Comparison of the Effect of Daily Vitamin D2 and Vitamin D3 Supplementation on Serum 25-Hydroxyvitamin D Concentration (Total 25(OH)D, 25(OH)D2, and 25(OH)D3) and Importance of Body Mass Index: A Systematic Review and Meta-Analysis.

BACKGROUND: Two previous meta-analyses showed smaller differences between vitamin D3 and vitamin D2 in raising serum 25-hydroxyvitamin D [25(OH)D] and a consistently high heterogeneity when only including daily dosing studies. OBJECTIVE: This study aimed to compare more frequently dosed vitamin D2 and vitamin D3 in improving total 25(OH)D and determine the concomitant effect of response modifiers on heterogeneity, and secondly, to compare the vitamin D2-associated change in 25(OH)D2 with the vitamin D3-associated change in 25(OH)D3. METHODS: PubMed, EMBASE, Cochrane, and the Web of Science Core collection were searched for randomized controlled trials of vitamin D2 compared with vitamin D3, daily or once/twice weekly dosed. After screening for eligibility, relevant data were extracted for meta-analyses to determine the standardized mean difference when different methods of 25(OH)D analyses were used. Otherwise, the weighted mean difference (WMD) was determined. RESULTS: Overall, the results based on 20 comparative studies showed vitamin D3 to be superior to vitamin D2 in raising total 25(OH)D concentrations, but vitamin D2 and vitamin D3 had a similar positive impact on their corresponding 25(OH)D hydroxylated forms. The WMD in change in total 25(OH)D based on 12 daily dosed vitamin D2-vitamin D3 comparisons, analyzed using liquid chromatography-tandem mass spectrometry, was 10.39 nmol/L (40%) lower for the vitamin D2 group compared with the vitamin D3 group (95% confidence interval: -14.62, -6.16; I2 = 64%; P < 00001). Body mass index (BMI) appeared to be the strongest response modifier, reducing heterogeneity to 0% in both subgroups. The vitamin D2- and vitamin D3-induced change in total 25(OH)D lost significance predominantly in subjects with a BMI >25 kg/m2 (P = 0.99). However, information on BMI was only available in 13/17 daily dosed comparisons. CONCLUSIONS: Vitamin D3 leads to a greater increase of 25(OH)D than vitamin D2, even if limited to daily dose studies, but vitamin D2 and vitamin D3 had similar positive impacts on their corresponding 25(OH)D hydroxylated forms. Next to baseline 25(OH)D concentration, BMI should be considered when comparing the effect of daily vitamin D2 and vitamin D3 supplementation on total 25(OH)D concentration. This study was registered in PROSPERO as CRD42021272674.

High-intensity versus low-intensity resistance training in patients with knee osteoarthritis: A randomized controlled trial.

OBJECTIVES: To assess whether (i) high-intensity resistance training (RT) leads to increased muscle strength compared to low-intensity RT in patients with knee osteoarthritis (OA); and (ii) RT with vitamin D supplementation leads to increased muscle strength compared to placebo in a subgroup with vitamin D deficiency. DESIGN: Randomized controlled trial. SETTING: Outpatient rehabilitation centre. SUBJECTS: Patients with knee OA. INTERVENTIONS: 12 weeks of RT at high-intensity RT (70-80% of 1-repetition maximum (1-RM)) or low-intensity RT (40-50% of 1-RM) and 24 weeks of vitamin D (1200 International units vitamin D3 per day) or placebo supplementation. MAIN MEASURES: Primary outcome measure was isokinetic muscle strength. Other outcome measure for muscle strength was the estimated 1-RM. Secondary outcome measures were knee pain and physical functioning. RESULTS: 177 participants with a mean age of 67.6 ± 5.8 years were included, of whom 50 had vitamin D deficiency. Isokinetic muscle strength (in Newton metre per kilogram bodyweight) at start, end and 24 weeks after the RT was 0.98 ± 0.40, 1.11 ± 0.40, 1.09 ± 0.42 in the high-intensity group and 1.02 ± 0.41, 1.15 ± 0.42, 1.12 ± 0.40 in the low-intensity group, respectively. No differences were found between the groups, except for the estimated 1-RM in favour of the high-intensity group. In the subgroup with vitamin D deficiency, no difference on isokinetic muscle strength was found between the vitamin D and placebo group. CONCLUSIONS: High-intensity RT did not result in greater improvements in isokinetic muscle strength, pain and physical functioning compared to low-intensity RT in knee OA, but was well tolerated. Therefore these results suggest that either intensity of resistance training could be utilised in exercise programmes for patients with knee osteoarthritis. No synergistic effect of vitamin D supplementation and RT was found, but this finding was based on underpowered data.

