Vitamin D status and supplementation before and after Bariatric Surgery: Recommendations based on a systematic review and meta-analysis.

Bariatric surgery is associated with a postoperative reduction of 25(OH) vitamin D levels (25(OH)D) and with skeletal complications. Currently, guidelines for 25(OH)D assessment and vitamin D supplementation in bariatric patients, pre- and post-surgery, are still lacking. The aim of this work is to analyse systematically the published experience on 25(OH)D status and vitamin D supplementation, pre- and post-surgery, and to propose, on this basis, recommendations for management. Preoperatively, 18 studies including 2,869 patients were evaluated. Prevalence of vitamin D insufficiency as defined by 25(OH)D < 30 ng/mL (75 nmol/L) was 85%, whereas when defined by 25(OH)D < 20 ng/mL (50 nmol/L) was 57%. The median preoperative 25(OH)D level was 19.75 ng/mL. After surgery, 39 studies including 5,296 patients were analysed and among those undergoing either malabsorptive or restrictive procedures, a lower rate of vitamin D insufficiency and higher 25(OH)D levels postoperatively were observed in patients treated with high-dose oral vitamin D supplementation, defined as ≥ 2,000 IU/daily (mostly D3-formulation), compared with low-doses (< 2,000 IU/daily). Our recommendations based on this systematic review and meta-analysis should help clinical practice in the assessment and management of vitamin D status before and after bariatric surgery. Assessment of vitamin D should be performed pre- and postoperatively in all patients undergoing bariatric surgery. Regardless of the type of procedure, high-dose supplementation is recommended in patients after bariatric surgery.

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.

Impact of vitamin D supplementation on falls and fractures-A critical appraisal of the quality of the evidence and an overview of the available guidelines.

INTRODUCTION: The beneficial effect of vitamin D supplementation on musculo-skeletal outcomes have been recently questioned and recommendations regarding supplementation vary widely. The aim of this paper is to systematically assess the quality of the evidence evaluating the effect of vitamin D supplementation on falls and fractures. METHODS: We conducted a systematic search in Medline, PubMed, and Embase and selected systematic reviews (SRs) / meta-analyses (MAs) of randomized controlled trials (RCTs) on vitamin D supplementation and falls or fracture, published between 2012 - 2018. We identified 5 MAs of RCTs on falls, 4 on fractures and 4 on both outcomes. We applied the critical appraisal tool "A MeaSurement Tool to Assess systematic Reviews 2" - AMSTAR 2 - to assess the quality of the identified MAs. RESULTS: Vitamin D and calcium supplementation (CaD), compared to calcium only or placebo, may reduce the risk of falls, in institutionalized individuals and/or those from the community, but the data is inconsistent. The largest and most consistent evidence for a protective effect of CaD, compared to placebo or control, is in reducing the risk of hip fracture, by 16-33%, and any fracture, by 5-19%. This effect was demonstrated when combining trials in community-dwelling and institutionalized individuals, potentially driven by data from institutionalized individuals as shown in 3 SRs/MAs. Major limitations to the quality of the evidence include variability in the methodology of MAs, but more importantly, differences between trials in terms of subjects' characteristics, vitamin D regimens, outcome definition and ascertainment, risk of bias, trial duration and/or low power. The quality of the included MAs was moderate to critically low. CONCLUSIONS: While the effect on falls is inconsistent, CaD reduces the risk of fracture (hip and any fracture), as shown in meta-analyses pooling data of studies combining institutionalized and community individuals. The evidence is however limited by major shortcomings and heterogeneity.

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.

Vitamin D in the Middle East and North Africa.

