Effectiveness, Ease of Use, and Satisfaction

First of all, I am extremely alarmed to see 50,000 I.U. (or 1.25mg) of Vitamin D, being prescribed to patients, by doctors! THIS prescribed AMOUNT OF Vitamin D, IS WAY TOO MUCH! By the way, the majority of doctors have the equivalent of a one half hour course, in nutritional education, IF THAT, included in their schooling. Food is medicine. Having said this, I will proceed with my personal experience, and knowledge, about Vit.D. I take Vit.D because, it is SO IMPORTANT for our overall health. I am 53 years old, and take a heart medicine, (called Atenolol,) which does not allow me to go out in the Sun. So, I have to take a Vit.D supplement. I take 400 I.U. (or 10mcg) of D3, everyday. (600 I.U. is the RDA, or the Recommended Daily Allowance, for people over the age of 70.) Vit.D is EXTREMELY IMPORTANT to the normal functioning of our bodies, and plays a large part in keeping us Cancer-free, as well. Our bodies, continuously, scan through EVERY CELL in our entire body. When this scanning mechanism encounters a cell with a “bite out of it,” (due to exposure to radiation, through x-rays, etc.,) or other mutation, it replicates this abnormal cell, and this is one of the ways Cancer occurs. Vit.D keeps this from happening. That’s why it is SO important. When we have healthy Vit.D levels, the mechanism that scans each and every cell, can recognize the mutated cell, or the cell with “the bite out of it’s DNA,” that is faulty, and NOT replicate it. It, instead, discards the cell from our body, and we stay healthy. 15 minutes of DAILY sunshine is, generally, enough for Caucasians to get the amount of needed Vit.D. African Americans, and those with more pigment in their skin, need a few more minutes, (if sunlight is allowed.) In addition to this, scientists have recently learned that, Vit.D (in larger doses, and over an extended period of time,) is extremely beneficial, in fighting the COVID-19 coronavirus, in it’s early stages. Vit.D is essential for normal growth and development. It promotes the use of calcium and phosphorus in the formation of our bones and teeth. It is especially needed for infants, children, and women, during pregnancy, and lactation. In mild cases, results of lack or deficiency of Vit.D, are the interference with utilization of calcium and phosphorus in bone and teeth formation. Irritability, and weakness are also results of a lack, or deficiency, of Vit.D. Severe deficiency leads to rickets. Valuable sources of Vit.D, are Sunlight and Fish-liver oil. Low concentrations are found in egg yolk, cream and butter. Milk may be enriched with it, (but, 1 quart of whole milk, fortified with V.itamin D, only equals 400 I.U.) Ultraviolet rays from special lamps, acting on the skin, are another way to get Vit.D. Lesser, or trace, amounts can be found in (fortified) yeast and sea vegetables (Nori, Dulse, etc.) Natural food sources of Vitamin D are meager. If one chooses to use Fish Oil, keep it under refrigeration, as that is where it is stable. We store Vit.D. in our liver. Again, the Recommended Daily Allowance is 400 I.U. until the age of 70 years old. Then, the (RDA) Recommended Daily Allowance, goes up to 600 I.U. I am a Vegetarian. So, additionally, I take B12, along with my Vit.D, DAILY. I, also, eat Iron, DAILY, as well, through Natural, Organic, Whole Food Sources, like: Egg Yolk, Beans, Oatmeal, Raisins, Apricots, Peaches, Prunes, Molasses, Peas, Green Leafy Vegetables, Almonds and Soy Beans. ~Note: If you take a Calcium – Magnesium Complex: Calcium (1,000mg.) – Magnesium (500mg.) *We can ONLY absorb 600mg. of Calcium, at a time. So, eat your supplement (of 600mg. Calcium) in the morning, AND at night. Read More Read Less

Effectiveness, Ease of Use, and Satisfaction

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With this Vit D deficiency, I was feeling extremely mooody. I got much better taking 5,000 units a day. Then I ran out and didn’t refill. I noticed a difference in my moods straight away. so did my family. Once I got back on Vit D I got much better in a couple of days. I plan to never run out again! This has a been a God send for me. And, it’s not a drug which is even better!

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I AM A DIABETIC AND HAVE FOUND MY BLOOD SUGARS HAVE GONE VERY HIGH ON 2000U RECOMENDED BY MY ENDOCRANOLIGIST ANYONE ELSE FIND THIS?

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When my dr. tested my blood levels, they were rock bottom. I take vitamin D3 daily now, feel much better (pain, mood.) One thing I’ve found out: take vitamin D3 in the morning! Taking at night may interfere with sleep. Make sure there is fat or oil in meal when you take the vitamin, also, to help absorb.

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Having stomach issues, cramping. Don’t know if it caused from the D3.

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Having stomach issues, cramping. Don’t know if it caused from the D3.

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I’m a 44 y.o. woman who was always tired and always complained to my husband about my bones and muscles hurting all the time. Went and had my annual check up and my Dr. did my annual labs and they came back that my vit d levels were extremely low so she had me start vit D3 50,000 iu once a day and after taking that first week I noticed a change immediately. I feel so much better and I don’t ache like I use to these pills are amazing and I’m so happy and starting to feel myself again.

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I am a 44 year old woman who is always tired, after taking this vitamin D3 I felt so much better. I am more awake and alert and find myself wanting to do more things. I have no no aide effects, but even if I did so what. The pros outweigh the cons.

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I started taking Vitamin D3 hoping it would help my bones and joints. I had a blood test and it told me I was low. The only problem is that I seem to be allergic to the Vitamin D3 supplement. My joint pain is better but I don’t think I can tolerate the nausea much more. I live in the Northwest where the sun doesn’t shine often. I need to move.

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I’ve been on the vitamin for about a month. I have notice that I’ve been having some pain in the stomach, a cramping.

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Have been taking 4,000iu of D3 for about 2 years. I have noticed that I am less moody than I was before taking this. I also have anxiety and depression. I feel less muscle pain and more happier taking this.

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I don’t about your situation but the first time I took the drug it was like a real feeling like I had a cure all pill, but months on the drug I started having headaches that turn into migraines from hell 1,000 units per day of sure migraine for some reason I could not figure out until I quit taking the drug

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With this Vit D deficiency, I was feeling extremely mooody. I got much better taking 5,000 units a day. Then I ran out and didn’t refill. I noticed a difference in my moods straight away. so did my family. Once I got back on Vit D I got much better in a couple of days. I plan to never run out again! This has a been a God send for me. And, it’s not a drug which is even better!

31 ShapeCreated with Sketch. 2 thumb_up copy 5Created with Sketch.Report this postFill 3Created with Sketch. Condition: Prevention of a Low Amount of Calcium in the Blood EffectivenessEase of UseSatisfaction

I have not had any side effects with this supplement.

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I was experiencing muscle aches and joint pain but once I took the time release d3 1000 unit, my pain disappeared. I am convince Vitamin D3 is the answer to joint/muscle aches

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I deal with anxiety and depression seems to of dissapeared. Monthly cramps, sugar lows. This vitamin has helped me tremendousley

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I went to my Dr. and told her about my muscle pain and joint pain and fatique. She ordered labs to check my Vitamin d . It was low way low and she prescribed 50,000 units for 4 weeks and i could tell the difference.

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Top 10 Vitamin D Supplements

SUMMARY

Labdoor analyzed 19 best-selling vitamin D supplements in the United States for vitamin D3 content, heavy metal contamination, and presenceabsence of GMO events.

All 19 products exceeded their claimed vitamin D3 content, averaging 22% over their stated label claims. 6 of the 19 products exceeded their label claims by greater than 40%.

Additionally, all products recorded at least 1000 IU vitamin D per serving, significantly above vitamin D’s 400 IU Daily Value (DV) and its 600 IU Recommended Dietary Allowance (RDA).

All supplements passed their heavy metals and GMO assays.

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LABEL ACCURACY

6 of the 19 products in this report exceeded their label claims by greater than 40%.

All 19 vitamin D supplements met or exceeded their claimed vitamin D3 content, ranging from +0 to +900.0 IU versus their stated label claims.

The average label variance in this testing batch was 22%.

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PRODUCT PURITY

All twenty vitamin D supplements tested in this batch passed heavy metal screens for arsenic, lead, and cadmium (below 1 PPM).

All products in this report were screened by Inductively Coupled Plasma (ICP)-based techniques for the presence of heavy metals. Samples of each product passed all three heavy metals assays, indicating that samples contained under 1 PPM (part per million) each of arsenic, lead, and cadmium compounds.

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NUTRITIONAL VALUE

The Recommended Dietary Allowance (RDA) is set at 600 IU per day for most adults. For people over 70 years old, the IOM recommends an increased RDA of 800 IU per day.

Most vitamin D supplements tested in this batch recorded similar Nutrition Facts panels, with only minimal variation in calorie, fat, carbohydrate, and sugar content.

All products recorded vitamin D3 levels in excess of the Institute of Medicine’s (IOM) 600 IU Recommended Dietary Allowance (RDA) in a single serving, ranging from Nature Made Vitamin D3, which exceeded the vitamin D RDA by 66.7%, to Natrol Vitamin D3, which exceeded the vitamin D RDA by 383. 3%.

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INGREDIENT SAFETY

Clinical studies indicate that toxicity is unlikely to occur at the 1000-2000 IU dosages of vitamin D commonly found in dietary supplements.

Three products – Vitafusion Vitamin D3 Gummy Vitamins, Source Naturals Vitamin D3, and Natrol Vitamin D3, – significantly exceeded their stated label claims, reaching vitamin D3 quantities at which two servings would exceed the 4000 IU per day Upper Limit (UL).

Even at these high doses; however, clinical studies indicate that toxicity is unlikely to occur. According to the National Institutes of Health (NIH), most clinical reports set a toxicity threshold of 10,000 IU – 40,000 IU vitamin D per day. The Mayo Clinic has noted toxic reactions after several months of consumption of 50,000 IU vitamin D daily.

Three products – Nature Made Adult Chewable Vitamin D, Trisorb Vitamin D, and Natrol Vitamin D3 – utilized sucralose (Splenda), an artificial sweetener, in their formulations. Sucralose has been suggested as a trigger of migraines in those who have previously suffered from migraines, but has shown no conclusive carcinogenic, reproductive, or neurological adverse effects in existing clinical research.

FD&C Blue No. 2 and FD&C Red No. 40 – both found in Nature Made Adult Chewable Vitamin D3 – have been linked to DNA damage and increased incidence of cancer in animal models. FD&C Red No. 40 has also been suggested as a cause of hyperactivity in humans.

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PROJECTED EFFICACY

Every vitamin D supplement analyzed for this report utilized vitamin D3 (cholecalciferol) instead of vitamin D2 (ergocalciferol).

All products recorded at least 1000 IU vitamin D per serving, significantly above vitamin D’s 400 IU Daily Value (DV), set by the U.S. FDA, and its 600 IU Recommended Dietary Allowance (RDA), set by the U.S. Institute of Medicine.

Additionally, every supplement utilized vitamin D3 (cholecalciferol) instead of vitamin D2 (ergocalciferol). Vitamin D3 is expected to work more effectively in the body since it is the form of vitamin D that is already synthetized by humans.

Vitamin D’s most established function is that of promoting calcium absorption in the gut – which maintains adequate serum calcium and phosphate concentrations – promoting neuromuscular health and normal mineralization of bone.

In a clinical setting, vitamin D (in combination with calcium) is most often used to treat and reverse conditions resulting in thin, brittle, and fragile bones: rickets in children, ostemalacia in adults, and osteoporosis in older adults.

Research has suggested a variety of other biological roles for vitamin D, including modulation of cellular growth, immune function, and reduction of inflammation. Vitamin D is also thought to regulate – at least, partially – genes encoding proteins involved in cellular proliferation, differentiation, and apoptosis (programmed cell death).

2020) – 8 Reasons Why

Vitamin D3 is promoted as a highly bioavailable form of this vitamin, effective in assisting a healthy bone system and teeth. The formula is marketed by one of the most popular American manufacturers of dietary supplements called Now Foods. Their formulations are sold internationally and enjoy the appreciation of a large number of consumers of such products. The range of supplements is very wide in terms of targeted ailments and variety of combinations.

Vitamin D3 is also available in various different forms: capsules, softgels or liquid form. The consumer also has the possibility to choose between several concentrations of active substance (400IU, 1,000IU, 2,000IU or 5,000IU vitamin D per serving) and different quantities (60-240 softgels/capsules).
This supplement is promoted based on a highly absorbable form of vitamin D, an essential nutrient that cannot be supplied only through diet, particularly because food sources that contain sufficient amounts of vitamin are rather limited. This is why supplementation with vitamin D is often the recommended alternative to ensure that optimal levels of this nutrient are present in the body.

