Effectiveness and safety of steady versus intermittent high dose vitamin D supplementation for the prevention of falls and fractures among adults: a protocol for systematic review and network meta-analysis.

INTRODUCTION: Clinical trials and systematic reviews of trials involving vitamin D supplementation have mainly focused on defining the optimal amount of vitamin D dosage. However, the comparative effectiveness of different dosing schedules (ie, daily vs bolus dosing schedule) has been largely unexplored; and currently, there is no consensus regarding the optimal vitamin D dosing schedule. Our objective is to conduct a systematic review and network meta-analysis (NMA) to evaluate the comparative effectiveness and safety of steady (eg, daily, weekly) and intermittent high-dose (eg, monthly, yearly) vitamin D dosing schedules; and to determine the effectiveness of the various dosing schedules and combinations of treatments. METHODS AND ANALYSIS: We will conduct a systematic search and review of literature from major medical databases (MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov) involving studies that compare vitamin D supplementation alone or in combination with calcium. Only randomised controlled trials (RCTs) will be considered. We will, however, consider various settings (eg, community, institutional care) and study designs (eg, cluster RCTs, cross-over trials). Our primary outcomes include falls and fractures including hip-fracture and non-vertebral fractures. Secondary outcomes will include muscle strength, physical performance, gait and mobility limitation. A Bayesian NMA will be conducted, and the results will be presented in the form of treatment effect estimates and ranking probabilities, with corresponding CIs. Pairwise meta-analysis will also be conducted for studies reporting head-to-head comparisons. Subgroup analysis will be performed with respect to pre-determined subgroups; including vitamin D status as measured by serum 25-hydroxyvitamin D levels, age and follow-up time. Sensitivity analysis will also be performed with respect to risk of bias. ETHICS AND DISSEMINATION: This study is a systematic review and meta-analysis of published RCTs; therefore, no ethical approval is required. Results will be disseminated through open access peer-reviewed publications. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018112662.

Metabolically healthy obesity, vitamin D, and all-cause and cardiometabolic mortality risk in NHANES III.

BACKGROUND & AIMS: Previous studies assessing the prognosis of metabolically healthy obesity (MHO) have been limited by a lack of a harmonized definition of MHO phenotype. Furthermore, obesity is a risk factor for vitamin D deficiency and low vitamin D status has been associated with a higher risk of mortality; however, few studies have evaluated the joint association between vitamin D, metabolic health phenotype, and mortality risk. Using a harmonized definition, we investigated whether MHO is associated with subsequent all-cause and cardiometabolic mortality, and whether serum 25-hydroxyvitamin D [25(OH)D] modifies these associations. METHODS: This study included participants aged ≥20 years from the Third National Health and Nutrition Examination Survey (NHANES III). MHO phenotype was defined as a combination of obesity (≥30 kg/m2) and zero component of metabolic syndrome. Multivariable Cox regression was used to assess the risk of mortality across metabolic phenotypes, and the joint association between metabolic phenotype and 25(OH)D. Fine and Gray regression was performed to account for competing risk events. RESULTS: Among 11,333 participants, a total of 2980 deaths (937 cardiometabolic death outcomes) occurred during a median follow-up of 19.1 years. In the absence of any metabolic abnormality, obesity (MHO) was not associated with a higher risk of all-cause (hazard ratio [HR], 0.89 [95% CI, 0.52-1.51]) or cardiometabolic mortality (cause-specific HR, 1.21 [95% CI 0.33-4.46]). Similar results were obtained from competing risk analysis. No significant differences in average 25(OH)D levels were observed between MHO and non-MHO participants; however, there was a significant interaction between metabolic health phenotype and serum 25(OH)D in relation to cardiometabolic mortality such that levels of serum 25(OH)D < 50 nmol/L were associated with increased risk of cardiometabolic mortality, particularly in participants within the normal-weight and obese BMI ranges. CONCLUSIONS: Our results support the hypothesis that MHO phenotype is a benign health condition. Vitamin D deficiency may exacerbate the risk of cardiometabolic death outcomes associated with metabolic dysfunction in normal weight and obese individuals. Further research is warranted to validate our findings.