Trends in Vitamin D Status Around the World.

Vitamin D status varies across all continents and countries. Vitamin D status usually is adequate in Latin America and Australia, but in contrast it is very low in the Middle East and some countries in Asia. Trends in vitamin D status, whether it improves or declines over the years, carry important messages. Trends usually are small, but can be predictors and indicators of general health. Vitamin D status has improved in the older population in the United States, and improvement relates to dairy use and vitamin D supplements. To the contrary, vitamin D status has declined in the Inuit population of Canada due to a change from a traditional fish diet to a Western diet. A large improvement was seen in Finland after mandatory fortification of dairy products was introduced. Determinants of decline are less sun exposure, increased use of sunscreen, increase of body mass index (BMI), less physical activity, and poor socioeconomic status. Determinants of increase are food fortification with vitamin D and vitamin D supplements. Food fortification can lead to a population-wide increase in vitamin D status as shown by the Finnish example. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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 µg) and vitamin-B12 (500 µg) 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 (44.5%) 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 µmol/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.

B-vitamins and body composition: integrating observational and experimental evidence from the B-PROOF study.

PURPOSE: Higher folate and vitamin-B12 have been linked to lower risk of overweight. However, whether this is a causal effect of these B-vitamins on obesity risk remains unclear and evidence in older individuals is scarce. This study aimed to assess the role of B-vitamin supplementation and levels on body composition in older individuals. METHODS: A double-blind, randomized controlled trial in 2919 participants aged ≥ 65 years with elevated homocysteine levels. The intervention comprised a 2-year supplementation with a combination of folic acid (400 µg) and vitamin B12 (500 µg), or with placebo. Serum folate, vitamin-B12, active vitamin-B12 (HoloTC), methylmalonic acid (MMA), and anthropometrics were measured at baseline and after 2 years of follow-up. Dietary intake of folate and vitamin-B12 was measured at baseline in a subsample (n = 603) using a validated food-frequency questionnaire. Fat mass index (FMI) and fat-free mass index (FFMI) were assessed with Dual Energy X-ray absorptiometry (DXA). RESULTS: Cross-sectional analyses showed that a 1 nmol/L higher serum folate was associated with a 0.021 kg/m2 lower BMI (95% CI - 0.039; - 0.004). Higher HoloTC (per pmol/L log-transformed) was associated with a 0.955 kg/m2 higher FMI (95% CI 0.262; 1.647), and higher MMA (per µgmol/L) was associated with a 1.108 kg/m2 lower FMI (95% CI - 1.899; - 0.316). However, random allocation of B-vitamins did not have a significant effect on changes in BMI, FMI or FFMI during 2 years of intervention. CONCLUSIONS: Although observational data suggested that folate and vitamin B12 status are associated with body composition, random allocation of a supplement with both B-vitamins combined versus placebo did not confirm an effect on BMI or body composition.

Vitamin D supplementation for the prevention of depression and poor physical function in older persons: the D-Vitaal study, a randomized clinical trial.