Vitamin D3 is recommended for adults concerned with maintaining their dental health and that of the bones. People who suffer from kidney disorders, hypercalcemia, people taking other medications, and pregnant/lactating women are advised to consult a healthcare professional before using this formula.

Vitamin D3 is promoted as particularly useful for those who avoid sun because of the harmful effects of sun exposure (UV radiation). This nutrient is required for proper Calcium absorption, an essential mineral for the normal functioning of the human body. Adequate amounts of vitamin D provide numerous other benefits in humans, which will be detailed further in this review.

Facts

1) Vitamin D3 Quick Facts

Vitamin D3 is one of the two active forms belonging to the Vitamin D group, also known as Cholecalciferol. It is also the natural form of vitamin D produced by humans, and is considered more potent than the other form (vitamin D2, or ergocalciferol).
Vitamin D3 can be synthesized from two main sources: sunlight (sun exposure) and foods like fish, fish oils, fortified cereals, and eggs. Both sources are considered limited suppliers of vitamin D3. Exposure to sunlight is reduced particularly during cold seasons and in the Nordic countries.

This nutrient has been researched for its possible connections to several healthcare issues, including bone disorders (osteoporosis in the elderly), diabetes, multiple sclerosis, cancer, and circulatory conditions. It is also considered an essential nutrient for the healthy growth and development of bone tissue in children and prevention of rickets. Vitamin D3 benefits are numerous, but further research is required to demonstrate all its claimed therapeutic effects.

The vitamin is required for proper absorption of Calcium at bone and muscle level. Insufficient amounts of this substance result in improper absorption of Calcium, which forces the body to get this mineral from the deposits found in the skeleton (where the highest concentrations of Calcium can be found). The long-term side effects are weak bones and inability of the body to form new, healthy bone tissue.
Vitamin D3 side effects (when excess of the vitamin is present in the blood) include nausea, constipation, weight loss and reduced appetite, confusion, and disorientation. The upper limit for adults is 4,000 IU daily.

Vitamin D3 enjoys a great popularity among consumers. A large number of testimonials available for online consulting support the benefits of this supplement.

Ingredients

2) Vitamin D3 Ingredients

Vitamin D3 contains the following ingredients: Vitamin D3 (as Cholecalciferol) (from Lanolin), Olive oil, and softgel capsule (gelatin, glycerin, water).

3) Is Vitamin D3 Right for You?

Vitamin D3 is one of the two bio-available forms of Vitamin D. However; Vitamin D3 is the natural form in response produced by the human body when exposed to direct sunlight. It is also present in various types of in foods including fortified cereals, fish, cod liver oil, and eggs. The amount of vitamin D provided by common food sources is considered rather limited which is why vitamin D deficiency is a common health issue nowadays. More so, in recent years, specialists all over the world have issued numerous warnings regarding the negative consequences of inappropriate or prolonged sun exposure, which also reduces the amount of vitamin D synthesized by our bodies. The major health concerns associated with low vitamin D levels are reduced low bone density (increasing the risk of osteoporosis and fracture in the elderly), poor immune function, hair growth and increased risk of cancer.

Vitamin D3 is an oil soluble chemical and is commonly recommended alongside a rich diet in fats to increase absorption of this nutrient. However, existing research does not adequately support this claim as it was observed that larger meals promote higher absorption rates than oily bases.
Vitamin D3 side effects include nausea, weakness, headache loss of appetite and weight loss, dry mouth, or metallic taste (particularly for high doses). Consuming over 4,000 IU of vitamin D3 daily for longer periods may increase calcium levels in the blood. Vitamin D supplements may interact with other medication including antacids (that contain Aluminum), Calcipotriene, Digoxin (Lanoxin), Verapamil, and Thiazide diuretics. The recommended daily dose for adults up to 70 years old is 600 IU and 800IU for adults over the age of 70.

There are testimonials posted about Vitamin D3. What is being stated includes the following:

• This stuff is great! D3 is awesome and helps keep me happy! It gives me some energy as well! After my annual visit to my doctor, blood work showed my Vitamin D was low, starting taking this and about three months later had a “follow-up” Blood work shows I have back in the normal range
• I like the size of these, and they are easy to swallow. 5000IU is a lot so only use this if recommended by a doctor.

Benefits

4) Vitamin D3 Benefits & Results

• The formula comes at a very affordable price and in numerous concentrations, forms and quantities, which makes it easier for consumers to choose the form that fits their individual needs
• The supplement is available for international purchase at various online retailers (the manufacturer only ships in the USA)
• There is a large number of testimonials that supports the benefits of the product
• The producer is an experienced and reputable company

Warnings

5) Vitamin D3 Product Warnings

• There is no money back guarantee or a free trial offered by the manufacturer
• The formula is not itself a clinically researched product

Cost

6) Vitamin D3 Cost

The soft gel form of Vitamin D3 is available in 3 quantities, respectively 120, 180 and 240 soft gels and different concentrations. The supplement also comes as capsules and liquid solution.
Those who want to buy Vitamin D3 produced by this manufacturer can do so by placing an online order on the official site, or from a third-party retailer. The official web page of the manufacturer offers a search engine for those who want to find a partner store that commercializes this product.
The manufacturer only ships its products on the US territory. Shipping charges start from a relatively small sum.
The manufacturer guarantees online ordering. There seems to be no money-back guarantee for unsatisfied clients.

Suggested Use

7) Suggested Use

The suggested dose varies depending on the concentration of active substance and form (capsule, softgel, or liquid).

Final Thoughts

8) Final Thoughts on Vitamin D3

Vitamin D3 is a dietary supplement based on a single nutrient considered fundamental for the overall health of humans. The formula is not unique, but has the advantage of being produced by a very important and trusted company, with an international reputation of providing high quality formulations.

The supplement does not contain sugar, salt, starch, gluten, soy, milk, egg, shellfish, wheat or yeast, which are common causes of allergic reactions. It is also a free of preservatives product. The extract of vitamin D comes from Lanolin, a waxy substance derived from sheep wool. This is a common source of vitamin D supplements and hence this product is not suited for vegetarians and vegans.

Vitamin D3 and the therapeutic benefits of vitamin D supplementation have been extensively researched. There is no doubt that a deficiency in this substance is an underlying cause of severe affections of the bone, heart, or some types of cancers. Those who are interested in buying Vitamin D3 can find the product in numerous pharmacies and healthcare stores.

Whole health includes a focus on brain health. That’s why we support those supplements with proven benefits in promoting brain health.

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Benefits, Best Sources And More – Forbes Health

Sources

Sizar O, Khare S, Goyal A, Bansal P, Givler A. Vitamin D Deficiency.Treasure Island, FL: StatPearls; 2021.

Vitamin D. National Institutes of Health. Accessed 4/13/2021.

DeLuca H.The metabolism and functions of vitamin D. Advances in Experimental Medicine and Biology.1986;196:361-75.

Sahay M, Sahay R. Rickets—vitamin D deficiency and dependency. Indian Journal of Endocrinology and Metabolism. 2012;16(2):164–176.

Giovannucci E, Liu Y, Hollis B, Rimm E. 25-hydroxyvitamin D and risk of myocardial infarction in men: A prospective study. JAMA Internal Medicine.  2008;168(11):1174-80.

Martin T, Campbell R. Vitamin D and diabetes. Diabetes Spectrum.  2011;24(2):113-118.

VDSCP: Vitamin D Standardization-Certification Program. Centers for Disease Control and Prevention. Accessed 4/13/2021.

Anglin R, Samaan Z, Walter S, McDonald S. Vitamin D deficiency and depression in adults: Systematic review and meta-analysis. Cambridge University Press. 2018;202(2).

Sunyecz J. The use of calcium and vitamin D in the management of osteoporosis. Therapeutics and Clinical Risk Management. 2008;4(4):827–836.

Zhang Y, Fang F, Tang J, et al. Association between vitamin D supplementation and mortality: Systematic review and meta-analysis.  British Medical Journal (BMJ).  2019;366:l4673.

Aranow C. Vitamin D and the immune system. Journal of Investigative Medicine.  2011;59(6):881–886.

Meltzer D, Best T, Zhang H, et al. Association of vitamin D status and other clinical characteristics with COVID-19 test results. JAMA Network Open. 2020;3(9):e2019722.

Rhodes, L, Webb A, Fraser H, et al. Recommended summer sunlight exposure levels can produce sufficient (> or =20 ng ml(-1)) but not the proposed optimal (> or =32 ng ml(-1)) 25(OH)D levels at UK latitudes. Journal of Investigative Dermatology. 2010;130(5):1411-8.

FoodData Central. U.S. Department of Agriculture. Accessed 4/13/2021.

Simon R, Borzelleca J, DeLuca H, Weaver C. Safety assessment of the post-harvest treatment of button mushrooms (Agaricus bisporus) using ultraviolet light. Food and Chemical Toxicology.  2013;56(278-289).

Vitamin D fact sheet. National Institutes of Health. Accessed 4/13/2021.

Burt L, Billington E, Rose M. Effect of high-dose vitamin D supplementation on volumetric bone density and bone strength. Journal of the American Medical Association (JAMA).  2019;322(8):736-745.

Holick M, Biancuzzo R, Chen T, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D.  The Journal of Clinical Endocrinology and Metabolism.  2008;93(3):677–681.

Jäpelt R, Jakobsen J. Vitamin D in plants: a review of occurrence, analysis, and biosynthesis. Frontiers In Plant Science.  2013;4:136.

Ritu H, Gupta A. Fortification of foods with vitamin D in India. Nutrients. 2014;6(9):3601–3623.

A systematic review on findings from meta-analyses summarizing trial data

Introduction

In recent years the number of studies exploring effects of vitamin D beyond its well-known effects on the musculo-skeletal system have increased markedly. The vitamin D receptor (VDR) and the enzyme (the 1α-hydroxylase) needed to hydroxylate 25-hydroxyvitamin D (25OHD) to its active form 1,25-dihydroxyvitamin D (1,25(OH)2D) has been identified in a large number of different cells. This widespread expression of the 1α-hydroxylase suggests that local production and action of 1,25(OH)2D to regulate VDR-directed gene expression may be of importance to the function of many tissues [1]. Moreover, gene array studies have shown that vitamin D may be involved in the regulation of as much as 5% of the human genome [1–3].

Studies in different populations from around the world have shown a high prevalence of vitamin D insufficiency, and observational studies have described associations between low circulating levels of 25OHD and a large number of diseases, including cardiovascular diseases (CVD), malignancies, diabetes, obesity, infections, neuropsychiatric, and autoimmune diseases [4–16].

As causality should not be infered from observational studies, there is a strong need for clinical and population based trials. So far, only relatively few randomized clinical trials (RCT), specifically designed to assess effects of vitamin D on non-skeletal outcomes, have been performed. Nevertheless, the number of papers published on potential causal effects of vitamin D supplementation is rapidly growing as findings from previously published RCTs, originally designed to evaluate skeletal effects, are being reanalysed in order to elucidate possible non-skeletal outcomes. In evidence-based medicine, results from systematic reviews (SR) of RCTs are considered as the highest level of evidence [17]. Within the last few years, an increasingly number of SRs has been published, including meta-analyses (MAs) with summary data on results from RCT on non-skeletal outcomes in response to supplementation with vitamin D [18–20]. In this paper, our aim is to provide a comprehensive umbrella review on SRs reporting MAs with summary results on clinically relevant non-skeletal outcomes from trials on vitamin D supplementation. In addition, we report characteristics of the individual trials included in MAs, in order to review the evidence-base providing data for published MAs.

Methods

The present paper is a part of a collaborative study between a number of European research institutions within a project on food-based solutions for eradication of vitamin D deficiency and health promotion throughout the life cycle (ODIN project, www. odin-vitd.eu) funded by the European Commission as part of the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities.

At a consensus meeting in Tromsø, Norway, we decided which outcomes to study. Criteria for selecting studied outcomes were:

1. Non-skeletal effects of supplementation with vitamin D in terms of either vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) have been investigated in at least two randomized trials.
2. At least one MA published in which findings fromRCTs has been summarized.
3. Outcomes should cover different organ systems and be of clinical importance to European citizens i.e., outcomes on biomarkers were not considered.
4. Reviews should be published in English

Based on these criteria, we selected to study effects of vitamin D supplementation in trials on CVD, blood pressure, type 2 diabetes (T2D), body weight, birth weight, malignant diseases, respiratory tract infections (excluding tuberculosis), depression, and mortality.

We searched PubMed, Embase, and the Cochrane Library until December 1^st, 2016 for SRs published in English within the last 10 years on findings from RCTs testing effects of vitamin D supplementations on the selected outcomes. The search strings used are detailed in the supplementary file (S1 File).