Lifetime risk of cardiometabolic mortality according to vitamin D status of middle and older-aged adults: NHANES III mortality follow-up.

The predictive value of total 25-hydroxyvitamin D (25(OH)D, a biomarker of vitamin D status) in relation to lifetime risk of cardiometabolic mortality is not known. The purpose of this study was to determine the association between standardized and annualized total 25(OH)D levels and lifetime risk for cardiometabolic mortality in middle- to older-aged adults. In this study, we followed up 7958 participants in the Third National Health and Nutrition Examination Survey from 1988 to 1994 (NHANES III) until the occurrence of cardiometabolic death or attainment of 95 years of age (median follow-up 17.9 years, 1371 cardiometabolic-deaths). Lifetime risks were estimated according to recommended total 25(OH)D cutoffs by national guidelines, and a combination of total 25(OH)D status and traditional risk factor burden. We also explored variation in lifetime risk estimates by levels of body mass index (BMI). The results of this study showed that annualized total 25(OH)D <30 nmol/L was associated with high lifetime risk of cardiometabolic mortality (40%). Lifetime risks of cardiometabolic mortality were similar for annualized levels between 30-< 50 nmol/L, 50-< 75 nmol/L and ≥75 nmol/L (31-33%). Lifetime risk was highest among participants with annualized total 25(OH)D <30 nmol/L and ≥2 major traditional risk factors (45%), whereas lifetime risk was lowest among participants with annualized 25(OH)D ≥30 nmol/L and low-intermediate risk factors (28%). Lifetime risk estimates were similar across BMI categories. In conclusion, a single measurement of vitamin D deficiency (annualized levels <30 nmol/L) in middle- to older-aged adults is a strong predictor of high lifetime risk for cardiometabolic mortality, particularly among those with high burden of traditional risk factors.

Clinical utility of serum 25-hydroxyvitamin D in the diagnosis of insulin resistance and estimation of optimal 25-hydroxyvitamin D in U.S. adults.

AIMS: To assess the clinical utility of measuring serum 25-hydroxyvitamin-D [25(OH)D] along with traditional risk factors in the diagnosis of insulin resistance (IR) and to estimate the optimal 25(OH)D level associated with normal glucose and insulin homeostasis. METHODS: A cross-sectional analysis of 6868 adults aged≥20years without diagnosed diabetes in the National Health and Nutrition Examination Survey, with available standardized 25(OH)D data (2001-2010). IR was defined by the homeostatic-model-assessment of insulin resistance (HOMA-IR; ≥75th percentile, sex-specific: 3.9 in men or 3.6 in women). Using logistic regression, two risk models were developed to estimate the risk of IR: Model 1 included established risk factors, and Model 2 additionally included serum 25(OH)D. Predictiveness curves and decision-curve analysis were used to assess differences in IR detection among models. Receiver-operating-characteristic curves were used to estimate the lower threshold for 25(OH)D. Results were validated in a testing sample. RESULTS: Model 2 marginally improved detection of IR: at a risk threshold of 0.2, adding 25(OH)D would identify an additional 2 to 4 cases per 1000 people. Overall, the lower 25(OH)D threshold was estimated at 60nmol/L, however, the threshold differed by ethnicity (Mexican-Americans: 54nmo/L, non-Hispanic whites: 68nmol/L, and non-Hispanic blacks: 41nmol/L). CONCLUSION: Addition of serum 25(OH)D to traditional risk factors provided small incremental improvement in detection of IR in asymptomatic adults. The optimal 25(OH)D threshold was estimated to be at least 60nmol/L, however, the threshold may differ by ethnic-background. Further research is needed to validate these results in other populations.

Standardized serum 25-hydroxyvitamin D concentrations are inversely associated with cardiometabolic disease in U.S. adults: a cross-sectional analysis of NHANES, 2001-2010.