BACKGROUND: Depressive symptoms and impaired physical functioning are prevalent among older adults. Supplementation with vitamin D might improve both conditions, particularly in persons with low vitamin D status. OBJECTIVE: The D-Vitaal study primarily aimed to investigate the effect of vitamin D supplementation on depressive symptoms, functional limitations, and physical performance in a high-risk older population with low vitamin D status. Secondary aims included examining the effect of vitamin D supplementation on anxiety symptoms, cognitive functioning, mobility, handgrip strength, and health-related quality of life. METHODS: This study was a randomized placebo-controlled trial with 155 participants aged 60-80 y who had clinically relevant depressive symptoms, ≥1 functional limitations, and serum 25-hydroxyvitamin D [25(OH)D] concentrations of 15-50/70 nmol/L (depending on season). Participants received 1200 IU/d vitamin D3 (n = 77) or placebo tablets (n = 78) for 12 mo. Serum 25(OH)D was measured at baseline and 6 mo; outcomes were assessed at baseline, 6 mo, and 12 mo. Linear mixed-models analyses were conducted to assess the effect of the intervention. RESULTS: The supplementation increased serum 25(OH)D concentrations in the intervention group to a mean ± SD of 85 ± 16 nmol/L compared with 43 ± 18 nmol/L in the placebo group after 6 mo (P < 0.001). No relevant differences between the treatment groups were observed regarding depressive symptoms, functional limitations, physical performance, or any of the secondary outcomes. CONCLUSIONS: Supplementation with 1200 IU/d vitamin D for 12 mo had no effect on depressive symptoms and physical functioning in older persons with relatively low vitamin D status, clinically relevant depressive symptoms, and poor physical functioning. This trial is registered with the Netherlands Trial Register (www.trialregister.nl) under NTR3845.

Effect of 6-Month Vitamin D Supplementation on Plasma Matrix Gla Protein in Older Adults.

Vitamin D supplementation has been widely promoted to restore 25-hydroxyvitamin D concentrations; however, experimental evidence suggests a nutrient interaction with vitamin K. We assessed the effects of 1200 IU vitamin D3 per day versus placebo for six months on vitamin K status in a randomized, double-blind, placebo-controlled trial with participants aged 60⁻80 years with depressive symptoms and ≥1 functional limitation for a secondary analysis. Stored baseline and six-month follow-up blood samples were available for 131 participants (n = 65 placebo vs. n = 66 vitamin D supplementation). We measured dephosphorylated uncarboxylated matrix gla protein (MGP) (dp-ucMGP) concentrations-a marker of vitamin K deficiency. Mean age was 68 years, and 89 participants (68%) were women. Vitamin K antagonists were used by 16 participants and multivitamin supplements by 50 participants. No differences in change between intervention and placebo were found (-38.5 ± 389 vs. 4.5 ± 127 (pmol/L), p = 0.562). When excluding vitamin K antagonist users and multivitamin users, dp-ucMGP at follow-up was significantly higher in the vitamin D group (n = 40) compared to placebo (n = 30), with a difference of 92.8 (5.7, 180) pmol/L, adjusting for baseline dp-ucMGP and sex. In conclusion, vitamin D supplementation for six months did not affect vitamin K status; however, among participants without vitamin K antagonist or multivitamin use, vitamin D supplementation influenced dp-ucMGP concentrations.

Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial.

BACKGROUND: Folic acid and vitamin B12 play key roles in one-carbon metabolism. Disruption of one-carbon metabolism may be involved in the risk of cancer. Our aim was to assess the long-term effect of supplementation with both folic acid and vitamin B12 on the incidence of overall cancer and on colorectal cancer in the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) trial. METHODS: Long-term follow-up of B-PROOF trial participants (N = 2,524), a multicenter, double-blind randomized placebo-controlled trial designed to assess the effect of 2 to 3 years daily supplementation with folic acid (400 µg) and vitamin B12 (500 µg) versus placebo on fracture incidence. Information on cancer incidence was obtained from the Netherlands cancer registry (Integraal Kankercentrum Nederland), using the International Statistical Classification of Disease (ICD-10) codes C00-C97 for all cancers (except C44 for skin cancer), and C18-C20 for colorectal cancer. RESULTS: Allocation to B vitamins was associated with a higher risk of overall cancer [171 (13.6%) vs. 143 (11.3%); HR 1.25; 95% confidence interval (CI), 1.00-1.53, P = 0.05]. B vitamins were significantly associated with a higher risk of colorectal cancer [43(3.4%) vs. 25(2.0%); HR 1.77; 95% CI, 1.08-2.90, P = 0.02]. CONCLUSIONS: Folic acid and vitamin B12 supplementation was associated with an increased risk of colorectal cancer. IMPACT: Our findings suggest that folic acid and vitamin B12 supplementation may increase the risk of colorectal cancer. Further confirmation in larger studies and in meta-analyses combining both folic acid and vitamin B12 are needed to evaluate whether folic acid and vitamin B12 supplementation should be limited to patients with a known indication, such as a proven deficiency.

