P=0.166). Energy intake from food decreased in both groups to the same extent (−0.5 MJ/day). Therefore, this decrease cannot be considered as compensation for the energy content of the product.Conclusions:This group of institutionalised elderly people does not compensate for the energy content of a concentrated nutritional supplement. Therefore, this supplement is effective for counteracting the development of malnutrition in this population.

Vitamin B12 Intake and Status and Cognitive Function in Elderly People

Current recommendations on vitamin B12 intake vary from 1.4 to 3.0 μg per day and are based on the amount needed for maintenance of hematologic status or on the amount needed to compensate obligatory losses. This systematic review evaluates whether the relation between vitamin B12 intake and cognitive function should be considered for underpinning vitamin B12 recommendations in the future. The authors summarized dose-response evidence from randomized controlled trials and prospective cohort studies on the relation of vitamin B12 intake and status with cognitive function in adults and elderly people. Two randomized controlled trials and 6 cohort studies showed no association or inconsistent associations between vitamin B12 intake and cognitive function. Random-effects meta-analysis showed that serum/plasma vitamin B12 (50 pmol/L) was not associated with risk of dementia (4 cohort studies), global cognition z scores (4 cohort studies), or memory z scores (4 cohort studies). Although dose-response evidence on sensitive markers of vitamin B12 status (methylmalonic acid and holotranscobalamin) was scarce, 4 of 5 cohort studies reported significant associations with risk of dementia, Alzheimers disease, or global cognition. Current evidence on the relation between vitamin B12 intake or status and cognitive function is not sufficient for consideration in the development of vitamin B12 recommendations. Further studies should consider the selection of sensitive markers of vitamin B12 status.

Nutri-RecQuest: a web-based search engine on current micronutrient recommendations

Background:The EURRECA (EURopean micronutrient RECommendations Aligned) Network of Excellence collated current micronutrient recommendations. A user-friendly tool, Nutri-RecQuest, was developed to allow access to the collated data and to create a database source for use in other nutritional software tools.Methods:Recommendations, that is, intakes of micronutrients sufficient to meet the requirements of the majority of healthy individuals of that population, from 37 European countries/organizations and eight key non-European countries/regions comprising 29 micronutrients were entered into a database. General information on the source of the recommendations, as well scientific background information, was added.Results:A user-friendly web-based interface was developed to provide efficient search, comparison, display, print and export functions.Conclusion:Easy access to existing recommendations through the web-based tool may be valuable for bodies responsible for setting recommendations, as well as for users of recommendations including scientists, policy makers, health professionals and industry. Adding related dietary reference values such as average nutrient requirements and upper limits may extend the utility of the tool.

The association between plasma homocysteine levels and bone quality and bone mineral density parameters in older persons

INTRODUCTION High plasma homocysteine levels have been associated with incident osteoporotic fractures, but the mechanisms underlying this association are still unknown. It has been hypothesized that homocysteine might interfere with collagen cross-linking in bone, thereby weakening bone structure. Therefore, we wanted to investigate whether plasma homocysteine levels are associated with bone quality parameters, rather than with bone mineral density. METHODS Cross-sectional data of the B-PROOF study (n=1227) and of two cohorts of the Rotterdam Study (RS-I (n=2850) and RS-II (n=2023)) were used. Data on bone mineral density of the femoral neck and lumbar spine were obtained in these participants using dual-energy X-ray assessment (DXA). In addition, participants of B-PROOF and RS-I underwent quantitative ultrasound measurement of the calcaneus, as a marker for bone quality. Multiple linear regression analysis was used to investigate the associations between natural-log transformed plasma levels of homocysteine and bone mineral density or ultrasound parameters. RESULTS Natural-log transformed homocysteine levels were inversely associated with femoral neck bone mineral density in the two cohorts of the Rotterdam Study (B=-0.025, p=0.004 and B=-0.024, p=0.024). In B-PROOF, no association was found. Pooled data analysis showed significant associations between homocysteine and bone mineral density at both femoral neck (B=-0.032, p=0.010) and lumbar spine (B=-0.098, p=0.021). Higher natural-log transformed homocysteine levels associated significantly with lower bone ultrasound attenuation in B-PROOF (B=-3.7, p=0.009) and speed of sound in both B-PROOF (B=-8.9, p=0.001) and RS-I (B=-14.5, p=0.003), indicating lower bone quality. Pooled analysis confirmed the association between homocysteine and SOS (B=-13.1, p=0.016). Results from ANCOVA-analysis indicate that differences in SOS and BUA between participants having a plasma homocysteine level above or below median correspond to 0.14 and 0.09 SD, respectively. DISCUSSION In this study, plasma levels of homocysteine were significantly inversely associated with both bone ultrasound parameters and with bone mineral density. However, the size of the associations seems to be of limited clinical relevance and may therefore not explain the previously observed association between plasma homocysteine and osteoporotic fracture incidence.

