Vitamin D Supplementation and Fractures in Adults: A Systematic Umbrella Review of Meta-Analyses of Controlled Trials.

CONTEXT: The growing number of systematic reviews/meta-analyses (SR/MAs) on vitamin D (±â€…calcium) for fracture prevention has led to contradictory guidelines. OBJECTIVE: This umbrella review aims to assess the quality and explore the reasons for the discrepancy of SR/MAs of trials on vitamin D supplementation for fracture risk reduction in adults. METHODS: We searched 4 databases (2010-2020), Epistemonikos, and references of included SRs/MAs, and we contacted experts in the field. We used A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR-2) for quality assessment. We compared results and investigated reasons for discordance using matrices and subgroup analyses (PROSPERO registration: CRD42019129540). We included 13 SR/MAs on vitamin D and calcium (Ca/D) and 19 SR/MAs on vitamin D alone, compared to placebo/control. RESULTS: Only 2 from 10 SRs/MAs on Ca/D were of moderate quality. Ca/D reduced the risk of hip fractures in 8 of 12 SRs/MAs (relative risk [RR] 0.61-0.84), and any fractures in 7 of 11 SR/MAs (RR 0.74-0.95). No fracture risk reduction was noted in SRs/MAs exclusively evaluating community-dwelling individuals or in those on vitamin D alone compared to placebo/control. Discordance in results between SRs/MAs stems from inclusion of different trials, related to search periods and eligibility criteria, and varying methodology (using intention to treat, per-protocol, or complete case analysis from individual trials). CONCLUSION: Ca/D reduces the risk of hip and any fractures, possibly driven by findings from institutionalized individuals. Individual participant data meta-analyses of patients on Ca/D with sufficient follow-up periods, and subgroup analyses, would unravel determinants for a beneficial response to supplementation.

The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis.

BACKGROUND: Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. This systematic review and meta-analysis assesses the impact of vitamin D status and supplementation on COVID-19 related mortality and health outcomes. METHODS: We searched four databases until December 18th 2020, and trial registries until January 20th 2021. Two reviewers screened the studies, collected data, assessed the risk of bias, and graded the evidence for each outcome across studies, independently and in duplicate. Pre-specified outcomes of interest were mortality, ICU admission, invasive and non-invasive ventilation, hospitalization, time of hospital stay, disease severity and SARS-CoV-2 positivity. We only included data from peer-reviewed articles in our primary analyses. RESULTS: We identified 31 peer-reviewed observational studies. In our primary analysis, there was a positive trend between serum 25(OH)D level <20 ng/ml and an increased risk of mortality, ICU admission, invasive ventilation, non-invasive ventilation or SARS-CoV-2 positivity. However, these associations were not statistically significant. Mean 25(OH)D levels was 5.9 ng/ml (95% CI [-9.5, -2.3]) significantly lower in COVID-19 positive, compared to negative patients. The certainty of the evidence was very low. We identified 32 clinical trial protocols, but only three have published results to-date. The trials administer vitamin D doses of 357 to 60,000 IU/day, from one week to 12 months. Eight megatrials investigate the efficacy of vitamin D in outpatient populations. A pilot trial revealed a significant decrease in ICU admission with calcifediol, compared to placebo (OR = 0.003), but the certainty of the evidence was unclear. Another small trial showed that supplementation with cholecalciferol, 60,000 IU/day, decreased fibrinogen levels, but did not have an effect on D-dimer, procalcitonin and CRP levels, compared to placebo. The third trial did not find any effect of vitamin D supplementation on COVID-19 related health outcomes. CONCLUSION: While the available evidence to-date, from largely poor-quality observational studies, may be viewed as showing a trend for an association between low serum 25(OH)D levels and COVID-19 related health outcomes, this relationship was not found to be statistically significant. Calcifediol supplementation may have a protective effect on COVID-19 related ICU admissions. The current use of high doses of vitamin D in COVID-19 patients is not based on solid evidence. It awaits results from ongoing trials to determine the efficacy, desirable doses, and safety, of vitamin D supplementation to prevent and treat COVID-19 related health outcomes.

Delta-like 1 (DLK1) is a possible mediator of vitamin D effects on bone and energy metabolism.