In addition, we manually searched references cited in the papers as well as papers citing the selected papers for additional articles. We only included SRs reporting summary data in terms of MAs. Only MAs on effects of treatment with calciferol (vitamin D2 or D3) were considered. However, we also accepted MAs including RCTs on activated vitamin D analogues in their summary estimate, as long as the majority (>50%) of included studies were on calciferol. In addition, we included a trial on effects of vitamin D supplementation on birth weight although published outside the predefined time range as this SR reports important information on potential bias in a previously published trial [21]. While writing the paper, a large MA on effects of vitamin D supplementation on risk of respiratory infections was published in February 2017 [22]. Although being published after the end of the time period defined a priori, we decided to include this paper, as it is the largest MA published so far on vitamin D and infections. A flow chart showing the search profile is shown in Fig 1.

For each MA we assessed its quality using the AMSTAR tool for which the quality is measured on a scale between 0 to 11 [23]. A total score of 9–11 is considered as ‘good’ quality, whereas a score of 5–8 shows ‘moderate’ quality and a score of 0–4 indicates a ‘poor’ quality [24]. Furthermore, for each MA we scrutinize the original papers included in the summary estimate on studied outcomes. Specific characteristics of the individual trials were systematically identified, including the population studied and whether (if relevant) subjects were diagnosed with the disease in question. We also collected information on type of vitamin D studied, dosing frequency, duration of the intervention, and whether calcium was co-administered. Furthermore, we noted whether only participants with low 25OHD levels were included (defined as 25OHD < 50 nmol/L). Finally, we retrieved information on baseline 25OHD levels and whether the intervention resulted in a more than 50% increase in 25OHD levels, as well as the main finding (conclusion) of the trial. We did not perform new MAs, but summarized the characteristics in tables in order to allow for a quantitative evaluation of characteristics of the studies forming the evidence base for published MAs.

Results

We identified 54 SRs reporting summary data in terms of a formal MA on effects of vitamin D supplementation on selected outcomes (Table 1). Included SRs had a mean AMSTAR score of 8.8 (range 6–11) suggesting an overall moderate to good quality. Within each group of studied non-skeletal health outcomes, mean AMSTAR score varied between 8.4 to 9.8 (Table 1). For each outcome, number of RCTs included in one or more of the MAs varied from four to 69 trials. A total of 210 RCTs were included in the MAs.

Cardiovascular diseases (CVDs)

A number of observational studies have reported an inverse association between 25OHD concentrations and risk of CVDs [25–27], including a greater carotid intima–medial thickness [28], peripheral arterial disease [29], and risks of cardiovascular (CV) death [30,31]. Moreover, MAs on data from observational studies have consistently found an increased risk of CVD in subjects with vitamin D insufficiency [32,33]. An effect of vitamin D on CV health is furthermore biologically plausible, as the 25OHD-1α-hydroxylase enzyme is expressed by CV tissues and the VDRs have been identified in vascular smooth muscle cells, cardiomyocytes, as well as in coronary arteries [34–36]. Given the presence of the VDR in the vascular system, vitamin D may potentially improve CV health through several biological pathways. For example, activation of the VDR has been shown to inhibit vascular smooth muscle cell proliferation, which is believed to be cardio-protective [37,38]. Moreover, a state of chronic inflammation is considered to play a key role in the initiation and progression of CVD [39,40], and several studies have shown an inverse association between 25OHD levels and markers of inflammation, suggesting that vitamin D also may protect against CVD by lowering the state of inflammation [41–43]. On the other hand, trials assessing the effects of vitamin D supplementation on arterial stiffness, a marker of cardiovascular risk, have shown ambiguous results. In a MA including data from seven RCTs involving a total of 547 participants, supplementation with vitamin D3 for 2 to 12 months showed no significant effects on changes in pulse wave velocity [44]. Nor did a MA including data from seven RCTs suggest beneficial effects of vitamin D supplementation on left ventricular function or exercise tolerance [45].

We identified 10 SR among which seven reported summary data for incident CVDs in terms of formal MAs, whereas three SRs considered the interventions and outcomes in published RCTs to be too heterogeneous for MA [36,46,47]. Table Aa in S1 File shows the seven SRs reporting pooled data on results from RCTs on effects of vitamin D supplementation on risk of CVDs [48–54]. None of the MAs showed neither beneficial nor harmful effects on estimates in response to the interventions on risk of CVDs, in terms of any CV events, myocardial infarctions (MI), stroke/ cerebrovascular disease, or CV death (Table Aa in S1 File). In several of the MAs summary risk estimates were stratified by whether vitamin D was provided alone or in combination with calcium (CaD), showing no effects of any of the interventions. Only one of the seven MAs addressed whether supplementation to individuals with low vitamin D levels may result in beneficial effects on cardiovascular health, showing no significant interaction when comparing risk estimates from studies with mean 25OHD levels below vs. above 50 nmol/L on stroke (P_{interaction [Pi]} = 0.36) or myocardial infarction (P_i = 0.83) [49]. Neither did interaction analyses suggest differences according to whether the intervention resulted in increased (unspecified) 25OHD levels on risk of stroke (P_i = 0. 41) or myocardial infarction (Pi = 0.34) [49].

Numbers of RCTs included in each MA varied from two to 11 RCTs, and the total number of randomized participants included in the RCTs varied between 2,988 and 48,647. The seven MAs included data from a total of 21 RCTs (Table Ab in S1 File), among which 16 were on effects of treatment with calciferol and five on treatment with activated vitamin D analogues. Only the study by Trivedi et al. [55] was included in all seven MAs, whereas two trials were included in six of the MAs.

Summary characteristics of the 21 RCTs are shown in Table 1. None of the trials had pre-specified CVD as their primary outcome. Most of the trials included only women, and none of the RCTs studied only men. Six of the RCTs were large-scale studies with more than 1000 participants. Only one of the trials included paticipants recruited based on cardiovascular risk factors in terms of systolic hypertension [56]. Thirteen RCTs investigated effects of vitamin D3, two studied effects of vitamin D2 and one study did not report specifically whether the intervention was D2 or D3. In five studies, all included (only) in the MA by Ford et al. [53], effects of activated vitamin D analogues were investigated. In most of the studies, vitamin D was administered as a daily dose and calcium was co-administered in approximately half of the studies. Only two trials had low 25OHD levels (< 50 nmol/L) as inclusion criteria [57,58], in which 352 participants who received treatment for one-year participated [57,58]. In addition, four RCTs reported mean 25OHD levels at baseline below 50 nmol/L [56,59–61], in which approximately 8000 participants were randomized to treatment for one to five years. Among the 16 trials investigating effects of vitamin D2 or D3, only four reported an increase in 25OHD levels of more than 50% in response to the treatment. None of the included RCTs reported neither beneficial nor harmful effects on risk of CVDs in response to the interventions. While writing this review, we noticed that findings from a large RCT (one of the so called ‘mega-RCTs’) were published on effects of vitamin D treatment on risk of CVD in the general population as primary endpoint. In the study, Scragg et al [62] randomized 5110 participants (42% females) to receive placebo (n  =  2552) or vitamin D3 (n  =  2558) with an initial dose of 200,000 IU, followed a month later by monthly doses of 100,000 IU, for a median of 3.3 years. The study showed no beneficial effects of vitamin D supplementation on risk of CVD (hazard ratio [HR] 1.02; 95% confidence interval [CI] 0.87 to 1.20). The study population had a mean (SD) baseline deseasonalized 25OHD concentration of 66 (26) nmol/L and 25% of studied subjects had 25OHD levels below 50 nmol/L at baseline. Similar to the main analysis, sub-analyses on effects of vitamin D supplementation within the group of participants with 25OHD levels below 50nmo/L showed no effects of the intervention.

In summary, a discrepancy seems to exist between findings from observational studies and randomized trials on effects of vitamin D on risk of CVDs. Nevertheless, none of the RCTs included in the MAs have been designed to specifically address whether supplementation with vitamin D affects CV health and available data from secondary analyses are, as reviewed above, characterized by a high degree of heterogeneity. However, the recently published study by Scragg et al [62] with CVD as primary outcome does not support beneficial effects of vitamin D supplementation on risk of CVD. Importantly, whereas observational studies have reported adverse health effects on CV health of low 25OHD levels, only few of the RCTs published have specifically investigated effects in a population with low 25OHD levels.

Blood pressure

A possible link between vitamin D and hypertension has been extensively investigated. Strong observational data associate low 25OHD levels with an increase in blood pressure and an increased risk of hypertension [63–65]. Moreover, a large Mendelian randomization analysis concluded that increased 25OHD levels might reduce risk of hypertension [66]. Vitamin D may control blood pressure through its regulatory effects on the renin–angiotensin–aldosterone system (RAAS) [67,68]. Vitamin D may suppress the renin biosynthesis [67], and human studies have shown increased levels of renin and angiotensin II in subjects with vitamin D deficiency [69,70]. Moreover, a positive correlation has been shown between PTH and angiotensin II/ aldosterone [68,71,72]. Trials with vitamin D supplementation have furthermore shown that vitamin D stimulates various effects on the endothelia, smooth muscle cells, and in macrophages. Such local mechanisms of action on the vessel wall have been suggested to be of importance for blood pressure regulation [73–77].

We identified nine SRs on RCTs reporting effect of vitamin D supplementation on blood pressure [46,49,78,79] [80–84] (Table Ba in S1 File). A significant reduction in SBP (range -6.18 mmHg. to -2.44 mmHg) with no effect on DBP was reported in two of the MAs each including four RCTs with approximately 400 participants [78,79]. In the study by Withham et al. [78] only participants from studies with elevated mean baseline blood pressure were included and effects on blood pressure was designated as the primary outcome. In contrast, in the MA by Wu et al. [79] studies on patients with hypertension were not considered, but the majority of included participants had, nevertheless, arterial hypertension.

No beneficial effects of vitamin D supplementation were, however, reported in two recent MAs by Beveridge et al [81] and Golzarand et al [83], including 38 and 30 RCTs, respectively. The two MAs included a meta-regression analysis on dose-response effects showing no associations between daily dose (-equivalent) of vitamin D supplementation and changes in BP. Similarly, the MA by Wu et al. (66) showed no dose-response effects. This is in contrast to the MAs published by Pittas et al. (39) showing a beneficial dose-response effect on DBP. In response to a daily dose above 1000 IU, DBP was significantly reduced compared with a daily dose below 1000 IU.

Three MAs have addressed effects of vitamin D in combination with calcium [46,79,83]. Two of the MAs showed no difference in change in SBP and DBP according to whether vitamin D was tested alone or in combination with calcium D, whereas the MA by Golzarand et al [83] found a significantly increase in SBP (3.64 mmHg, 95%CI: 3.15–4. 13) and DBP (1.71 mmHg, 95%CI: 1.25–2.18) in response to treatment with CaD.

Two MAs have investigated effects of vitamin D supplementation in specific populations. By pooling results from 15 RCTs on patients with T2D, Lee et al. [84] found no effects of vitamin D on SBP, although DBP was slightly but significantly (p = 0.02) reduced (SMD –0.160 (95% CI –0.298 to –0.022) mmHg, I2 = 0%). In contrast, an increase in SBP (WMD: 0.237; 95% CI, 0.110 to 0.365) was found in a trial level MAs by Manousopoulou et al. [82], including five RCTs on adults with obesity.

Only two of the MAs have investigated whether baseline 25OHD levels are of importance. In the MA by Withham et al. [77], all four studies included reported mean 25OHD level below 50 nmol/L with a summary estimate showing a significantly decreased SBP in response to the intervention. In contrast, a trial-level meta-regression analyses in the SR by Beveridge et al [81] showed no significant effects on responses in blood pressure of baseline 25OHD levels or increases of 25OHD levels in response to supplementation.

The nine MAs included data from 59 RCTs with a total of 42,814 participants. The majority of the participants were from the WHI study, whereas the number of participants ranged from 16 to 511 in the other 58 RCTs (Table 3B in Bb S1 File). The studies have been published between 1983 and 2015. Eight of the RCTs had a duration of one-year or more and none of these studies with long duration showed a reduced BP in response to the intervention.

In 49% of the studies, vitamin D was administered as a daily dose and calcium was co-administered in 12 of the studies. Most trials used oral vitamin D3, but one study [85] reports the effect of UVB vs. UVA radiation and in one study the effect of a single dose vitamin D2 was investigated [86]. Although 25OHD levels below 50 nmol/L was only required as an inclusion criteria in eight (14%) of the studies, mean 25OHD levels at baseline were below 50 nmol/L in 63% of the trials and increased by more than 50% in response to the supplementation in almost two-third of the trials (Table 1).

