Associations of serum 25(OH)D levels with physical performance and anabolic hormones in young men.

Purpose: The present study examined the association of vitamin D measured by serum 25(OH)D with physical performance outcomes and serum levels of anabolic hormones in young men. Methods: 412 young men (age 19 ± 1 year) entering their compulsory military service volunteered to participate in the study. The study consisted of two groups from two different military bases: Group A was studied in January and group B in July. The groups were first compared with each other and due to statistically significant (p < 0.001 analyzed with independent samples t-test) differences in physical condition (sit-up, push-up, and standing long jump-tests and testosterone levels) between the groups, groups were analyzed separately. The serum levels of 25(OH)D, testosterone (TES), sex hormone binding globulin (SHBG), and insulin-like growth factor-1 (IGF-1) were analyzed by electrochemiluminescence immunoassay. Physical performance tests consisted of muscular fitness (sit-ups, push-ups, standing long jump) and aerobic fitness (12-minute-running) tests. The association of serum 25(OH)D with physical performance tests and anabolic hormones was analyzed using linear regression. Results: After controlling for the group, body mass index, and leisure-time physical activity, serum 25(OH)D level was positively associated with aerobic and muscular fitness (ß = 0.15-0.20, all p < 0.05). Also, the participants with sufficient serum 25(OH)D levels (≥75 nmol/L) had better aerobic and muscular fitness and higher TES in group B, and better upper extremity muscular fitness in group A (all p < 0.05). In group A, there were 166 participants with serum levels of 25(OH) D < 75 nmol/L and 18 ≥ 75 nmol/L. In group B, the amounts were 92 (<75 nmol/L) and 136 (≥75 nmol/L), respectively. Conclusion: Serum 25(OH)D was positively associated with both aerobic and muscular fitness and those with sufficient vitamin D levels, had higher levels of TES. Thus, maintaining a sufficient serum 25(OH)D level may be beneficial for physical performance and anabolic state in young men.

Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials.

BACKGROUND: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D3, vitamin D2, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units [IU] vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633. FINDINGS: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I2=35·6%, pheterogeneity=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65-0·94]; 19 studies; I2=53·5%, pheterogeneity=0·003), at daily dose equivalents of 400-1000 IU (0·70 [0·55-0·89]; ten studies; I2=31·2%, pheterogeneity=0·16), for a duration of 12 months or less (0·82 [0·72-0·93]; 29 studies; I2=38·1%, pheterogeneity=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 [0·57-0·90]; 15 studies; I2=46·0%, pheterogeneity=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86-1·07]; 36 studies; I2=0·0%, pheterogeneity=0·99). Risk of bias within individual studies was assessed as being low for all but three trials. INTERPRETATION: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation. FUNDING: None.

Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials.

BACKGROUND: A 2017 meta-analysis of data from 25 randomised controlled trials of vitamin D supplementation for the prevention of acute respiratory infections revealed a protective effect of the intervention. Since then, 20 new RCTs have been completed. METHODS: Systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry from inception to 1st May 2020. Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration, were obtained from study authors. The study was registered with PROSPERO (no. CRD42020190633). FINDINGS: We identified 45 eligible RCTs (total 73,384 participants). Data were obtained for 46,331 (98.0%) of 47,262 participants in 42 studies, aged 0 to 95 years. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.91, 95% CI 0.84 to 0.99; P for heterogeneity 0.01). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of ≤12 months (OR 0.82, 95% CI 0.72 to 0.93). No significant interaction was seen between allocation to vitamin D vs. placebo and dose frequency, dose size, or study duration. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.97, 95% CI 0.86 to 1.09). Risk of bias within individual studies was assessed as being low for all but three trials. A funnel plot showed left-sided asymmetry (P=0.008, Egger's test). INTERPRETATION: Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation. FUNDING: None.

Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.

BACKGROUND: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity. OBJECTIVES: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry. STUDY SELECTION: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected. STUDY APPRAISAL: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity. RESULTS: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality. LIMITATIONS: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately. CONCLUSIONS: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013953. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.

Vitamin D and respiratory infection in adults.