Rationale and Plan for Vitamin D Food Fortification: A Review and Guidance Paper.

Vitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may also prevent extraskeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications and premature deaths. Vitamin D has a unique metabolism as it is mainly obtained through synthesis in the skin under the influence of sunlight (i.e., ultraviolet-B radiation) whereas intake by nutrition traditionally plays a relatively minor role. Dietary guidelines for vitamin D are based on a consensus that serum 25-hydroxyvitamin D (25[OH]D) concentrations are used to assess vitamin D status, with the recommended target concentrations ranging from ≥25 to ≥50 nmol/L (≥10-≥20 ng/mL), corresponding to a daily vitamin D intake of 10 to 20 µg (400-800 international units). Most populations fail to meet these recommended dietary vitamin D requirements. In Europe, 25(OH)D concentrations <30 nmol/L (12 ng/mL) and <50 nmol/L (20 ng/mL) are present in 13.0 and 40.4% of the general population, respectively. This substantial gap between officially recommended dietary reference intakes for vitamin D and the high prevalence of vitamin D deficiency in the general population requires action from health authorities. Promotion of a healthier lifestyle with more outdoor activities and optimal nutrition are definitely warranted but will not erase vitamin D deficiency and must, in the case of sunlight exposure, be well balanced with regard to potential adverse effects such as skin cancer. Intake of vitamin D supplements is limited by relatively poor adherence (in particular in individuals with low-socioeconomic status) and potential for overdosing. Systematic vitamin D food fortification is, however, an effective approach to improve vitamin D status in the general population, and this has already been introduced by countries such as the US, Canada, India, and Finland. Recent advances in our knowledge on the safety of vitamin D treatment, the dose-response relationship of vitamin D intake and 25(OH)D levels, as well as data on the effectiveness of vitamin D fortification in countries such as Finland provide a solid basis to introduce and modify vitamin D food fortification in order to improve public health with this likewise cost-effective approach.

Effects of vitamin D supplementation on markers for cardiovascular disease and type 2 diabetes: an individual participant data meta-analysis of randomized controlled trials.

Background: Evidence from randomized controlled trials (RCTs) for the causal role of vitamin D on noncommunicable disease outcomes is inconclusive. Objective: The aim of this study was to investigate whether there are beneficial or harmful effects of cholecalciferol (vitamin D3) supplementation according to subgroups of remeasured serum 25-hydroxyvitamin D [25(OH)D] on cardiovascular and glucometabolic surrogate markers with the use of individual participant data (IPD) meta-analysis of RCTs. Design: Twelve RCTs (16 wk to 1 y of follow-up) were included. For standardization, 25(OH)D concentrations for all participants (n = 2994) at baseline and postintervention were re-measured in bio-banked serum samples with the use of a certified liquid chromatography-tandem mass spectrometry method traceable to a reference measurement procedure. IPD meta-analyses were performed according to subgroups of remeasured 25(OH)D. Main outcomes were blood pressure and glycated hemoglobin (HbA1c). Secondary outcomes were LDL, HDL, and total cholesterol and triglycerides; parathyroid hormone (PTH); fasting glucose, insulin, and C-peptide; and 2-h glucose. In secondary analyses, other potential effect modifiers were studied. Results: Remeasurement of 25(OH)D resulted in a lower mean 25(OH)D concentration in 10 of 12 RCTs. Vitamin D supplementation had no effect on the main outcomes of blood pressure and HbA1c. Supplementation resulted in 10-20% lower PTH concentrations, irrespective of the 25(OH)D subgroups. The subgroup analyses according to achieved 25(OH)D concentrations showed a significant decrease in LDL-cholesterol concentrations after vitamin D supplementation in 25(OH)D subgroups with <75, <100, and <125 nmol of -0.10 mmol/L (95% CI: -0.20, -0.00 mmol/L), -0.10 mmol/L (95% CI: -0.18, -0.02 mmol/L), and -0.07 mmol/L (95% CI: -0.14, -0.00 mmol/L), respectively. Patient features that modified the treatment effect could not be identified. Conclusions: For the main outcomes of blood pressure and HbA1c, the data support no benefit for vitamin D supplementation. For the secondary outcomes, in addition to its effect on PTH, we observed indications for a beneficial effect of vitamin D supplementation only on LDL cholesterol, which warrants further investigation. This trial was registered at www.clinicaltrials.gov as NCT02551835.