Overall, eight RCTs reported a beneficial response of vitamin D on blood pressure [85–92], whereas 51 studies found no effects (Table Bb in S1 File). Among the eight studies reporting a beneficial response, two had low 25OHD levels as inclusion criteria [86,87] and six of the trials reported a mean 25OHD level at baseline below 50 nmol/L [85–87]. Furthermore, five of the studies reported a mean increase in 25OHD levels of 50% or more in response to the intervention [85,87,88,90,92]. Type of vitamin D intervention varied widely between the eight studies showing beneficial effects. Three studies used vitamin D in combination with calcium [87,89,91] and one study used UVB exposure [85]. The remaining four studies administrated vitamin D using different dosing regimens in terms of a daily dose [90], a weekly dose [92], a single high dose [86], or a 50,000 IU dose of D3 administrated twice three weeks apart [88]. The populations studied in the eight trials varied widely. Some studies included patients with mild hypertension, others pregnant women or healthy normotensive persons. In additin, as recently highlighted in a paper by Veloudi et al. [93], only a small proportion of the trials on effects of vitamin D supplementation on blood pressure have actually examined effects in patients with low vitamin D levels. Similarly, we found that only eight of 51 trials (16%) included in published MAs had a 25OHD level below 50 nmol/L as inclusion criterion.

In summary, two of nine published MA and eight of 59 individual RCTs included in the MAs, showed beneficial effect of vitamin D supplementation on BP, whereas one MA found an increase in SBP in obese adults in response to vitamin D supplementation. Overall, these results do not provide substantial support for the findings from the observational studies on an importance of vitamin D on blood pressure regulation. Nevertheless, as most trials on effects of vitamin D supplementation has been performed in populations without low 25OHD levels, the hypothesis raised by observational studies on adverse effects of low vitamin D levels has in reality not been tested to a large extent by trials performed so far.

Diabetes

Numerous observational studies have shown lower 25OHD levels in patients with T2D compared with the general population, as well as an inverse association between 25OHD levels and fasting plasma glucose, impaired glucose tolerance, and HbA1c levels [94–103]. In studies on potential biological actions of vitamin D in relation to glucose homeostasis, vitamin D has been suggested to be of importance to insulin secretion and action. The pancreatic islet cells have been shown to express the VDR as well as the 1α-hydroxylase enzyme, enabling conversion of 25OHD into its active form directly by the β-cells [104,105]. In animal experimental studies, vitamin D deficiency inhibits pancreatic secretion of insulin [106] and vitamin D repletion of rats with vitamin D insufficiency has been shown to improve glucose tolerance and glucose-stimulated insulin release [107,108]. Trials in humans on potential effects of vitamin D supplementation on indices of glucose homeostasis have, however, not demonstrated a clear beneficial effect. Recent MAs on results from RCTs showed no significant improvement on indices of glucose homeostasis including HbA1c levels in those treated with vitamin D compared with placebo [19,109–111]. Restricting study subjects to patients with diabetes or impaired glucose tolerance, one of the MA showed, nevertheless, a small but significant improvement in fasting glucose levels (−0.32 mmol/L, 95% CI, −0.57, −0.07) and a small improvement in insulin resistance (SMD −0.25, 95% CI, −0.48, −0.03) [109]. As these reviews provides a comprehensive update on findings from randomized trials on effects of vitamin D on biochemical indices of glucose homeostasis, we chose to focus on clinical outcomes in terms of effects of vitamin D supplementation on risk of incident T2D.

We identified three SRs on risk of incident T2D in RCTs on vitamin D supplementation [12,112,113]. However, only one of the SRs provided a summary risk estimate based on a MA [12] (Table Ca in S1 File). The MA included data from four RCTs [114–117], and showed no effects of vitamin D supplementation on risk of incident T2D [12]. Stratification by glucose levels at baseline showed no effects on risk of progression in participants with normal glucose levels or in patients with an impaired glucose tolerance at baseline. The SR did not report findings according to baseline levels of 25OHD or changes in 25OHD levels in response to supplementation.

Table Cb in S1 File shows characteristics of the four RCTs included in the MA and characteristics of the RCTs are summarized in Table 1. Only one of the four studies had development of diabetes as a co-primary end-point [117]. This was a small study that included only 109 patients with pre-diabetes [117]. One study included patients diagnosed with pre-diabetes, whereas two studies included participants from the general population and one study included patients with a previous fracture. None of the studies had low 25OHD levels as a prerequisite for inclusion and mean 25OHD levels at baseline was only below 50 nmol/L in only one of the trials [116]. None of the individual RCTs showed beneficial effects of vitamin D supplementation on risk of incident T2D.

In summary, there is a discrepancy between findings from observational studies and RCTs on effects of vitamin D on risk of T2D. The number of trials is relatively small and the majority of subjects included in the trials did not have low 25OHD levels. Accordingly, the findings from observational studies on an increased risk among those with vitamin D insufficiency cannot be considered as being disproved by data from RCTs.

Body weight/obesity

Obesity has been associated with low levels of 25OHD in a large number of observational studies [118–121]. This may be attributable to different mechanisms. Following endogenous synthesis or dietary intake, vitamin D is readily stored in adipose tissue [122]. As the body pool of fat is larger in obese compared with non-obese individuals, vitamin D may be diluted or sequestered in the larger body pool of fat resulting in lower plasma levels [123]. Moreover, in a study by Wortsman et al. [124], it was found that following endogenous synthesis; the release of vitamin D3 from the skin into the circulation is decreased in obesity. It has also been suggested that obese subjects are less exposed to sunlight, leading to lower 25OHD levels. This may be due to clothing habits and less involvement in outdoor activities (reduced mobility) resulting in less skin exposure [125]. Finally, a recently published bi-directional Mendelian randomization analysis of multiple cohorts showed that a higher BMI leads to lower plasma 25OHD levels whereas low 25OHD levels did not appear to lead to a high BMI [126].

In contrast to the above reviewed findings, suggesting that low vitamin D levels are a consequence of obesity, findings from a number of other studies have suggested that low 25OHD levels may predispose to obesity. The VDR is expressed by adipose tissue and adipose tissue has the ability to synthesize 1,25(OH)₂D [127,128]. Studies have also suggested that vitamin D may regulate adipose tissue mass, differentiation and metabolism in ways that might contribute to obesity [129]. Furthermore, secondary hyperparathyroidism is a well-known consequence of vitamin D insufficiency and increased PTH levels promote calcium influx into the adipocytes. In adipocytes, intracellular calcium may enhance lipogenesis, and PTH excess may thereby promote weight gain [130,131]. Conflicting results have been reported on the potential anti-inflammatory effects of vitamin D. Obesity is considered as a state of chronic low-grade inflammation [132]. Although several in-vitro and animal experimental studies have suggested anti-inflammatory effects of vitamin D in obesity, results from human intervention studies have not shown effects on inflammatory cytokines in response to vitamin D supplementation [133–135].

In our search for SRs reporting effects of vitamin D supplementation on changes in body weight, we identified four SRs [82,136–138] among which three provided summary data in terms of a formal MA including data from 32 RCTs (Table Da in S1 File). Overall, the MAs showed no effects of vitamin D supplementation on changes in body weight, fat mass (FM), percentage FM (%FM), or lean body mass. Only the MA by Chandler et al. [138] showed a beneficial effect on weight loss of supplementation with CaD as compared to placebo.

Table Db in S1 File shows characteristics of the 32 RCTs included in the MA and summary characteristics of the trials are shown in Table 1. The 32 RCTs have been published between 1987 and 2014. One of the trials included in the MA by Chandler et al. [138] reported effects on treatment with active vitamin D [139], whereas the other 31 trials reported effects of treatment with vitamin D2 (2 RCTs) or D3 (29 RCTs). The majority of the individual trials reported null-findings. Only two trials found beneficial effects of supplementation [139,140]. In the WHI trial, a secondary analysis on weight changes showed that women randomized to the CaD group had smaller average annual weight gains than women assigned to the placebo group [140]. In contrast, Maki et al. [141] reported a significantly increased body weight in response to eight weeks of treatment with a daily multivitamin and mineral supplement containing D3 1,200 IU D3/d compared with the same supplement without D3. Weight loss was a primary endpoint in five of the trials [142–146] and none of these showed beneficial effects of vitamin D intervention. Most of the studies assessed effects in both men and women (N = 16 trials). Number of subjects included was less than 1000 in all of the trials except for the WHI trial [140]. Eleven (34%) of the trials included participants with (signs of) obesity, none of them showing beneficial effects of supplementation.

Six (19%) of the studies had low 25OHD levels (<50 nmol/L) at baseline as a criterion for inclusion, but mean 25OHD levels were below 50 nmol/L in almost half of the studies (N = 15) and 25OHD levels increased by more than 50% in N = 15 (47%) of the trials in response to the intervention (Table 1). Only one of the MAs have addressed the importance of 25OHD levels, showing no effects of either 25OHD levels archived in response to supplementation nor change in 25OHD levels from baseline in meta-regression analyses on obesity measures [137].

In summary, an inverse association between body weight and 25OHD levels is well documented. While it is generally agreed that obesity results in low 25OHD levels, it is still disputed whether low 25OHD levels may contribute to weight gain. Although most of the individual RCTs included in the MAs were relatively small in terms of number of participants and of short duration, the studies did, nevertheless, investigate effects of vitamin D supplementation in populations in which mean 25OHD levels were below 50 nmol/L, as well as 25OHD levels increased by more than 50% in approximately half of the studies. Accordingly, trial data do not support a beneficial effect of vitamin D supplementation on weight loss.

Birth weight

Vitamin D insufficiency is common in pregnant women [147–149], and a number of studies have investigated effects of vitamin D status on pregnancy outcomes. Results from three SRs on findings from observational studies, suggest a reduced birth weight in infants born by mothers with low 25OHD levels [18,150,151]. In a MA by Aghajafari et al. [150] a significantly lower birth weight (weighted mean difference −131g; 95% CI, −187g to −75g) was found in infants born by mothers with 25OHD levels below 37. 5 nmol/L during pregnancy. The MA also showed a significant inverse association between low 25OHD levels and risk of small gestational age (SGA) infants (OR 1.85; 95% CI, 1.52 to 2.26), as well as risk of gestational diabetes, pre-eclampsia, and bacterial vaginosis [150]. Similar findings were reported in a SR by Wei et al. [151], in which a MA of observational data showed an increased risk of SGA infants (OR 1.52, 95% CI, 1.08 to 2.15) if maternal 25OHD levels were below 50 nmol/L during pregnancy. Moreover, in an umbrella review of SRs, Theodoratou et al. [18] reported concordant results from MA of observational studies and randomised trials, suggesting an increased birth weight with improved vitamin D status.

Several biological mechanisms responsible for potential effects of vitamin D on fetal development have been suggested, including an importance of vitamin D on placental development through effects on human chorionic gonadotropin expression and placental sex steroid synthesis [152]. Moreover, an increased expression of 1α-hydroxylase and VDR in early pregnancy trophoblast and decidua tissue has been reported, suggesting an importance of vitamin D in early foetal development [153].

In our search for SRs on effects of vitamin D supplementation on birth weight, we identified eight SR [21,113,154–158] among which six [21,154,155,157–159] reported MAs on pooled data from RCTs on effects of vitamin D supplements on weight of new-born infants (Table Ea in S1 File). Three of the MAs were Cochrane reviews which have been continuously updated [21,155,159]. In the first of the published MA, Mahomed et al. [21] found a reduced birth weight in response to vitamin D supplementation in a daily dose of 1000 IU/d. However, this was based on data from two studies with a total of only 176 pregnant women. In one of the studies, the reported SD of mean birth weight was very low (reported to be 70–90g) whereas it normally is approximately 600 g [160]. It is likely that the standard error was reported instead of SD and this may have affected the pooled estimate of the MA. Accordingly, the authors of the MA conclude that too few data were available to draw conclusions on effects of supplementation on birth weight [21]. In the other five MAs, two showed an increased birth weight in response to vitamin D supplementation [158,159], whereas three reported null findings [154,155,157] (Table Ea in S1 File). In one of the SR, data were stratified by dose of vitamin D supplementation [157], showing no effects on birth weight in neither studies using high doses nor studies using low doses (Table Ea in S1 File).

The six MAs included data from 14 RCTs. Table Eb in S1 File shows characteristics of the individual trials included in the MAs and characteristics of the individual trials are summarized in Table 1.

Overall, four of the individual trials reported beneficial effects of the supplementation, whereas 10 RCTs reported null-findings. Birth weight/fetal growth was considered as a (co-)primary endpoint in three of the four studies reporting beneficial effects of supplementation [161–163]. The number of pregnant women included in the 14 trials varied from 50 to 350. In most studies, vitamin D supplementation was initiated in the 3^rd trimester, as only a few studies started the supplementation in the 2^nd trimester [163–166].

