Effect of Daily Vitamin D3 Supplementation on Muscle Health: An Individual Participant Meta-analysis.

BACKGROUND: The role of vitamin D on muscle health is debated. METHODS: An individual participant metanalysis of 4 randomized placebo-controlled trials, investigating short-term (3-9months) effects of vitamin D3 in moderate (2800 IU) to high (7000 IU) daily oral doses on muscle health and quality of life (QoL). Inclusion criteria were either obesity (n = 52), newly diagnosed primary hyperparathyroidism (n = 41), Graves' disease (n = 86), or secondary hyperparathyroidism (n = 81). RESULTS: Overall (n = 260) as well as in a subgroup analysis including only vitamin D insufficient [25(OH)D < 50 nmol/L] individuals (n = 176), vitamin D supplementation did not affect measures of muscle health (isometric muscle strength, Timed Up and Go test, chair rising test, body composition, and balance) or QoL. However, a beneficial effect was present on QoL (physical component score) in vitamin D deficient [25(OH)D < 25 nmol/L] individuals (n = 34). Overall, relative changes in 25(OH)D inversely affected maximum muscle strength in a dose-response manner. Stratified into body mass index 30 kg/m2, vitamin D supplementation had divergent effects on isometric muscle strength, with beneficial effects in obese individuals (n = 93) at knee flexion 90° (P = 0.04), and adverse effects in nonobese individuals (n = 167) at handgrip (P = 0.02), knee extension 60° (P = 0.03) and knee flexion 60° (P < 0.01). CONCLUSION: Overall, short-term treatment with moderate to high daily doses of vitamin D did not affect muscle health or QoL. A potential beneficial effect was present on muscle strength in severely obese individuals and on QoL in vitamin D deficient individuals. Subgroup analyses, however, suggested negative effects of large relative increases in p-25(OH)D.

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.

Causes of Vitamin D Deficiency and Effect of Vitamin D Supplementation on Metabolic Complications in Obesity: a Review.

Obese subjects are often characterized by low plasma 25-hydroxy-vitamin D (25OHD) levels. Many explanations for this association have been proposed. Low plasma 25OHD is associated with obesity-related comorbidities such as insulin resistance, type 2 diabetes mellitus, and low-grade inflammation. In this review, we discuss the proposed mechanisms for low 25OHD in obesity and explore the results of recent RCTs on vitamin D (VD) supplementation on obesity and its metabolic complications such as insulin resistance and type 2 diabetes. Although the results from these clinical randomized controlled trials vary, the general picture is that VD treatment of obese individuals does not seem to be an effective treatment of obesity-related metabolic complications.

Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data.

IMPORTANCE: Low levels of vitamin D are associated with elevated blood pressure (BP) and future cardiovascular events. Whether vitamin D supplementation reduces BP and which patient characteristics predict a response remain unclear. OBJECTIVE: To systematically review whether supplementation with vitamin D or its analogues reduce BP. DATA SOURCES: We searched MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.com augmented by a hand search of references from the included articles and previous reviews. Google was searched for gray literature (ie, material not published in recognized scientific journals). No language restrictions were applied. The search period spanned January 1, 1966, through March 31, 2014. STUDY SELECTION: We included randomized placebo-controlled clinical trials that used vitamin D supplementation for a minimum of 4 weeks for any indication and reported BP data. Studies were included if they used active or inactive forms of vitamin D or vitamin D analogues. Cointerventions were permitted if identical in all treatment arms. DATA EXTRACTION AND SYNTHESIS: We extracted data on baseline demographics, 25-hydroxyvitamin D levels, systolic and diastolic BP (SBP and DBP), and change in BP from baseline to the final follow-up. Individual patient data on age, sex, medication use, diabetes mellitus, baseline and follow-up BP, and 25-hydroxyvitamin D levels were requested from the authors of the included studies. For trial-level data, between-group differences in BP change were combined in a random-effects model. For individual patient data, between-group differences in BP at the final follow up, adjusted for baseline BP, were calculated before combining in a random-effects model. MAIN OUTCOMES AND MEASURES: Difference in SBP and DBP measured in an office setting. RESULTS: We included 46 trials (4541 participants) in the trial-level meta-analysis. Individual patient data were obtained for 27 trials (3092 participants). At the trial level, no effect of vitamin D supplementation was seen on SBP (effect size, 0.0 [95% CI, -0.8 to 0.8] mm Hg; P=.97; I2=21%) or DBP (effect size, -0.1 [95% CI, -0.6 to 0.5] mm Hg; P=.84; I2=20%). Similar results were found analyzing individual patient data for SBP (effect size, -0.5 [95% CI, -1.3 to 0.4] mm Hg; P=.27; I2=0%) and DBP (effect size, 0.2 [95% CI, -0.3 to 0.7] mm Hg; P=.38; I2=0%). Subgroup analysis did not reveal any baseline factor predictive of a better response to therapy. CONCLUSIONS AND RELEVANCE: Vitamin D supplementation is ineffective as an agent for lowering BP and thus should not be used as an antihypertensive agent.

Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency - a double-blind, randomized, placebo-controlled trial.