PURPOSE: The Middle East and North Africa (MENA) region registers some of the lowest serum 25­hydroxyvitamin D [25(OH)D] concentrations, worldwide. We describe the prevalence and the risk factors for hypovitaminosis D, completed and ongoing clinical trials, and available guidelines for vitamin D supplementation in this region. METHODS: This review is an update of previous reviews published by our group in 2013 for observational studies, and in 2015 for randomized controlled trials (RCTs) from the region. We conducted a comprehensive search in Medline, PubMed, and Embase, and the Cochrane Library, using MeSH terms and keywords relevant to vitamin D, vitamin D deficiency, and the MENA region, for the period 2012-2017 for observational studies, and 2015-2017 for RCTs. We included large cross-sectional studies with at least 100 subjects/study, and RCTs with at least 50 participants per arm. RESULTS: We identified 41 observational studies. The prevalence of hypovitaminosis D, defined as a 25­hydroxyvitamin D [25(OH)D] level below the desirable level of 20 ng/ml, ranged between 12-96% in children and adolescents, and 54-90% in pregnant women. In adults, it ranged between 44 and 96%, and the mean 25(OH)D varied between 11 and 20 ng/ml. In general, significant predictors of low 25(OH)D levels were female gender, increasing age and body mass index, veiling, winter season, use of sun screens, lower socioeconomic status, and higher latitude.We retrieved 14 RCTs comparing supplementation to control or placebo, published during the period 2015-2017: 2 in children, 8 in adults, and 4 in pregnant women. In children and adolescents, a vitamin D dose of 1000-2000 IU/d was needed to maintain serum 25(OH)D level at target. In adults and pregnant women, the increment in 25(OH)D level was inversely proportional to the dose, ranging between 0.9 and 3 ng/ml per 100 IU/d for doses ≤2000 IU/d, and between 0.1 and 0.6 ng/ml per 100 IU/d for doses ≥3000 IU/d. While the effect of vitamin D supplementation on glycemic indices is still controversial in adults, vitamin D supplementation may be protective against gestational diabetes mellitus in pregnant women. In the only identified study in the elderly, there was no significant difference between 600 IU/day and 3750 IU/day doses on bone mineral density. We did not identify any fracture studies.The available vitamin D guidelines in the region are based on expert opinion, with recommended doses between 400 and 2000 IU/d, depending on the age category, and country. CONCLUSION: Hypovitaminosis D is prevalent in the MENA region, and doses of 1000-2000 IU/d may be necessary to reach a desirable 25(OH)D level of 20 ng/ml. Studies assessing the effect of such doses of vitamin D on major outcomes, and confirming their long term safety, are needed.

Vitamin D replacement in children, adolescents and pregnant women in the Middle East and North Africa: A systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Hypovitaminosis D affects one-third to two-thirds of children and pregnant women from the Middle East and North Africa (MENA) region. OBJECTIVE: To evaluate in infants, children, adolescents and pregnant women, from the MENA region, the effect of supplementation with different vitamin D doses on the change in 25-hydroxyvitamin D [25(OH)D] level reached, and other skeletal and non-skeletal outcomes. METHODS: This is a systematic review of randomized controlled trials of vitamin D supplementation conducted in the MENA region. We conducted a comprehensive literature search in 7 databases, without language or time restriction, until November 2016. Two reviewers abstracted data from the included studies, independently and in duplicate. We calculated the mean difference (MD) and 95% CI of 25(OH)D level reached when at least 2 studies were eligible in each comparison (low (<800IU), intermediate (800-2000IU) or high (>2000IU) daily dose of vitamin D, or placebo). We pooled data using RevMan version 5.3. RESULTS: We identified a total of 15 eligible trials: one in infants, 4 in children and adolescents and 10 in pregnant women. In children and adolescents, an intermediate vitamin D dose (1901IU/d), resulted in a mean difference in 25(OH)D level of 13.5 (95% confidence interval (CI) 8.1-18.8) ng/ml, compared to placebo, favoring the intermediate dose (p<0.001). The proportion of children and adolescents reaching a 25(OH)D level≥ 20ng/ml was 74% in the intermediate dose group. In pregnant women, four trials started supplementation at 12-16weeks of gestation and continued until delivery, and six trials started supplementation at 20-28weeks' gestation and stopped it at delivery. The MD in 25(OH)D level reached was 8.6 (95% CI 5.3-11.9) ng/ml (p<0.001) comparing the high dose (3662IU/d) to the intermediate dose (1836IU/d), and 12.3 (95% CI 6.4-18.2) ng/ml (p<0.001), comparing the high dose (3399IU/d) to the low dose (375IU/d). Comparing the intermediate (1832IU/d) to the low dose (301IU/d), the MD in 25(OH)D level achieved was 7.8 (95% CI 4.5-10.8) ng/ml (p<0.001). The proportion of pregnant women reaching a 25(OH)D level≥20ng/ml was 80%-90%, 73% and 27%-43% in the high, intermediate, and low dose groups, respectively. The risk of bias in the included studies, for children, adolescents and pregnant women, ranged from low to high across all doamins. CONCLUSION: In children, adolescents and pregnant women from the MENA, an intermediate vitamin D dose of 1000-2000IU daily may be necessary to allow for the majority of the population to reach a desirable 25(OH)D level of 20ng/ml. Further high quality RCTs are required to confirm/refute the beneficial impact of vitamin D supplementation on various clinically important outcomes.