European micronutrient recommendations aligned: a general framework developed by EURRECA

Background:In Europe, micronutrient recommendations have been established by (inter)national committees of experts and are used by public health-policy decision makers to monitor and assess the adequacy of the diets of population groups. Current micronutrient recommendations are, however, heterogeneous, whereas the scientific basis for this is not obvious. Alignment of setting micronutrient recommendations is necessary to improve the transparency of the process, the objectivity and reliability of recommendations that are derived by diverse regional and (inter)national bodies.Objective:This call for alignment of micronutrient recommendations is a direct result of the current sociopolitical climate in Europe and uncovers the need for an institutional architecture. There is a need for evidence-based policy making, transparent decision making, stakeholder involvement and alignment of policies across Europe.Results:In this paper, we propose a General Framework that describes the process leading from assessing nutritional requirements to policy applications, based on evidence from science, stakeholder interests and the sociopolitical context. The framework envisions the derivation of nutrient recommendations as scientific methodology, embedded in a policy-making process that also includes consumer issues, and acknowledges the influences of the wider sociopolitical context by distinguishing the principal components of the framework: (a) defining the nutrient requirements for health, (b) setting nutrient recommendations, (c) policy options and (d) policy applications.Conclusion:The General Framework can serve as a basis for a systematic and transparent approach to the development and review of micronutrient requirements in Europe, as well as the decision making of scientific advisory bodies, policy makers and stakeholders involved in this process of assessing, developing and translating these recommendations into public health nutrition policy.

Explaining the variability in recommended intakes of folate, vitamin B12, iron and zinc for adults and elderly people

OBJECTIVE To signal key issues for harmonising approaches for establishing micronutrient recommendations by explaining observed variation in recommended intakes of folate, vitamin B12, Fe and Zn for adults and elderly people. DESIGN We explored differences in recommended intakes of folate, vitamin B12, Fe and Zn for adults between nine reports on micronutrient recommendations. Approaches used for setting recommendations were compared as well as eminence-based decisions regarding the selection of health indicators indicating adequacy of intakes and the consulted evidence base. RESULTS In nearly all reports, recommendations were based on the average nutrient requirement. Variation in recommended folate intakes (200-400 μg/d) was related to differences in the consulted evidence base, whereas variation in vitamin B12 recommendations (1.4-3.0 μg/d) was due to the selection of different CV (10-20 %) and health indicators (maintenance of haematological status or basal losses). Variation in recommended Fe intakes (men 8-10 mg/d, premenopausal women 14.8-19.6 mg/d, postmenopausal women 7.5-10.0 mg/d) was explained by different assumed reference weights and bioavailability factors (10-18 %). Variation in Zn recommendations (men 7-14 mg/d, women 4.9-9.0 mg/d) was also explained by different bioavailability factors (24-48 %) as well as differences in the consulted evidence base. CONCLUSIONS For the harmonisation of approaches for setting recommended intakes of folate, vitamin B12, Fe and Zn across European countries, standardised methods are needed to (i) select health indicators and define adequate biomarker concentrations, (ii) make assumptions about inter-individual variation in requirements, (iii) derive bioavailability factors and (iv) collate, select, interpret and integrate evidence on requirements.

Homocysteine and the methylenetetrahydrofolate reductase 677C -> T polymorphism in relation to muscle mass and strength, physical performance and postural sway

Background/objectives:Elevated plasma homocysteine has been linked to reduced mobility and muscle functioning in the elderly. The relation of methylenetetrahydrofolate reductase (MTHFR) 677CT polymorphism with these associations has not yet been studied. This study aimed to investigate (1) the association of plasma homocysteine and the MTHFR 677CT polymorphism with muscle mass, handgrip strength, physical performance and postural sway; (2) the interaction between plasma homocysteine and the MTHFR 677CT polymorphism.Subjects/methods:Baseline data from the B-PROOF study (n=2919, mean age=74.1±6.5) were used. Muscle mass was measured using dual X-ray absorptiometry, handgrip strength with a handheld dynamometer, and physical performance with walking-, chair stand- and balance tests. Postural sway was assessed on a force platform. The data were analyzed using regression analyses with plasma homocysteine levels in quartiles.Results:There was a significant inverse association between plasma homocysteine and handgrip strength (quartile 4: regression coefficient B=−1.14, 95% confidence interval (CI)=−1.96; −0.32) and physical performance score (quartile 3: B=−0.53, 95% CI=−0.95; −0.10 and quartile 4: −0.94; 95% CI=−1.40; −0.48) in women only, independent of serum vitamin B12 and folic acid. No association was observed between the MTHFR 677CT polymorphism and the outcomes. High plasma homocysteine in the 677CC and 677CT genotypes, but not in the 677TT genotype, was associated with lower physical performance.Conclusions:Elevated plasma homocysteine concentrations are associated with reduced physical performance and muscle strength in older women. There is an urgent need for randomized controlled trials to examine whether lowering homocysteine levels might delay physical decline.