OBJECTIVES: Vitamin D insufficiency is common in subjects with type 2 diabetes. Observational studies suggest that vitamin D plays a role in the pathogenesis of type 2 diabetes. However, results of intervention studies have been inconsistent. We investigated the effects of improving vitamin D status on insulin sensitivity, insulin secretion, and inflammatory markers in patients with type 2 diabetes. MATERIALS/METHODS: A double blind, randomized, placebo controlled trial was conducted. Sixteen patients with type 2 diabetes and hypovitaminosis D were recruited. Eight patients received colecalciferol and (280 µg daily for 2 weeks, 140 µg daily for 10 weeks) and 8 patients received identical placebo tablets for 12 weeks. Before and after intervention, patients underwent IVGTT, hyperinsulinemic euglycemic clamp, assessment of baseline high-frequency insulin pulsatility, glucose-entrained insulin pulsatility, DXA scans, 24-hour-ambulatory blood pressure monitorings, and fasting blood samples. RESULTS: Serum-25(OH) vitamin D and serum-1,25(OH)2 vitamin D increased significantly after 12 weeks in the intervention group (p=0.01, p=0.004). Serum-25(OH) vitamin D was also significantly higher in the vitamin D group compared to the placebo group (p=0.02) after intervention. Although no significant changes in insulin sensitivity, inflammation, blood pressure, lipid profile, or HbA1c were found, we observed borderline (p between 0.05 and 0.10) improvements of insulin secretion, in terms of c-peptide levels, first phase incremental AUC insulin and insulin secretory burst mass. CONCLUSIONS: Improvement in vitamin D status does not improve insulin resistance, blood pressure, inflammation or HbA1c, but might increase insulin secretion in patients with established type 2 diabetes.

The effect of high-dose vitamin D supplementation on calciotropic hormones and bone mineral density in obese subjects with low levels of circulating 25-hydroxyvitamin d: results from a randomized controlled study.

Low levels of 25-hydroxyvitamin D (25OHD) are associated with increased bone turnover and risk of fractures. Plasma 25OHD is inversely related to body mass index, and vitamin D deficiency is common in obesity. We aimed to determine whether vitamin D supplementation affects bone turnover and bone mineral density (BMD) in obese subjects. Fifty-two healthy obese men and women aged 18-50 years with plasma 25OHD levels below 50 nmol/L were randomized to 7,000 IU of cholecalciferol daily or placebo for 26 weeks. We measured plasma levels of 25OHD, parathyroid hormone (PTH), and markers of bone turnover, as well as BMD at the hip, spine, forearm, and whole body. Compared with placebo, treatment with cholecalciferol increased mean plasma 25OHD from 35 to 110 nmol/L (p < 0.00001) and significantly decreased PTH (p < 0.05). BMD increased significantly at the forearm by 1.6 ± 0.7 % (p = 0.03). The bone resorption marker C-terminal telopetide of type 1 collagen (CTX) decreased borderline significantly in the cholecalciferol group compared with the placebo group (p = 0.07). Changes in plasma 25OHD correlated inversely with changes in plasma levels of bone-specific alkaline phosphatase (r = -0.38, p = 0.01) and CTX (r = -0.33, p = 0.03). Changes in CTX correlated inversely with changes in spine BMD (r = -0.45, p = 0.04). Increasing circulating 25OHD levels by cholecalciferol treatment is of importance to bone health in young obese subjects as increased levels of 25OHD are associated with a decrease in both PTH and bone turnover and with an increase in BMD at the forearm.

Rosiglitazone decreases bone mass and bone marrow fat.

CONTEXT: Activation of peroxisome proliferator-activated receptor-γ is believed to promote adipocyte development from mesenchymal stem cells in the bone marrow at the expense of osteoblasts, leading to decreased bone mineral density (BMD) and increased marrow fat. OBJECTIVE: The objective of the study was to examine the effect of the peroxisome proliferator-activated receptor-γ agonist, rosiglitazone, on BMD assessed by dual-energy x-ray absorptiometry in 53 healthy postmenopausal women and spine bone marrow fat assessed by magnetic resonance imaging proton spectroscopy. DESIGN: This was a 14-wk prospective, double-blind, randomized, placebo-controlled trial. SETTING: The study was conducted in the general community. PATIENTS: Fifty-three healthy postmenopausal women participated in the study. INTERVENTION: Intervention included rosiglitazone tablets of 8 mg/d. MAIN OUTCOME MEASURES: The primary end point was a change in BMD. RESULTS: At the femoral neck, BMD decreased by 1.34 ± 0.60% (mean ± sem) in the rosiglitazone group, whereas BMD increased by 0.28 ± 0.56% in the placebo group (P = 0.055). At the lumbar spine, BMD decreased by 1.03 ± 0.34% in the rosiglitazone group and 0.42 ± 0.35% in the placebo group (P = 0.22). The bone resorption marker carboxy-terminal telopeptide increased by 20.4 ± 7.7% (mean ± sem) in the rosiglitazone group and decreased by 7.1 ± 4.7% in the placebo group (P = 0.003). Spine fat decreased by 13.5 ± 5.5% (mean ± sem) in the rosiglitazone group and increased by 6.8 ± 7.4% in the placebo group (P = 0.056). CONCLUSIONS: Contrary to what was expected, spine fat decreased during rosiglitazone treatment. Furthermore, rosiglitazone treatment resulted in uncoupling of bone resorption and formation leading to bone loss. Our data suggest that the bone marrow osteoblast-adipocyte relationship is more complex than was assumed and that the two cell types can be independently affected.