Vitamin D effects on bone and mineral metabolism are well recognized, and its anti-inflammatory actions are gaining particular interest. Delta-like 1 (DLK1) is a protein, expressed by progenitor cells of different tissues, and increases the size of progenitor cell population during the inflammatory phase of tissue regeneration. DLK1 also plays a role in energy metabolism as it antagonizes insulin signaling in bone. In this one-year randomized clinical trial of overweight elderly individuals that received either 600 or 3750 IU daily cholecalciferol we assessed the effect of vitamin D supplementation on pre-specified secondary outcomes: DLK1, leptin, adiponectin, C-Reactive Protein (CRP) and Vascular Cell Adhesion Molecule (VCAM). We also examined correlations between DLK1 and bone (BMD, bone markers), fat (adipokines, body composition), insulin sensitivity and inflammatory markers. Multivariate analyses were conducted to further explore these associations. Overall, there was a significant increase in serum DLK1 and leptin and a decrease in VCAM, but no change in CRP, after 12 months of vitamin D supplementation. DLK1 was negatively correlated with BMD and positively correlated with bone markers, associations that persisted after adjusting for age, gender and BMI. DLK1 was also positively associated with indices of insulin resistance and negatively with indices of insulin sensitivity. Correlations between DLK1 and fat parameters, such as adipokines, and DXA derived fat mass were less consistent. There were no correlations between DLK1 and inflammatory markers. In conclusion, twelve months supplementation of vitamin D3 increased serum DLK1. DLK1 was negatively associated with indices of bone health and fuel metabolism, and with 1,25(OH)2D levels. Similar to the role of DLK1 in animal models, our findings support the hypothesis that DLK1 can be targeted to regulate bone and energy metabolism and develop drugs to improve BMD and insulin sensitivity. However, further studies are needed to explore the role of DLK1 and its relationship to vitamin D metabolites in vivo.

Vitamin D supplementation in obesity and during weight loss: A review of randomized controlled trials.

Vitamin D deficiency is common in obese individuals and during weight loss. The recommended vitamin D doses in this specific population are higher than for healthy adults. We reviewed vitamin D supplementation trials in obesity, and during medical or surgical weight loss, and report the effects on 25-hydroxyvitamin D [25(OH)D] concentrations and other relevant outcomes. We conducted a systematic search in PubMed, Medline, Embase and the Cochrane library for relevant randomized controlled trials (RCTs) of oral vitamin D supplementation for at least 3 months in obese individuals without weight loss (OB), and those on medical weight loss (MWL) (2010-2018), and following bariatric surgery (Bar S) (without time restriction). Two reviewers screened the identified citations in duplicate and independently and performed full text screening. One reviewer completed data extraction. We identified 13 RCTs in OB, 6 in MWL and 7 in Bar S. Mean baseline 25(OH)D concentrations ranged between 7 and 27 ng/ml in OB, 15-29 ng/ml in MWL and 15-24 ng/ml in Bar S. In OB (Total N 2036 participants), vitamin D doses of 1600-4000 IU/d increased mean 25(OH)D concentrations to ≥30 ng/ml. Based on three trials during MWL (Total N 359 participants), vitamin D doses of 1200-4600 IU/d for 12 months increased 25(OH)D concentration to ≥30 ng/ml. In Bar S (Total N 615 participants), doses ≥2000 IU/d were needed to reach 30 ng/ml. The change in 25(OH)D concentration was inversely proportional to the administered dose, and to BMI and baseline level with doses of 600-3000 IU/day. With these doses, the change in 25(OH)D concentration [Δ25(OH)D] per 100 IU/d was 0.5-1.2 ng/ml. Three trials assessed bone mineral density as a primary outcome, but only one of them showed a protective effect of vitamin D against bone loss at all sites post-Bar S. There was no effect of vitamin D on weight loss. Data on extra-skeletal parameters, namely glycemic and vascular indices were mostly identified in OB, and findings were inconsistent. In conclusion, Vitamin D doses ≥1600-2000 IU/d may be needed to reach a 25(OH)D concentration of 30 ng/ml in obese individuals and following bariatric surgery. The optimal concentration in this population is unknown, and whether the above doses protect against weight loss induced bone loss and fractures still needs to be confirmed. There is no clear evidence for a beneficial effect of vitamin D supplementation on cardio-metabolic parameters in obese individuals, and data on such parameters with weight loss are very scarce. Well-designed long term RCTs assessing the effect of vitamin D supplementation during weight loss on patient important outcomes are needed.