Supplementation with vitamin D3 was used in most trials (N = 9), and in three of the four trials showing beneficial effects on birth weight. All four studies showing a beneficial effect used high dose treatment in the 3^rd trimester either as a single high dose or high doses given 2–3 times. All of the four studies were performed as open label trials in non-western contries (three in India and one in Iran).

None of the studies had vitamin D insufficiency (25OHD < 50 nmol/L) as criteria for inclusion, and eight of the trials did not report 25OHD levels at baseline or changes in response to supplementation. None of the four studies showing beneficial effects reported changes in 25OHD levels in response to treatment and only one of the four studies reported baseline 25OHD levels. None of the published MAs, reported effects according to baseline 25OHD levels or changes in 25OHD levels.

Only the studies by Brooke et al. [167] and Hollis et al. [164] reported a 50% increase in 25OHD levels in response to treatment. The study by Brooke et al. [167] had, however, a rather small sample size whereas the study by Hollis et al. [164] had a reasonable sample size and used a relatively high vitamin D dose although including women who did not have vitamin D insufficiency (Table Eb in S1 File).

In summary, in contrast to findings from observational studies, results from most RCTs have not shown beneficial effect of vitamin D supplementation on birth weight. The quality of the trials showing an increased birth weight in response to supplementation is limited by the lack of blinding and measurement of 25OHD levels. Accordingly, available data from RCTs on effects of vitamin D supplementation on birth weight do not clearly support findings from observational studies. Of notice, the sample size in most trials have been relatively small and in most of the studies, the intervention has been of short duration and initiated in late pregnancy, whereas several observational studies showing an inverse association between 25OHD levels and birth weight have assessed vitamin D status in early/mid pregnancy [168]. Accordingly, the hypothesis raised by findings from observational studies on effects of vitamin D status on birth weight has not been properly tested in RCTs.

Malignant diseases

A potential antineoplastic effect of vitamin D has been suggested by findings from in vitro studies, as vitamin D may affect several cellular processes, including proliferation, differentiation, angiogenesis, and apoptosis [169,170]. Although an association between vitamin D and risk of cancer has not been found in all human studies, several observational studies have reported an inverse association between risk of cancer and a low dietary intake of vitamin D, a low degree of sun exposure, or low plasma levels of 25OHD [171–173]. Studies on VDR polymorphisms (BsmI, TaqI, FokI, and ApaI) [174,175], and MAs on data from observational studies also support an association between low 25OHD levels and an increased risk of malignant diseases [176–180] as well as cancer mortality [181].

We identified eight SRs reporting data from RCT on risk of incident malignant diseases in response to vitamin D supplementation [52,54,113,182–186]. However, a formal MA reporting summary risk estimates was only performed in five of the SRs [52,54,184–186] (Table Fa in S1 File).

Following the Evidence/Technology Assessment report on health outcomes of vitamin D and calcium published in 2009 by Chung et al. [182], Chung and colleagues [183] published an update in 2011 on cancer outcomes. The SR reports data from three RCTs [55,187,188], but no pooled summary estimates are reported. The SR concludes that the available data do not allow for any firm conclusions on harm or benefits of vitamin D supplementation for cancer prevention. Moreover, in a SR on non-skeletal effects of vitamin D by Rosen et al [113], commissioned by The Endocrine Society, data from three RCTs are reviewed. The three studies included are similar to those reviewed by Chung et al [183]. No formal MA was performed. In accordance with the conclusion by Chung et al [183], Rosen et al [113] conclude that there is not sufficient evidence to draw conclusions on whether vitamin D may affect cancer incidence or mortality from cancer. However, the paper did not consider a prior analysis performed by Bolland et al. [189] showing an interaction between use of personal CaD supplements and randomization to CaD vs. placebo in the WHI trial. The analysis showed a significantly decreased risk of breast cancers and a non-significantly reduced risk of colorectal cancer in women randomized to CaD supplementation who did not take personal CaD supplements at randomization [189].

In a SR commissioned by the U.S. Preventive Services Task Force (USPSTF), aiming at updating the evidence on benefits and harms of vitamin and mineral supplementation to prevent cancer, Fortmann et al. [52] and Keum et al. [186] performed MAs on data from four RCTs on primary prevention of cancers in the general adult population. None of the analyses showed effects of vitamin D supplementation on risk of incident cancers, and this was not changed by stratification on whether the supplementation was provided as vitamin D alone or vitamin D in combination with calcium (Table Fa in S1 File).

Bjelakovic et al [184] published an elaborated Cochrane review including data from 18 RCTs on risk of incident cancers and cancer mortality. In the SR, a number of MAs were performed showing no significant effects of vitamin D supplementation on risk of developing cancer. However, based on data from four studies, the MA showed a significantly reduced risk on cancer mortality (RR 0.88; 95% CI, 0.78, 0.98). Similarly, a reduced risk of death due to malignancies (RR 0.88; 95% CI, 0.79–0.98, p = 0.03, I² 0%) was also been reported in MAs by Zheng et al. [190] and Keum et al. [186], both pooling findings from three trials [55,188,191] with a total of 44,260 randomized participants.

In another SR, Bolland and colleagues [54] identified SRs published since 2009 that summarized data from RCTs on effects of vitamin D supplementation on risk of cancer. Three MAs were identified including seven RCT [182,183,192]. Bolland et al. [54] performed a new MA, based on data from the seven RCTs included in theses three SRs. The new MA showed no effects of vitamin D supplementation, either alone or in combination with calcium, on risk of incident cancers (Table Fa in S1 File).

In addition, Sperati et al [185] performed a SR focusing specifically on effects of vitamin D on risk of breast cancer. The authors identified only two studies fulfilling their pre-defined criteria for inclusion of studies (Table Fa in S1 File). The MA showed no beneficial effects of vitamin D supplementation and neither was vitamin D dosage nor mode of administration found to affect risk of breast cancer [185].

Table Fb in S1 File shows characteristics of the 19 RCT included in the five MA and Table 1 summarizes characteristics of the individual studies.

None of the RCTs assessed risk of cancer as a primary outcome. The majority of the studies was performed in women-only (58%) with less than 1000 randomized participants (68%) and no RCT included in published SRs provides data on effects of vitamin D supplementation in patients already diagnosed with cancer. Mean levels of 25OHD at baseline were below 50 nmol/L in less than half of the studies and only one study had low 25OHD levels as an inclusion criteria. Only one of the MAs addressed whether vitamin D status at baseline is of importance to responses, showing no difference in risk of incident cancers between trials with mean baseline levels below 50 nmol/L (RR 0.99; 95% CI, 0.93–1.05) compared with studies with mean 25OHD levels above 50 nmol/L (RR 1.12; 95% CI, 0.94, 1.34) [184].

The majority of studies investigated effects of vitamin D3 administered as a daily supplement. The MA by Bjelakovic et al [184], also included data from three studies on treatment with activated vitamin D analogues. More than half of the studies investigated effects of vitamin D alone, whereas calcium was co-administered in seven studies to either only the vitamin D group (5 RCT) or to both the vitamin D and the control group (3 RCT). Most of the studies (79%) had a duration of at least one year. The intervention with vitamin D supplementation increased plasma 25OHD levels by more than 50% in only one-third of the studies. Only one of the 19 RCTs showed a reduced incidence of cancers in response to supplementation with vitamin D. This study was performed by Lappe et al [187] and did not have malignant diseases as a primary outcome (Table Fb in S1 File). Most recently, Lappe et al [193] have published results from a subsequent double-blind RCT comparing effect of four-years of treatment with a daily supplement of D3 2000 IU plus 1500 mg of calcium with placebo on risk of incident all-type cancer (primary endpoint). The trial included 2,303 healthy elderly women with a mean age of 65±7 years and a mean baseline 25OHD level of 82±26 nmol/L. The study showed no significant beneficial effects on cancer incidence (HR 0.70; 95% CI, 0.47 to 1.02). However, the study probably had a too low statistical power to show such an effect [194].

Conclusions: MAs on results from RCTs on effects of vitamin D supplementation on risk of cancer have concluded that no evidence exists to support a causal relationship. It should, however, be emphasized that most RCTs included in the SRs have been carried out in groups of participants without low 25OHD levels and mean changes in 25OHD levels in response to supplementation have either not been assessed or been less than 50% of baseline values in most studies. In addition, the duration of the intervention has in most studies been rather short. Interestingly, the WHI study [189] as well as the trials by Lappe et al [187,187] had a relatively long duration and did suggest beneficial effects. More so, data on specific types on malignant diseases are largely missing. Accordingly, the evidence-base by which the MAs are grounded does not seem to be appropriate to reject the findings from observational studies on an increased risk of cancer in vitamin D insufficiency.

Respiratory tract infections

For more than a century, vitamin D deficiency has been suggested to increase the susceptibility to infection. Early observations showed increased risk of respiratory tract infections (RTI) in children with nutritional rickets and vitamin D was considered of importance in the treatment of tuberculosis [195,196]. The seasonality of RTIs such as those caused by rhinovirus (“common cold”) and influenza virus is well known, and low 25OHD levels during wintertime have been suggested to be the “seasonal stimulus” which increases the susceptibility to such infections [197]. If so, this is of major importance to public health, as RTI are a major contributor to mortality [198,199]. Recent studies have provided further evidence of vitamin D as an important regulator of human immune function, as vitamin D may stimulate the innate immune response which provides front-line protection against infectious agents [200]. The VDR has been shown to be expressed in different cells of the myeloid and lymphoid lineage and vitamin D may increase the expression of antimicrobial peptides in human monocytes and neutrophils [201,202]. Particularly, vitamin D may enhance the expression of the human cathelicidin antimicrobial peptide (hCAP-18) which is of specific importance in host defenses against respiratory tract pathogens [203]. In accordance with the findings from epidemiological and in-vitro studies, a number of observational studies have suggested an inverse association between vitamin D status and risk of infections. Thus, risk of a recent RTI was significantly increased by 24% among participants with low compared with high 25OHD levels (below/above 75 nmol/L) in the Third National Health and Nutrition Examination Survey in the USA, which included 18,883 study subjects [204]. Similarly, an inverse association between vitamin D status and risk of developing RTIs has also been reported in other cohorts as well as a replete vitamin D status has been associated with fewer days of absence from duty due to RTIs [205–209].

In our search for SRs on effects of vitamin D supplementation on risk of RTIs, we identified 10 SR [22,210–218] among which seven [22,211–213,216–218] reported MAs on pooled data from RCTs on risk of RTIs in response to vitamin D supplementation (Table Ga in S1 File). In two trial-level MAs, vitamin D supplementation was found to significantly reduce risk of RTI by approximately 40% [211,212], which also applied to pediatric populations [211]. The first of the trial MA found a protective effect by summarizing data from five RCTs [211], the second trial MA included data from 11 RCTs [212]. A subsequent trial-level MA by Mao et al [213], however, found no beneficial effects of vitamin D supplementation on risk of RTI. Mao et al [213] included only data from seven RCTs, as this MA excluded studies which were considered to be of low quality in terms of a modified Jadad score ≤ 3 [219]. Most recently, an individual patient data analysis (IPD) has been published, including individual data from 10,933 study subjects included in 25 RCTs [22]. The analysis showed a significantly reduced risk of acute RTI (OR 0.88, 95% CI, 0.81 to 0.96). Sub-group analyses suggested protective effects in response to a daily or weekly vitamin D dose (adjusted odds ratio 0.81, 0. 72 to 0.91), but not in response to one or more bolus doses (adjusted OR 0.97, 95% CI, 0.86 to 1.10; P_i = 0.05). Moreover, among those receiving daily or weekly vitamin D, the protective effects were stronger in those with a baseline 25OHD <25 nmol/L (adjusted OR 0.30, 95% CI, 0.17 to 0.53) than in those with a baseline 25OHD ≥25 nmol/L (adjusted OR 0.75, 95% CI, 0.60 to 0.95; P_i = 0.006) [22]. However, two of the other published MAs found no differences between studies with mean baseline levels above or below 75 nmol/L [212] or 50 nmol/L [218].

The seven MAs included data from a total of 30 RCTs. Table Gb in S1 File shows characteristics of the individual RCTs included in the seven MAs and characteristics of the individual trials are summarized in Table 1. None of the MAs included data from all the 30 RCTs.