Guidelines on vitamin D replacement in bariatric surgery: Identification and systematic appraisal.

INTRODUCTION: Bariatric surgery is the most effective therapeutic option to reduce weight in morbidly obese individuals, but it results in a number of mineral and vitamin deficiencies. Clinical Practice Guidelines (CPGs) attempt to balance those benefits and harms to provide guidance to physicians and patients. OBJECTIVES: We compare and evaluate the quality of the evidence and of the development process of current CPGs that provide recommendations on vitamin D replacement in patients undergoing bariatric surgery, using a validated tool. METHODS: We searched 4 databases, with no time restriction, to identify relevant and current CPGs. Two reviewers assessed eligibility and abstracted data, in duplicate. They evaluated the quality of CPGs development process using the Appraisal of Guidelines, Research, and Evaluation II (AGREE II) tool that consists of 6 domains. A content expert verified those assessments. RESULTS: We identified 3 eligible CPGs: (1) the Endocrine Society (ES) guidelines (2010); (2) the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic & Bariatric Surgery (ASMBS) guidelines (update 2013); and (3) the Interdisciplinary European (IE) guidelines on Metabolic and Bariatric Surgery (latest update 2014). The ES and the AACE/TOS/ASMBS guidelines recommended high doses of vitamin D, varying from 3000IU daily to 50,000IU 1-3 times weekly. Vitamin D doses were not mentioned in the IE guidelines. The recommendations were based on a low quality of evidence, if any, or limited to a single high quality trial, for some outcomes. In terms of quality, only the IE guidelines described their search methodology but none of the CPGs provided details on evidence selection and appraisal. None of the three CPGs rigorously assessed the preferences of the target population, resource implications, and the applicability of these guidelines. According to the AGREE II tool, we rated the ES guidelines as average in quality, and the other two as low in quality. CONCLUSION: Current CPGs recommendations on vitamin D supplementation in bariatric surgery differ between societies. They do not fulfill criteria for optimal guideline development, in part possibly due to limited resources, and are based on expert opinion. Thus, the pressing need for high quality randomized trials to inform CPGs, to be developed based on recommended standards.

Hypovitaminosis D in bariatric surgery: A systematic review of observational studies.