Vitamin D insufficiency is a global issue that has significant implications for health. The classical role of vitamin D in bone mineralisation is well known; vitamin D deficiency leads to rickets, osteomalacia or osteoporosis. The role of vitamin D in an immune system is less known. Vitamin D is not an actual vitamin but a secosteroid hormone produced in the skin from 7-dehydrocholesterol after exposure to sunlight UVB radiation. Nutrition and supplements are main sources of vitamin D in wintertime in northern countries as sunlight exposure is inadequate for the production. For activation vitamin D needs to be hydroxylated in liver to form 25-hydroxyvitamin D and in kidney to 1,25-dihydroxyvitamin D, the most active hormone in Ca absorption in the gut. For determination of vitamin D status serum 25-hydroxyvitamin D level, the major circulating form of the hormone is to be measured. Vitamin D regulates gene expression through binding with vitamin D receptors, which dimerises with retinoid X receptor. This complex binds to vitamin D-responsive elements inside the promoter regions of vitamin D-responsive genes. Vitamin D has a key role in innate immunity activation; the production of antimicrobial peptides (cathelicidin and defensins) following Toll-like receptor stimulation by pathogen lipopeptides is dependent on sufficient level of 25-hydroxyvitamin D. Clinically, there is evidence of the association of vitamin D insufficiency and respiratory tract infections. There is also some evidence of the prevention of infections by vitamin D supplementation. Randomised controlled trials are warranted to explore this preventive effect.

An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men.

BACKGROUND: The effects of vitamin D in regulating bone mineralization are well documented. The action of vitamin D as a key link between Toll-like receptor activation and antibacterial responses in innate immunity has recently been shown. The data suggest that differences in the ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection. OBJECTIVE: We aimed to explore whether an association exists between vitamin D insufficiency and acute respiratory tract infection in young Finnish men. DESIGN: Young Finnish men (n = 800) serving on a military base in Finland were enrolled for this study. Their serum 25-hydroxyvitamin [25(OH)D] concentrations were measured in July 2002. They were followed for 6 mo, and the number of days of absence from duty due to respiratory infection were counted. RESULTS: The mean (+/- SD) serum 25(OH)D concentrations were 80.2 +/- 29.3 nmol/L (n = 756). Subjects with serum 25(OH)D concentrations < 40 nmol/L (n = 24) had significantly (P = 0.004) more days of absence from duty due to respiratory infection (median: 4; quartile 1-quartile 3: 2-6) than did control subjects (2; 0-4; n = 628; incidence rate ratio 1.63; 95% CI: 1.15, 2.24). We found a significant (P = 0.004) association between serum 25(OH)D concentrations and the amount of physical exercise before induction into military service. We also found significantly (P < 0.001) lower serum 25(OH)D concentrations in subjects who smoked (72.8 +/- 26.6 nmol/L; n = 192) than in control subjects (82.9 +/- 29.7 nmol/L; n = 537). CONCLUSION: Clinical trials of vitamin D supplementation are needed to investigate whether it enhances immunity to microbial infections.

Association between serum 25(OH)D concentrations and bone stress fractures in Finnish young men.

UNLABELLED: Low vitamin D level may predict rickets, osteomalacia, or osteoporosis. We examined serum 25(OH)D concentration as a predisposing factor for bone stress fracture in 756 military recruits. The average serum 25(OH)D concentration was significantly lower in the group with fracture, suggesting a relationship between vitamin D and fatigue bone stress fracture. INTRODUCTION: Low vitamin D level may predict rickets, osteomalacia, or osteoporosis. Fatigue bone stress fracture is one of the most frequently seen types of overuse injuries in athletes and military recruits. An association was recently shown between vitamin D and BMC. A correlation has also been found between low femoral BMD and stress fractures. We measured serum 25(OH)D concentration in a population sample of military recruits to determine if vitamin D is a predisposing factor for fatigue bone stress fracture. MATERIALS AND METHODS: We prospectively followed 800 randomly selected, healthy Finnish military recruits with a mean age of 19 years for developing stress fractures in homogenous circumstances. Blood for serum 25(OH)D concentration was drawn at entry into military service, and the weight, height, body mass index (BMI), muscle strength, and 12-minute running were measured for all subjects. Serum 25(OH)D concentrations were measured with enzyme immunoassay. At end of the 90-day follow-up, 756 subjects completed the study. Subjects without fracture constituted controls. RESULTS: Twenty-two recruits with stress fracture were identified (2.9%), the incidence being 11.6 (95% CI: 6.8-16.5) per 100 person-years. In the final multivariate analysis, the significant risk factor for stress fracture in conscripts was a below median serum 25(OH)D level (75.8 nM), OR being 3.6 (95% CI: 1.2-11.1). No significant associations between BMI (p = 0.255), age (p = 0.216), or smoking (p = 0.851) and bone stress fracture were found in this study population. CONCLUSIONS: A lower level of serum 25(OH)D concentration may be a generally predisposing element for bone stress fractures. Considering the obvious need of additional vitamin D in prevention of stress fractures, the effects of vitamin D fortification of foods and supplementation will be subjects of interest for future research.

Abnormal behavioral organization of grooming in mice lacking the vitamin D receptor gene.