BACKGROUND: Previously reported associations between vitamin D status, as measured by serum 25-hydroxyvitamin D [25(OH)D] concentrations, and cardiometabolic risk factors were largely limited by variability in 25(OH)D assay performance. In accordance with the Vitamin D Standardization Program, serum 25(OH)D measurement was recently standardized in the National Health and Nutrition Examination Survey (NHANES) to reduce laboratory and method related differences in serum 25(OH)D results. We evaluated the overall and ethnic-specific associations between the newly standardized serum 25(OH)D concentrations and cardiometabolic risk in U.S. adults. METHODS: This study examined standardized 25(OH)D data from five cycles of the NHANES (2001-2010). The total sample included 7674 participants (1794 Mexican-Americans, 4289 non-Hispanic whites, and 1591 non-Hispanic blacks) aged ≥ 20 years who were examined in the morning after overnight fasting. Serum 25(OH)D was directly measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 2007-2010, and was predicted from LC-MS/MS equivalents for 2001-2006. Serum 25(OH)D levels were categorized into quartiles (<43.4, 43.4-58.6, 58.7-74.2, ≥74.3 nmol/L). Cardiometabolic risk was defined by the homeostatic model assessment of insulin resistance (HOMA-IR), metabolic syndrome (MetS), and Framingham cardiovascular disease (CVD) risk. Prevalence ratios and 95% confidence intervals were calculated using modified Poisson regression. RESULTS: After full adjustment for confounders, serum 25(OH)D ≥74.3 nmol/L was associated with lower cardiometabolic risk compared to 25(OH)D <43.4 nmol/L in the overall sample [HOMA-IR: 0.70 (0.59, 0.84); MetS: 0.82 (0.74, 0.91); CVD risk: 0.78 (0.66, 0.91)]. These associations remained significant in Mexican-Americans [HOMA-IR: 0.54 (0.35, 0.82); MetS: 0.73 (0.55, 0.96)], non-Hispanic whites [HOMA-IR: 0.81 (0.68, 0.96); MetS: 0.84 (0.73, 0.95); CVD risk: 0.78 (0.64, 0.93)]; and in non-Hispanic blacks [HOMA-IR: 0.67 (0.45, 0.99); MetS: 0.75 (0.56, 0.97); CVD risk: 0.58 (0.41, 0.81)]. CONCLUSIONS: Low vitamin D status is a significant risk factor for cardiometabolic disease in U.S. adults based on standardized serum 25(OH)D results, irrespective of ethnic background. Future studies using standardized 25(OH)D data are needed to confirm these results, particularly amongst U.S. blacks with 25(OH)D concentrations above 75 nmol/L.

Bioavailability and Safety of Vitamin D3 from Pizza Baked with Fortified Mozzarella Cheese: A Randomized Controlled Trial.

PURPOSE: To assess the bioavailability and safety of vitamin D3 from fortified mozzarella cheese baked on pizza. METHODS: In a randomized, double-blind trial, 96 apparently healthy, ethnically diverse adults were randomized to consume 200 IU or 28 000 IU vitamin D3 fortified mozzarella cheese with pizza once weekly for a total of 8 weeks. Blood and urine samples were collected at baseline (week 1) and final (week 10) visits for serum 25-hydroxyvitamin D and other biochemical measures. The primary outcome compared serum 25-hydroxyvitamin D between groups at 10 weeks. The secondary outcome evaluated the safety of vitamin D dosing protocol as measured by serum and urine calcium, phosphate, creatinine, and serum parathyroid hormone (PTH). RESULTS: Serum 25-hydroxyvitamin D increased by 5.1 ± 11 nmol/L in the low-dose group (n = 47; P = 0.003), and by 73 ± 22 nmol/L in the high-dose group (n = 49; P < 0.0001). None of the subjects in either group developed any adverse events during the supplementation protocol. Serum PTH significantly decreased in the high-dose group only (P < 0.05). CONCLUSIONS: Vitamin D3 is safe and bioavailable from fortified mozzarella cheese baked on pizza.