The majority of studies included both men and women. Only two studies were of a large scale with more than 1000 participants [220,221] and most studies had a relatively short duration. Twenty-three (77%) of the RCTs investigated effects of vitamin D supplementation as a primary endpoint (Table Gb in S1 File). Eleven trials (37%) included patients diagnosed with an infection at time of inclusion or at increased risk of acquiring infections. However, the specific infections studied varied widely between studies e.g., some investigated risk of pneumonia, upper or lower RTI, or exacerbations in patients with COPD or asthma as well as some studies included new-borns or infants where other studies focused on adults or elderly (Table Gb in S1 File). All studies investigated effects of supplementation with vitamin D3 and half of the trials (53%) administered D3 as a daily dose without concomitant calcium supplementation. Only one of the trials had low 25OHD levels (< 50 nmol/L) as inclusion criteria and mean 25OHD levels at baseline were only reported in two-thirds of the studies among which only seven trials reported mean levels below 50 nmol/L. Nine trials (30%) reported a more than 50% increase in 25OHD levels in response to treatment. A beneficial effect of vitamin D supplementation on risk of infections was found in nine (30%) of the trials, but none of the above mentioned indices were in general a characteristic of the trials showing beneficial effects of the supplementation (Table Gb in S1 File).

In summary, most published studies on effects of vitamin D supplementation on risk of RTI have been relatively small and of short duration without specifically addressing effects in populations with vitamin D insufficiency. Beneficial effects of vitamin D supplementation have been reported in nine of the 30 RCTs included in the 7 published MAs and three of the MAs have concluded that vitamin D supplementation may lower risk of infections. Noteworthy, the populations studied in the individual trials have varied widely from newborns to elderly as well as effects of a wide range of different types of infections have been included raising the question whether results from such different settings can be merged into MA reporting summary estimates. Nevertheless, the overall findings suggest a beneficial effect of vitamin D on respiratory tract infections.

Depression

Vitamin D may affect brain function as the VDR as well as the 1α-hydroxylase enzyme is expressed by brain tissues, suggesting that 25OHD is activated and functions within the central nervous system (CNS) [222–224]. This is further supported by findings showing effects of 1,25-OH₂D3 on the synthesis of nerve growth factor (NGF) [225,226], as well as the synthesis of tryptophan is transcriptionally activated by vitamin D and low 25OHD levels may accordingly cause low levels of serotonin [227].

Several cross-sectional- and cohort-studies have reported an inverse association between plasma 25OHD concentrations and depression [228–234]. In a MA on results from observational studies, low plasma 25OHD levels were associated with an increased risk of depression in cross-sectional studies (n = 11 studies with 43,137 participants; OR 0.96; 95% CI, 0.94, 0.99, I² = 63%) as well as in cohort studies (n = 5 studies with 12,648 participants; OR 0.92; 95% CI, 0.87, 0.98, I² = 50%) [235]. Nevertheless, other epidemiological studies have not found such associations [236–238].

We identified six SRs [239–244] among which four [239–242] provided formal MAs reporting pooled data on results from 30 RCTs on effects of vitamin D supplementation on depression (Table Ha in S1 File).

Performing a systematic literature search, Spedding et al. [239] identified 15 RCTs reporting effects of vitamin D supplementation on depression scores including mood disorders such as (seasonal) recurrent depressive disorder. Studies were subsequently grouped according to the presence of biological flaws. Biological flaws were considered if baseline 25OHD levels were not measured, if baseline levels indicated a replete vitamin D status, or if the interventions did not cause a significant increase in 25OHD levels. Among the 15 studies identified, eight (53%) were found to have biological flaws [61,245–251], whereas seven studies (47%) were classified as being without flaws [252–258]. MAs were performed on studies with or without biological flaws. In the MA on studies without biological flaws, only two of the seven studies were included [253,257], as they used the same outcome measure in terms of Beck Depression Inventory (BDI), whereas other measures were used in the remaining five studies. Among the eight studies grouped as being with biological flaws, only two were included in MA [61,251] as they both used the 12-item Short Form Health Survey (SF-12) questionnaire, whereas other measures were used in the remaining six studies. As shown in Table Ha S1 File, the authors found beneficial effects of vitamin D supplementation in the MA on studies without biological flaws, whereas no effect was present in the MA on studies classified as being with biological flaws.

In a systematic review by Li et al. [240] studies were only included if vitamin D was provided orally as mono-intervention and compared with placebo in adults considered to be at risk of depression, having depressive symptoms, or being diagnosed with depression (secondary or tertiary prevention). The protocol for the study was published prior to the results from the MA [259]. The MA included data from six RCTs (Table Hb in S1 File) among which one of the studies used calcitriol as treatment [250]. For some of the included studies, only sub-groups of the randomized population were considered for data-analyses. For example, in the study by Sanders et al. [61], only 137 of the 2258 randomized women were included, as only this subgroup provided concurrent information on changes in 25OHD levels and changes in scores as assessed by the WHI-5 questionnaire. Overall, the meta-analysis by Li et al. [240] showed no effects of vitamin D supplementation on studied indices (Table Ha in S1 File). In subgroup analysis stratified by vitamin D dosages, sex, study location, and different study populations, no effects of vitamin D were found. In a post hoc analysis stratified by vitamin D status at baseline (sufficient vs deficient), no significant differences between groups were observed [240]. Similarly, Shaffer et al [241] and Gowda et al [242] found no significant differences when comparing studies with mean baseline 25OHD levels below or above 50 nmol/L. For most of the analyses performed, a substantial unexplained heterogeneity was present and the quality of evidence obtained from the included trials was graded as low by the authors [240]. Similarly, no overall beneficial effects of vitamin D supplementation were found in the MAs by Shaffer et al (221) and Gowda et al [242] and a substantial and unexplained heterogeneity was also found in most analyses (Table Ha in S1 File).

Table Hb in S1 File shows summary characteristics of the 12 RCTs included in the four MAs. The trials have been published between 2003 and 2013. In four (33%) of the trials, depression was considered as a primary end-point. Four of the RCTs included only women (none of the studies included only men). Three studies included solely patients with a diagnosis of depression; none of them on treatment with antidepressant at time of inclusion. One study included only elderly women with known seasonal affective disorders (treatment status unknown). The remaining studies included community-dwelling men and women among which two of the studies excluded participants on treatment with antidepressants. In three studies, participants were only included if they had 25OHD levels below 40 or 55 nmol/L or between 25–75 nmol/L. In 10 of the studies, vitamin D supplementation was given orally as vitamin D3 tablets/capsules (9 studies) or as fortified cheese (1 study). One study used intramuscular D3-injections and one study tested calcitriol. Vitamin D was given daily (7 studies), weekly (3 studies), yearly (1 study), or as a single dose (1 study). Time from initiation of treatment to end of follow-up varied from six weeks to five years. Effects were assessed by Beck Depression Inventory (BDI) in five studies, by the Geriatric Depression Scale (GDS) in two studies, and by the SF-12 questionnaire in two studies. One study used the Burnam 8-item scale for depressive disorders whereas another study used a questionnaire designed for patients with fibromyalgia which included depression as a domain. Only three of the individual RCTs showed beneficial effects [254,257,260] among which effects of the intervention was considered as a primary endpoint in two of the trials [257,260]. In one study, a per-protocol analysis showed a decrease in depressive symptoms compared with placebo in the cognitive-affective domain (subscale 1–13) of BDI [253]. In a sub-analysis from the WHI study, the Burnam-score was worsened by vitamin D compared with placebo (0.009; 95% CI, 0.002, 0.017) in the group of women without evidence of prior depression [246]. No major effects were shown in sub-analyses in any of the other studies.

In summary, only one of four MAs has suggested a beneficial effect of vitamin D supplementation on depression. This MA included only few of the published studies, whereas the three MAs showing no effects of vitamin D supplementation allowed for inclusion of more of the published RCTs. However, the methods used to assess effects in the various RCTs varied widely and only few (N = 5) studies reported an increase in 25OHD levels above 50% in response to the intervention. Moreover, most of the studies (N = 11) did not require their participants to have vitamin D insufficiency (25OHD<50 nmol/L) at inclusion and only five studies reported mean baseline 25OHD levels below 50 nmol/L. It is nevertheless noteworthy that both the MA by Li et al. [240] and the MA by Shaffer et al [241] suggested beneficial effects of vitamin D supplementation among those with a replete vitamin D status, but not in subjects with low vitamin D levels which does not support findings from observational studies of a major role of vitamin D in the pathogenesis of depression.

Mortality

Observational studies have shown an inverse association between 25OHD levels and mortality, including death from CVD, cancer, and non-vascular, non-cancer causes [194,261–266]. The mechanism by which supplementation with vitamin D may reduce mortality has not been fully clarified, but it has been suggested that the reduced risk of death may be due to the possible pleiotropic effect that involved the musculo-skeletal- as well as several extraskeletal-systems, including anti-inflammatory and immune modulating effects [267,268].

We identified 12 SRs with MAs on mortality in response to supplementation with vitamin D. Eight of the MAs showed a significantly reduced mortality in response to supplementation (Table Ia in S1 File). In most of the MAs, stratification by type of calciferol showed a significantly reduced mortality in response to treatment with vitamin D3, whereas no beneficial effects were found in response to treatment with vitamin D2 [190,263,269–271]. Discrepant results have been reported on whether mortality is reduced in response to treatment with vitamin D alone [263,269] or only if vitamin D is combined with calcium supplements [190,270–272]. In two MAs, effects of the intervention was significant in summary estimates on trials with low baseline vitamin D status [190,271], but a clear dose-response relationship has not been documented [49,269,271,272].

The 12 MAs included data from a total of 59 RCTs. Table Ib in S1 File shows characteristics of the individual RCTs included in the 12 MAs and characteristics of the individual trials are summarized in Table 1. None of the RCTs had mortality as a primary endpoint and none of them showed a significantly reduced mortality in response to treatment. Actually, two small trials showed an increased mortality in response to the supplementation [273,274]. In the study by Latham et al. [273], a single high dose (300,000 IU) of vitamin D3 increased mortality during the following six months compared with placebo in a group of 243 frail elderly people. Similarly, a high dose of D2 (100,000 IU every 3^rd month) increased mortality compared with no treatment during a 10 months study period in a group of 3,717 nursing home residents [274]. On the other hand, none of the studies with daily administration of vitamin D supplements has shown increased mortality in response to supplementation, including a recently published trial on three-years of daily supplementation with 4000 IU D3 or placebo to 400 patients with heart failure [275]. Most studies have been relatively small with less than 1000 randomized participants and have investigated effects of a daily dose of vitamin D3 with calcium being co-administered in approximately half of the studies. Only few of the studies (N = 5) had low 25OHD levels as a criterion for inclusion. Seventeen of the 59 studies reported an increase in 25OHD levels of more than 50% in response to the intervention. Mean 25OHD levels were below 50 nmol/L in approximately half of the studies. Several of the MAs compared effects between studies with mean baseline levels below or above 50 nmol/L showing no significant interactions [49,270,276,277]. However, stratified analyses showed a significantly decreased mortality when pooling results from studies with mean 25OHD levels below 50 nmol/L, but not when combining results from studies with mean levels above 50 nmol/L [190,270,276].

In summary, supplementation with vitamin D seems to be causally related to a reduce all-cause mortality, which is in accordance with the findings from observational studies. Moreover, as reviewed in the section on malignant diseases, MAs on cause specific mortality have shown a reduced mortality due to malignant diseases [184,186,190]. Only vitamin D3 has been shown to reduce mortality, and some MAs have suggested that the effect only is present if calcium is co-administered, whereas other MAs have shown an effect of vitamin D3 alone. The lack of a clear dose-response relationship may be attributable to characteristics of the RCTs included in the MAs, as most of the trials have investigated effects of low doses (Table Ib in S1 File) which may limit the statistical power to show dose-effect relationships. Furthermore, as recently shown in a simulation analysis, based on findings from a large cohort study, the expected impact on mortality of vitamin D supplementation is presumably much higher if targeted to individuals with low 25OHD levels [278].

Discussion

Overall, 16 of the 54 MAs suggested beneficial effects of vitamin D supplementation on different extra-skeletal outcomes among which eight of 12 MAs (66%) reported a decreased mortality. Beneficial effects were also suggested by MAs on blood pressure (2 of 9 [22%] MAs), birth weight (2 of 6 [33%] MAs), RTIs (3 of 7 [43%] MAs), and depression (1 of 4 [25%] MAs). No beneficial effects were reported in any of the MAs on CVD, T2D, body weight, or malignant diseases.