Non-skeletal health effects of vitamin D supplementation: A systematic review on findings from meta-analyses summarizing trial data.

BACKGROUND: A large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D (25OHD) levels on non-skeletal outcomes. We performed a systematic quantitative review on characteristics of randomized clinical trials (RCTs) included in meta-analyses (MAs) on non-skeletal effects of vitamin D supplementation. METHODS AND FINDINGS: We identified systematic reviews (SR) reporting summary data in terms of MAs of RCTs on selected non-skeletal outcomes. For each outcome, we summarized the results from available SRs and scrutinized included RCTs for a number of predefined characteristics. We identified 54 SRs including data from 210 RCTs. Most MAs as well as the individual RCTs reported null-findings on risk of cardiovascular diseases, type 2 diabetes, weight-loss, and malignant diseases. Beneficial effects of vitamin D supplementation was reported in 1 of 4 MAs on depression, 2 of 9 MAs on blood pressure, 3 of 7 MAs on respiratory tract infections, and 8 of 12 MAs on mortality. Most RCTs have primarily been performed to determine skeletal outcomes, whereas non-skeletal effects have been assessed as secondary outcomes. Only one-third of the RCTs had low level of 25OHD as a criterion for inclusion and a mean baseline 25OHD level below 50 nmol/L was only present in less than half of the analyses. CONCLUSIONS: Published RCTs have mostly been performed in populations without low 25OHD levels. The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels.

Changes in vitamin D endocrinology during aging in adults.

Worldwide, vitamin D deficiency is a common finding. Within individuals 25-hydroxyvitamin D (25OH)D) concentrations remain fairly stable over time although large differences in individual longitudinal changes exist. During aging vitamin D metabolism and activity changes in several different ways. Intestinal resistance to 1,25(OH)2D develops which hampers intestinal calcium uptake. Vitamin D receptor number decreases with aging in several organs involved in calcium metabolism and 1alpha-hydroxylase activity decreases mainly due to a decrease in renal function reducing vitamin D activation. Effects of 1,25(OH)2D on cell proliferation and differentiation may influence potential anti-cancer effects whereas regulation of telomere length may result in longevity. In older individuals, vitamin D supplementation has positive effects on fracture risk, number of falls and physical function. Supplementation in older populations warrants specific attention. Effects on "non-classical" outcomes may be revealed by ongoing large randomized clinical trials with high doses of vitamin D.

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.

Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia.

B-vitamin trials failed to demonstrate beneficial effects on cardiovascular outcomes, but hyperhomocysteinemia still stands out as an independent cardiovascular risk factor, particularly in elderly individuals. B-vitamins may influence early vascular dysfunction, such as endothelial dysfunction, or may have adverse effects, for example on inflammation. We investigated the effect of B-vitamins on endothelial function and inflammation within an interventional study. This study was conducted within the framework of the B-PROOF trial, which included 2919 hyperhomocysteinemic elderly individuals, who received daily vitamin B12 (500 µg) and folic acid (400 µg) or placebo for 2 years. Using an electrochemiluminescence platform, we measured intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), serum amyloid A (SAA), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) at baseline and follow-up in a subsample of 522 participants (271 intervention group; 251 placebo). Treatment effects were analyzed with ANCOVA. The participants had a mean age of 72 years, and 55% of them were male. At the 2-year follow-up, B-vitamins did not change the ICAM-1 (+36% change in the intervention group versus +32% change in the placebo group; p = 0.72), VCAM-1 (+27% vs +25%; p = 0.39), VEGF (-1% vs +4%; p = 0.40), SAA (+34% vs +38%; p = 0.85) or CRP levels (+26% vs +36%; p = 0.70) as compared to placebo. In conclusion, in elderly patients with hyperhomocysteinemia, vitamin B12 and folic acid are unlikely to influence either endothelial function or low-grade systemic inflammation. ClinicalTrials.gov Identifier: NCT00696514.