BACKGROUND: Obesity is a public health problem that carries global and substantial social and economic burden. Relative to non-surgical interventions, bariatric surgery has the most substantial and lasting impact on weight loss. However, it leads to a number of nutritional deficiencies requiring long term supplementation. OBJECTIVES: The aims of this paper are to review 25-hydroxyvitamin D [25(OH)D] status pre and post bariatric surgery, describe the dose response of vitamin D supplementation, and assess the effect of the surgical procedure on 25(OH)D level following supplementation. METHODS: We searched Medline, PubMed, the Cochrane Library and EMBASE, for relevant observational studies published in English, from 2000 to April 2015. The identified references were reviewed, in duplicate and independently, by two reviewers. RESULTS: We identified 51 eligible observational studies assessing 25(OH)D status pre and/or post bariatric surgery. Mean pre-surgery 25(OH)D level was below 30ng/ml in 29 studies, and 17 of these studies showed mean 25(OH)D levels ≤20ng/ml. Mean 25(OH)D levels remained below 30ng/ml following bariatric surgery, despite various vitamin D replacement regimens, with only few exceptions. The increase in post-operative 25(OH)D levels tended to parallel increments in vitamin D supplementation dose but varied widely across studies. An increase in 25(OH)D level by 9-13ng/ml was achieved when vitamin D deficiency was corrected using vitamin D replacement doses of 1100-7100IU/day, in addition to the usual maintenance equivalent daily dose of 400-2000IU (total equivalent daily dose 1500-9100IU). There was no difference in mean 25(OH)D level following supplementation between malabsorptive/combination procedures and restrictive procedures. CONCLUSION: Hypovitaminosisis D persists in obese patients undergoing bariatric surgery, despite various vitamin D supplementation regimens. Further research is needed to determine the optimal vitamin D dose to reach desirable 25(OH)D levels in this population, and to demonstrate whether this dose varies according to the surgical procedure.

Serum 25-Hydroxyvitamin D Levels: Variability, Knowledge Gaps, and the Concept of a Desirable Range.

Hypovitaminosis D is prevalent worldwide but proportions vary widely between regions, depending on genetic and lifestyle factors, the threshold to define deficiency, and accuracy of 25-hydroxyvitamin D (25OHD) assays used. Latitude, pollution, concealing clothing, sun exposure, gender, dietary habits, and lack of government regulation account for up to 50% in variations in serum 25OHD levels, whereas genetic polymorphisms in the vitamin D pathway account for less than 5%. Organizations/societies have developed guidelines for recommended desirable 25OHD levels and vitamin D doses to reach them, but their applicability across age groups and populations are still debated. This article and the accompanying online Supporting Information highlight sources of variations in circulating 25OHD levels, uncertainties and knowledge gaps, and analytical problems facing 25OHD assays, while keeping efficacy and safety data as the dominant factors when defining a desirable range for 25OHD levels. We propose a desirable range of 20 to 40 ng/mL (50 to 100 nmol/L), provided precise and accurate assays are used. Although slightly lower levels, 15 to 20 ng/mL, may be sufficient for some infants and adults, higher levels, 40 to 60 ng/mL, may still be safe. This desirable range allows physicians to tailor treatment while taking season, lifestyle, vitamin D intake, and other sources of variation into account. We reserve 25OHD measurements for at-risk patients, defined by disease or lifestyle, and the use of 25OHD assays calibrated against the recommended international standards. Most target groups reach desirable target levels by a daily intake of 400 to 600 IU for children and 800 IU for adults. A total daily allowance of vitamin D of up to 1000 IU in the pediatric age groups, and up to 2000 IU in adults, tailored to an individual patient risk profile, is probably safe over long durations. Additional data are needed to validate the proposed range and vitamin D doses, especially in children, pregnant women, and non-white populations.

The role of vitamin d deficiency in the incidence, progression, and complications of type 1 diabetes mellitus.

The "nonclassic" role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been recently widely recognized. In type 1 diabetes mellitus (T1D), it plays an immunomodulatory role through the vitamin D receptor (VDR) present on pancreatic and immune cells. Specific VDR allelic variants have been associated with T1D in many countries. Furthermore, vitamin D deficiency has been prevalent in T1D, and the seasonal and latitude variability in the incidence of T1D can be partly explained by the related variability in vitamin D level. In fact, retrospective studies of vitamin D supplementation during pregnancy or infancy showed a lower incidence of T1D. We will review the different mechanisms of the vitamin D protective effect against insulitis and present the available data on the role of vitamin D deficiency in the control, progression, and complications of T1D.