For all studied outcomes, only one-fourth of the individual RCTs included in the MAs had assessed effects studied as a primary endpoint. None of the trials included in the 12 MAs on mortality had mortality as a designated primary outcome. Most studies have been performed only in women or in a mixed gender population, whereas only very few studies included only men. The sex distribution is probably because many of the included studies have investigated skeletal effects as primary outcomes. As osteoporosis and fractures are more common in women than in men, these studies have preferentially included women in order to achieve effects in a population at high risk. However, although many of the trials have assessed effects of vitamin D supplementation on skeletal outcomes, only a minority of the studies have actually investigated effects in populations with low 25OHD levels. Plasma 25OHD levels below 50 nmol/L were only inclusion criteria in one-fourth of the analyses.

Moreover, mean 25OHD levels at baseline below 50 nmol/L has only been measured in less than half of the studies, indicating that the populations studied did not, on average, suffer from vitamin D insufficiency and the duration of studies has in many studies been relatively short. The WHI study is the trial with the longest time of intervention (7 years) and the most participants included [279].

The vast majority of observational studies have reported low 25OHD levels to be associated with an increased risk of adverse health outcomes, but caution is needed in interpreting observational data. Although most studies have adjusted for differences between groups, residual confounding can never be excluded in observational studies. Effects may be due to lifestyle factors, a “healthy user” bias or other differences between groups, which has not been fully accounted for in adjusted analyses. This may result in reverse causation, in which vitamin D status is more a marker for an underlying condition/disease than causally related to the disease investigated. Accordingly, RCTs are needed to determine whether a causal link is present. Following the publications of a large number of observational studies showing adverse health outcomes of low 25OHD levels, the requests of data from RCTs have increased. For each of the outcomes we studied, a variable number of RCTs have been published and most of them have failed to document a beneficial effect as shown in observational studies. Accordingly, it may seem questionable whether the findings from observational studies actually reflect a beneficial effect of vitamin D by itself. Due to such findings, a recent large scale review by Autier et al [19] concluded that the inverse association between 25OHD levels and various health outcomes, could be the result of disease process causing low 25OHD levels rather than low 25OHD levels causing the disease i.e., low 25OHD levels are a marker of ill health.

In our review, we aimed to summarize characteristics of the published RCTs on effects of vitamin D supplementation. Although, RCTs are considered as the highest level of evidence, and especially if results from RCTs are summarized in MA, the degree of confidence on the findings from the RCTs do, however, depend on how the studies were performed and whether they actually had a design and statistical power to detect possible effects. Our review highlights that most of the available trials were not designed to study non-skeletal outcomes of vitamin D supplementation. For most of the selected outcomes reviewed in this paper, the RCTs included in MAs did not have the disease in question as primary outcome. For several of the diseases studied, some of the outcomes were assessed as adverse event reports and many of the studies had a questionable statistical power to detect effects such as incident CVDs or cancers. The lack of trials assessing effects of intervention on specific health outcomes as a primary endpoint does, however, not provide a complete answer to the discrepancy between findings from observational and randomized trials. For example, in analyses on mortality, none of the individual RCTs showed beneficial effects and none of the trials were designed to assess mortality. However, several of the pooled risk estimates in MAs did show a significantly reduced risk of death in response to treatment. Notably, the MAs on mortality have included substantially more studies than most of the MAs on other studied outcomes and mortality may be assessed in a more valid manner than other “adverse effects” observed during a trial. If vitamin D supplementation affects studied outcomes the sample size may have been too small to show effects, which may have been further hampered by a relatively short duration of treatment. CVD, obesity, T2D, and cancers develop over a long time, and the duration of the trials available may not be sufficiently long to affect such disease processes. Historically, it has been shown multiple times that RCTs are difficult to perform in terms of testing the right dose for an appropriate time-period in a suitable population of study subjects and that null-finings do not necessary disprove important effects [17,280,281]. Interestingly, a beneficial effect of vitamin D supplementation was shown in several of the trials on RTIs, which are outcomes that seems more likely to be affected by a relatively short duration of treatment compared with for example CVD or cancer. The most noticeable difference between the observational and randomized trials is, however, that only few of the RCTs included participants with vitamin D insufficiency. Many studies did not report mean 25OHD levels, but among studies reporting these values, mean levels were below 50 nmol/L in less than half of the studies and the intervention did not result in a marked increase in 25OHD levels in several of the trials. Only a few of the included MAs investigated whether findings differed according to baseline vitamin D status showing no significant interaction between results from studies with mean 25OHD levels below vs. above 50 nmol/L or according to whether supplementation resulted in increased 25OHD levels on cardiovascular outcomes [49], blood pressure [81], body weight [137], malignant diseases [184], RTI [212,218] or mortality [49,270,276,277]. A significant interaction term (P_i = 0.006) was only shown for RTI in the recently published MA by Martineau et al [22] showing a larger decrease in risk of RTI if baseline 25OHD levels are below as compared with above 25 nmol/L. Of importance, a mean level below 50 nmol/L implies that only approximately half of the population had levels below 50 nmol/L, which may have blunted a potential effect in subjects with low levels. Accordingly, it is questionable whether available trials as well as MAs performed by combining trial results in reality have tested the hypothesis raised by observational studies on adverse health effects of low 25OHD levels. A beneficial effect of vitamin D supplementation is most likely difficult to demonstrate if studies are performed in populations with adequate levels. Moreover, factors such as compliance, sources of vitamin D, etc. have to be considered when evaluating findings from RCTs as well as in the design of further studies [194,282]. We choose to classify studies according to a cut-off plasma level of 25OHD equal to 50 nmol/L, as consensus exist on considering this threshold limit as a state of inadequacy [283], although some have suggested that a sufficient vitamin D status requires levels above 80 nmol/L [284]. Importantly, the optimal 25OHD level for non-skeletal health outcomes have not yet been clarified and the available RCTs do not allow for such definitions [27]. Lack of effects may be attributable to use of too low doses of vitamin D to archice a sufficient response. In terms of this, it may be of relevance in future studies also to consider the relationship between vitamin D dose, baseline and achieved 25OHD concentrations as well as the fact that the relationship between vitamin D dose and 25OHD concentration is nonlinear and can vary due to personal factors [194].

A further limitation to some of the RCTs might be that some of the studies have used intermitten treatment with high doses of vitamin D. Although such dosing regimes results in high levels of 25OHD, levels of cholecalciferol are neglible for most of the time due to the rapid 25-hydroxylation of vitamin D3 into 25OHD. Vitamin D3 acts as a substrate in many tissues thereby being of importance to the vitamin D endocrine/autocrine system. Accordingly, it is likely that vitamin D3 should be available on a daily basis through supplementation or endogenous synthesis in order to archive effects of vitamin D3 [285]. It may also be questioned whether effects of supplementation with vitamin D are equal to endogenous synthesis. In recent studies, novel secosteroids with potential actions similar to 25OHD have been shown to be synthesized in vivo in human epidermis and in pig adrenal glands [286]. These compounds may function as substrates for the 1α-hydroxylase and thereby potentially act in a manner similarly to activated vitamin D. Further studies are needed to determine whether this is of importance to the effects of vitamin D and if it makes a difference whether vitamin D is synthesized endogenously or provided as in terms of supplementation with cholecalciferol. Additionally, UV irradiation through sun-exposure may also cause liberation of nitric oxide from subcutaneous nitrogen stores thereby affecting non-skeletal outcomes such as blood pressure beyond potential effects of vitamin D synthesis [287–289]. Finally, it should also be noted that our assessement of findings on non-skeletal outcomes is not exhaustive, as effects of vitamin D supplementation also have been studied on other outcomes such as dental caries [290].

Directions for further investigations

As highlighted by our review, the quality of data from available RCTs is of limited value in terms of assessing non-skeletal effects of vitamin D supplementation. Further MAs performed on these data are therefore not to be considered as a priority. MA does not compensate for shortcomings in the original studies. Further RCTs designed to assess effects of vitamin D supplementation on specific outcomes within a population at risk are warranted. A number of large-scale trials are currently being performed. These studies aim at assessing non-skeletal outcomes of vitamin D supplementation and first results are expected within the next year [291,292]. Although these studies plan to include from 6,000 to 25,874 participants, and thereby potentially provide a substantial statistical power to detect potential effects, most of these studies are not targeted towards subjects with vitamin D insufficiency [293]. Accordingly, they do not assess effects of the intervention in a population at specific risk where potential effects of improving vitamin D status may be blunted by inclusion of individuals with a replete vitamin D status.

Assessing effects of vitamin D supplementation in randomized trials is complicated by a number of factors [294]. Even if a large-scale study was performed in a population with vitamin D insufficiency at baseline, changes in vitamin D status may occur in the control group during the course of the trial due to altered dietary habits and/or sun-exposure, including seasonal-variations [295–297]. Moreover, vitamin D supplements are readily available and controls may start using vitamin supplements. Finally, assessment of effects in diseases which develop over a long time span such as CVD or obesity may be difficult during the course of a trial which most often only runs for a few years. Effects may also depend on the age of studied subjects and risk for developing such chronic diseases may be grounded in early life [298,299]. If so, a replete vitamin D status throughout life or at certain ages may be of importance. Although RCTs are considered to provide the highest degree of evidence on causal relationships, this methodology may not be appropriate to rely on, if the effects of vitamin D are of importance at a certain period of life or during a long time span. Thus, the importance of well-designed longitudinal studies should not be entirely rejected. Development of new methods or reliance on the Bradford Hill criteria may be necessary to refind our understanding of vitamin D [300]. A major limitation to the interpretation of prior longitudinal studies is lack of standardization of 25OHD measurements [301]. It has been documented that use of different methods for measuring 25OHD levels may cause huge variations in levels measured and thereby affect the classification of vitamin D status [302–305]. Further observational studies should therefore aim at using standardized methods for vitamin D measurements in order to allow for comparisons across studies and time periods. Such observational studies may also help to provide guidance on threshold values of 25OHD levels of importance to non-skeletal outcomes.

Conclusions

Observational studies have suggested an inverse association between vitamin D status and a number of diseases. Results from RCTs and MAs of RCTs do, however, only provide limited support for such effects, as most studies have failed to document significant effects. Nevertheless, several MAs have suggested a reduced mortality in response to vitamin D s supplementation, as well as three of seven MAs showed a beneficial effect on RTIs, including a recently published large individual patient data analysis [22]. Only sparse evidence are available for a beneficial effect of supplementation on other non-skeletal outcomes such as blood pressure, depression, and increased birth weight. No MAs based on findings from RCTs have so far provided support for a beneficial effect of supplementation on risk of CVD, T2D, body weight, or malignant diseases. More than half of the available trials have been performed in individuals without vitamin D insufficiency and the intervention has not resulted in an adequate increase in 25OHD levels in many of the trials. Furthermore, the sample size in most RCTs was relatively small and the trials had a short duration of follow-up. In accordance with the null findings in most RCTs, most meta-analyses have not shown effects of vitamin D supplementation on non-skeletal outcoms. Importantly, as evaluated by the AMSTAR score, the quality of published MAs has largely been fair to good. The null findings of MAs are therefore not attributable to an inappropriate methodology when combining data from RCTs. MAs cannot be expected to proof potential effects of supplementation with vitamin D, if the trials forming the basis for the MAs have not been performed in populations with low 25OHD levels. Overall, a definite causal link between vitamin D insufficiency and non-skeletal diseases has not been proven, but the RCTs performed so far cannot be considered to have tested the hypothesis raised by observational studies on adverse health outcomes of low vitamin D levels. As a “healthy user” bias and reverse causation cannot be excluded in observational studies, further RCTs designed to test the hypothesis of a beneficial effect of optimizing vitamin D status in individuals with an impaired vitamin D status are warranted, as well as long-term cohort studies using standardized methods for serial measurement of 25OHD levels.

Comparative analysis of nutritional guidelines for vitamin D

Aquadetrim (Vitamin D3) solution 15 thousand. IU / ml 10ml

Vitamin D3 is an active antirachitic factor. The most important function of vitamin D3 is to regulate calcium and phosphate metabolism, which contributes to proper mineralization and skeletal growth.