Vitamin D is a steroid hormone with several important functions in the nervous system. Numerous human and animal data link alterations in the vitamin D system to various behavioral disorders. Grooming is an important element of rodent behavior with a general pattern of cephalocaudal progression (paw licking - nose/face wash - body wash - tail/genitals wash). Here we studied whether genetic ablation of vitamin D nuclear receptors (VDR) in mice may be associated with altered behavioral sequencing of grooming. Overall, VDR null mutant mice showed abnormal grooming, including a higher percentage of "incorrect" transitions and longer duration of "incorrect" grooming (contrary to the cephalocaudal progression); a higher percentage of interrupted grooming bouts; and the atypical regional distribution of grooming (more leg grooming, less body and tail/genitals grooming), compared to their wild-type controls. Grooming of heterozygous mice was similar to the wild-type group, indicating that abnormal grooming patterning is inherited as a recessive. In contrast, behavioral sequencing of another complex behavior (mating with a female) was unaltered in all three genotypes, suggesting grooming-specific abnormal sequencing in these mutant mice. Our results suggest that a neurosteroid vitamin D and VDR may play an important role in controlling sequencing of grooming in mice, and further confirm the important role of the vitamin D system and VDR in the regulation of behavior.

Impaired motor performance in mice lacking neurosteroid vitamin D receptors.

Vitamin D is a neuroactive seco-steroid and its importance to the nervous system is receiving increasing recognition. Since numerous data link vitamin D dysfunctions to various neurological and behavioural disorders, we studied whether genetic ablation of vitamin D receptors (VDR) may be associated with motor impairments in mice subjected to several behavioural tests. The data obtained in the vertical screen and swim tests show that VDR genetic ablation produces severe motor impairment (shorter screen retention and poor swimming) in mutant mice compared to wild-type and heterozygous control animals. These impairments appear to be unrelated to visual, vestibular and activity/emotionality parameters of mice, and are likely associated with disturbed calcium homeostasis. This study confirms the important role of the vitamin D system in motor functions and suggests that animal genetic models targeting the vitamin D/VDR system may be a useful tool to study vitamin D-related motor/behavioural disorders.

Increased anxiety in mice lacking vitamin D receptor gene.

Vitamin D is a steroid hormone with many important functions in the brain, mediated through the vitamin D nuclear receptor. Numerous human and animal data link vitamin D dysfunctions to various behavioural disorders. To examine this problem, we studied whether genetic ablation of vitamin D receptors in mice may be associated with altered emotional behaviours. Here we show that the receptor-deficient mice demonstrate increased anxiety-like behaviours when subjected to a battery of behavioural tests. These studies suggest that vitamin D and its receptors are an important factor in the brain, whose imbalance may significantly affect emotional behaviour.

25-hydroxyvitamin D3 is an active hormone in human primary prostatic stromal cells.

According to the present paradigm, 1alpha,25-dihydroxyvitamin D3 [1alpha,25-(OH)2D3] is a biologically active hormone; whereas 25-hydroxyvitamin D3 (25OHD3) is regarded as a prohormone activated through the action of 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase). Although the role of vitamin D3 in the regulation of growth and differentiation of prostatic epithelial cells has been well studied, its action and metabolism in prostatic stroma are still largely unknown. We investigated the effects of 25OHD3 and 1alpha,25-(OH)2D3 on two human stromal primary cultures termed P29SN and P32S. In a cell proliferation assay, 25OHD3 was found at physiological concentrations of 100-250 nM to inhibit the growth of both primary cultures, whereas 1alpha,25-(OH)2D3 at a pharmacological concentration of 10 nM exhibited the growth-inhibitory effects on P29SN cells but not on P32S cells. Quantitative real-time RT-PCR analysis revealed that both 25OHD3 and 1alpha,25-(OH)2D3 induced 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) mRNA in a dose- and time-dependent manner. By inhibiting 1alpha-hydroxylase and/or 24-hydroxylase enzyme activities, the induction of 24-hydroxylase mRNA by 250 nM 25OHD3 was clearly enhanced, suggesting that 1alpha-hydroxylation is not a prerequisite for the hormonal activity of 25OHD3. Altogether our results suggest that 25OHD3 at a high but physiological concentration acts as an active hormone with respect to vitamin D3 responsive gene regulation and suppression of cell proliferation.

Antiproliferative action of vitamin D.

During the past few years, it has become apparent that vitamin D may play an important role in malignant transformation. Epidemiological studies suggest that low vitamin D serum concentration increases especially the risk of hormone-related cancers. Experimentally, vitamin D suppresses the proliferation of normal and malignant cells and induces differentiation and apoptosis. In the present review we discuss the mechanisms whereby vitamin D regulates cell proliferation and whether it could be used in prevention and treatment of hyperproliferative disorders like cancers.