Systematic Review of the Relationship between Vitamin D and Parkinson's Disease.

BACKGROUND: Although vitamin D may have both protective and symptomatic effects in Parkinson's disease (PD), the evidence is scarce and not well understood. Also, 25-hydroxyvitamin D (vitamin D) is suggested to play a neuroprotective and neurotrophic role in the brain. Therefore, this review investigates the relationship between vitamin D and PD. OBJECTIVE: Investigate the evidence for a relationship between vitamin D and PD by summarizing observational and interventional studies in humans, as well as relevant experimental studies. METHODS: A systematic search was made in the Medline, Cochrane and Embase databases (from inception to March 2014). All identified titles were independently evaluated by two reviewers. Articles were selected based on the presence of PD-related outcome data. Included were observational studies (including genetic studies) and interventional studies in humans, as well as relevant animal studies. RESULTS: A total of 20 studies (14 observational, 1 interventional and 5 rodent studies) were selected for analysis. Eight observational studies showed that serum 25(OH) D levels tend to be low in PD. One observational study indicated that low serum 25(OH) D may worsen automatic postural responses and one interventional study suggested that vitamin D supplementation can prevent worsening (based on the Hoehn and Yahr rating scale). Studies in rodent models of PD showed a protective effect of vitamin D treatment on dopaminergic neurons in the substantia nigra. Results of genetic studies on the association between vitamin D receptor polymorphisms and the risk of PD were contradictory. CONCLUSION: The literature supports possible protective and symptomatic effects of vitamin D in PD. However, more observational and interventional studies in humans are needed to confirm and further elucidate the suggested beneficial effect of vitamin D on PD.

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.

The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects.

BACKGROUND: Folate and its synthetic form folic acid function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B12 on bone fracture incidence (B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study). Participants with mildly elevated homocysteine levels, aged 65-75 years, were randomly assigned to take 400 µg folic acid and 500 µg vitamin B12 per day or a placebo during an intervention period of 2 years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n = 44 folic acid/vitamin B12, n = 43 placebo) using the Infinium HumanMethylation450 BeadChip. RESULTS: After intervention with folic acid and vitamin B12, 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B12 versus placebo revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development. Furthermore, serum levels of folate and vitamin B12 or plasma homocysteine were related to DNA methylation of 173, 425, and 11 regions, respectively. Interestingly, for several members of the developmental HOX genes, DNA methylation was related to serum levels of folate. CONCLUSIONS: Long-term supplementation with folic acid and vitamin B12 in elderly subjects resulted in effects on DNA methylation of several genes, among which genes implicated in developmental processes.

Vitamin D supplementation to prevent depression and poor physical function in older adults: Study protocol of the D-Vitaal study, a randomized placebo-controlled clinical trial.

BACKGROUND: Depressive symptoms and decreased physical functioning are interrelated conditions and common in older persons, causing significant individual and societal burden. Evidence suggests that vitamin D supplementation may be beneficial for both mental and physical functioning. However, previous randomized controlled trials have yielded inconsistent results and often had suboptimal designs. This study examines the effect of vitamin D supplementation on both depressive symptoms and physical functioning in a high-risk population of older persons with low vitamin D status. METHODS/DESIGN: The D-Vitaal study is a randomized, double-blind, placebo-controlled trial investigating the effects of a daily dose of 1200 IU vitamin D3 versus placebo for one year on depressive symptoms and physical functioning (primary outcomes) in older adults. Participants (N = 155, age 60-80 years) were recruited from the general population. Eligibility criteria included the presence of depressive symptoms, ≥1 functional limitation and serum 25-hydroxyvitamin D levels between 15 and 50/70 nmol/L (depending on season). Secondary outcomes include incidence of major depressive disorder, anxiety symptoms, health-related quality of life, cognitive function and cost-effectiveness of the intervention. DISCUSSION: With this study, we aim to elucidate the effects of vitamin D supplementation on depressive symptoms and physical functioning in older persons who are at high risk of developing more substantial mental and physical problems. If effective, vitamin D supplementation can be a preventive intervention strategy that is easy to implement in the primary care setting. TRIAL REGISTRATION: Netherlands Trial Register NTR3845. Registered 6 February 2013.

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.