Vitamin D3 is a natural form of vitamin D, which is formed in the human skin by exposure to sunlight. Compared to vitamin D2, it is characterized by 25% higher activity.
Vitamin D binds to a specific vitamin D receptor (VDR), which regulates the expression of many genes, including the TRPV6 ion channel genes (provides calcium absorption in the intestine), CALB1 (calbindin; provides calcium transport into the bloodstream), BGLAP (osteocalcin; provides mineralization bone tissue and calcium homeostasis), SPP1 (osteopontin; regulates osteoclast migration), REN (renin; regulates blood pressure, being a key element of the RAAS), IGFBP (binding protein insulin-like growth factor; enhances the action of insulin-like growth factor), FGF23 and FGFR23 (factor fibroblast growth 23; regulate the levels of calcium, phosphate anion, processes of cell division of fibroblasts), TGFB1 (transforming growth factor beta-1; regulates the processes of cell division and differentiation of osteocytes, chondrocytes, fibroblasts and keratinocytes), LRP2 (LDL receptor-associated protein 2; mediates low-density lipoprotein endocytosis), INSR (receptor insulin; provides the effects of insulin on all types of cells).
Colecalciferol plays an essential role in the absorption of calcium and phosphates in the intestine, in the transport of mineral salts and in the process of bone calcification, and also regulates the excretion of calcium and phosphates by the kidneys.
The concentration of calcium ions in the blood determines the maintenance of muscle tone of the skeletal muscles, myocardial function, promotes the conduction of nervous excitement, regulates the process of blood coagulation.
Lack of vitamin D in food, impaired absorption, calcium deficiency, and insufficient exposure to the sun during the period of rapid growth of the child leads to rickets, in adults – to osteomalacia, pregnant women may experience symptoms of tetany, impaired calcification of the bones of newborns.
An increased need for vitamin D occurs in women during menopause, as they often develop osteoporosis due to hormonal disorders.
Vitamin D has a number of so-called non-skeletal effects.
Vitamin D is involved in the functioning of the immune system by modulating cytokine levels and regulates T-helper lymphocyte division and B-lymphocyte differentiation. A number of studies have noted a decrease in the incidence of respiratory tract infections while taking vitamin D.
It has been shown that vitamin D is an important link in the homeostasis of the immune system: it prevents autoimmune diseases (including type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases).
Vitamin D has antiproliferative and differentiating effects, which determine the oncoprotective effect of vitamin D. It has been noted that the incidence of some tumors (breast cancer, colon cancer) increases with a low level of vitamin D in the blood.
Vitamin D is involved in the regulation of carbohydrate and fat metabolism by influencing the synthesis of IRS1 (substrate of insulin receptor 1; participates in the intracellular pathways of insulin receptor signaling), IGF (insulin-like growth factor; regulates the balance of adipose and muscle tissue), PPAR-δ (activated peroxisome proliferator receptor, type δ; promotes the processing of excess cholesterol).
According to epidemiological studies, vitamin D deficiency is associated with the risk of metabolic disorders (metabolic syndrome and type 2 diabetes mellitus).
Vitamin D receptors and metabolizing enzymes are expressed in arterial vessels, heart and practically in all cells and tissues related to the pathogenesis of cardiovascular diseases. In animal models, anti-atherosclerotic action, renin suppression and prevention of myocardial damage have been shown, and more. Low levels of vitamin D in humans are associated with unfavorable risk factors for cardiovascular disease, such as diabetes mellitus, dyslipidemia, arterial hypertension, and are associated with the risk of cardiovascular accidents, incl.h. strokes.
In studies on experimental models of Alzheimer’s disease, vitamin D3 has been shown to reduce the accumulation of amyloid in the brain and improve cognitive function. Non-interventional studies in humans have shown that the incidence of dementia and Alzheimer’s disease increases with low vitamin D levels and low dietary vitamin D intake. Cognitive function and Alzheimer’s disease have been impaired with low vitamin D levels.

Reviews on the use of vitamin D

Reviews on the use of vitamin D – D vitamīns

Parents tell us about their experiences with vitamin D

• The first year, starting from August last year, the whole family drank vitamin D – and winter passed without colds and viruses! Well, okay, a couple of times there was a slight runny nose – but that doesn’t count! / Anna Liepina, Cesis /

• I like Nateo Forte drops the most – my husband and I take 4 drops a day, children (8 and 10 years old) 2 drops. / Zaiga, mother of two children /
• If I leave a bottle on the table in a conspicuous place, then I do not forget to give it to the child and take it myself! / Iveta from Sigulda /

• Once a year I take an analysis for the level of vitamin D, and give my daughter for prophylaxis without tests. / Sigita, Anita’s mother /

• The whole family at the end of summer, or rather in September, did an analysis for the level of vitamin D and were extremely surprised, since only my son’s vitamin level turned out to be more than 30 ng / ml, probably because he was in a sports camp.Now we are all taking vitamin D. Next year we will have tests again! / Maya, Riga /

You will also be interested in:

• This year, the whole family took vitamin D diligently. Children (one year old and three year old) also gave Nateo Forte one drop a day. In winter, we did not get sick, even the flu passed us, although many were sick in kindergarten. For the sake of interest, they did tests, and everyone’s level turned out to be excellent! Now we continue to take to maintain this level.But in the summer we’ll just sunbathe in nature.

• I take Nateo Forte capsules. I like the fact that you can always have it with you in your purse and do not forget that you need to take a vitamin. No need to think about the dose – the capsule contains the required daily dose.

• The family doctor prescribed vitamin D to the newborn from the first days. Unfortunately, the use of the vitamin prescribed by the doctor caused an allergic reaction. We tried Nateo – no allergies! At the same time, it is convenient to dose and bury the child, he likes the pipette.

• Previously, I did not pay attention to the level of vitamin D, but in the spring I began to get sick often: I began to feel a lack of energy, dry skin and headaches. The family doctor prescribed a referral for an analysis of the level of vitamin D, which turned out to be catastrophically low. Now I take the dose prescribed by the doctor and my health is gradually improving.

• Recently in a sports club, in a conversation with friends, it turned out that many of us have very low levels of vitamin D.Before that, I hadn’t even thought about the scale of this problem.

• My baby was sweating a lot in the first two months of life. The family doctor increased the dose of vitamin D and the sweating stopped.

• The teenager complained that it was difficult for him to wake up in the morning, he had no strength, and was struggling with sleepiness in the classroom. The family doctor ordered a test and found that the vitamin D level was only 14 ng / ml. We thought we were eating so well, but it turned out that this is not enough.Now we also take vitamin D.

• The family doctor said that in order for the children to be less sick, it is necessary to maintain a sufficiently high level of vitamin D. Throughout the autumn and winter, I diligently gave the children Nateo Forte drops. In April, they passed the tests, and I was extremely surprised that one child had a vitamin D level of 49 units, and the second – 66. I was even worried if it was too high, but the doctor reassured me, saying that this level was the best and everyone should strive to achieve it.This year, the children really got sick much less often.

90,000 Good vitamin D: reviews

Hello everyone!

Today I will tell you about Vitamin D from the Naturelo brand.

It is believed that the main source of vitamin D (cholecalciferol) is the sun, which is not entirely true. The intensity of solar radiation is different in different parts of the world, and it would be logical to assume that southerners are not deficient in vitamin D, unlike northerners.In reality, a paradoxical situation is observed: everything is exactly the opposite. In Spain, Italy, South America and even in Africa, the deficit sometimes reaches 80%, and in Finland and in the north of Russia – about 40% popularity.

The point here is different: in different parts of the world people eat differently, and in the issue of obtaining cholecalciferol, this nuance is of decisive importance.Northerners eat more oily sea fish (while southerners prefer less fatty fish and seafood), and venison is regularly included in their menu. Both fish and deer eat lichens – a specific product, a symbiosis of fungi and algae. They get vitamin D from lichens, which people then get from the liver of oily fish and deer.

In our territories, the sun’s radiation is not intense enough and you can fully sunbathe only in summer, so getting vitamin D from food or supplements is the best solution.Traditional products: fish liver (not a carcass, this is a mistake – there is very little vitamin D there) and fish oil. For northerners, there is also the liver of a seal and a deer. There is so little vitamin D in milk, butter, cheese and other dairy products that the daily allowance cannot be covered even if the entire diet consists exclusively of them.

Additives are traditionally made from three types of sources:

• marine fish liver
• sheep wool
• lichen, which was discussed at the beginning of the article

It is about the lichen-based additive that I will talk about today.

Manufacturer – American brand Naturelo, specializing in the production of whole food vitamins from natural sources. Does not use dyes, flavors or preservatives. The list of excipients is extremely laconic: cellulose capsule.

Each capsule contains 125 μg, or 5000 IU of vitamin D. This is convenient, since the vitamin is fat-soluble, accumulates in the liver and there is no need to take it daily in low dosages like water-soluble vitamins.In the event of a deficiency, one capsule should be taken daily, and after the deficiency has been eliminated, two to three capsules per week should be taken to maintain the achieved level. It is best to determine your level not by symptoms, but based on the results of a blood test, which will give an absolutely accurate picture of what is happening.

I take 2 capsules a week. There are 180 capsules in a can, and even if taken daily, it will last for six months, which makes the purchase very justified from a financial point of view.

Medium sized capsules, easy to swallow.They should be taken after meals, preferably after breakfast, and washed down with a glass of water.

I am very pleased, they do everything that is expected from good vitamin D – they increase energy and efficiency, improve mood, which is especially noticeable on cloudy rainy days. I have something to compare with, I tried both premium and budget options, and I can confidently say that the product is definitely worth its money.

PLUSES NATURELO VITAMIN D3:

• 5000 IU in a capsule
• natural composition
• no auxiliary ingredients, preservatives and colorants
• 180 capsules in a can
• medium-sized capsules and easy to swallow
• does not cause any side effects
• does not contain GMOs, soy, yeast, gluten, sugar
• Suitable for vegetarians and vegans

Rating: 5 + / 5

Where to buy: iHerb

Best Vitamin D on iHerb Ayherb.How to choose, dosage, analyzes. Reviews. Mama_beauty – LiveJournal

🔻 Download “Free Guide to iHerb” in my Telegram, Instagram and Vkontakte

Today we are dealing with vitamin D, one of the most important vitamins for pregnant women, lactating women, children, the elderly and adults.

In 2018, Russia launched the National Program of Vitamin D Deficiency in Children. It published the results of recent studies illustrating the relevance of controlling the level of vitamin D in the body and revised preventive dosages of vitamin D for children and adults.

We are used to associating vitamin D with the body’s ability to absorb calcium and phosphorus, but this is not its only function, the more scientists study this vitamin, the larger the list of diseases associated with vitamin D deficiency in the body becomes:

❎ Diabetes mellitus

❎ Hypertension and diseases of the cardiovascular system

❎ Obesity

❎ Infertility

❎ Oncology

❎ Bronchial asthma

❎ Diseases of the musculoskeletal system

❎ Multiple sclerosis

❎ Depression and chronic fatigue syndrome

Receptors for vitamin D are found in every cell of the body, so its deficiency can adversely affect the functioning of the entire body.

Today, scientists and doctors call it not vitamin D, but hormone D. Because it has an effect on our body like hormones.

How vitamin D supplementation can help:

✅ Improving immunity

✅ Acceleration of metabolism

✅ Normalization of the work of the heart and blood vessels

✅ Maintaining blood pressure in the norm

✅ Prevention of neoplasm development

✅ Improvement of blood composition and clotting

✅ Normalization of the thyroid gland

✅ Prevention of myasthenia gravis development

✅ Elimination of dry skin and hair

Studies show that the majority of residents of sunny countries have vitamin D deficiency in their bodies, let alone the inhabitants of northern latitudes.

It is difficult to achieve the optimal level of vitamin D in the body with the help of food and sunbathing, therefore my whole family takes vitamin D in the form of supplements in the winter period. Children, the elderly part of the family and my sister and I during pregnancy take it on an ongoing basis.

♥ Best form of admission:

– Cholecalciferol

✅ Helps to assimilate (additives synergists):

Vitamins B2, B6, B9, K2, C, Magnesium, Calcium, Selenium, Manganese

❌ Interferes with absorption (additives antagonists):

Vitamin A, E

Which vitamin D to choose?

🔸 The most easily absorbed form of vitamin D is the D3 form or cholecalciferol.

🔸 98% of all vitamin D is produced from highly refined lanolin and fish oil. My preference is for the inexpensive vitamin D3 from lanolin. Vegans may consider vitamin D options from mushrooms, lichens, and other natural ingredients.

🔸 Vitamin D3 is a fat-soluble vitamin, so for better absorption, choose supplements with added oils (olive, coconut, safflower) and take the vitamin with meals. Doctors recommend taking vitamin D in the morning after breakfast.

🔸 If your recommended dosage is higher than 5000IU, choose vitamin D in combination with K2 for better absorption. It is better to choose K2 in kind MK-7. 100 mcg of vitamin K2 per 5000 IU of vitamin D.

🔸 For gallbladder problems, give preference to a water-soluble or liposomal supplement.

1. Thorne Research, D-1000

2. Solgar, Vitamin D3 (Cholecalciferol), 1000 IU

3. Doctor’s Best, Vitamin D3, 25 mcg (1000 IU)

4. Now Foods, Vitamin D-3, High Potency, 1000 IU

5. Ddrops, Liquid Vitamin D3, 1000 IU

1. California Gold Nutrition, Vitamin D-3, 50 mcg (2000 IU)

2. Doctor’s Best, Vitamin D3, 50 mcg (2,000 IU)

3. Now Foods, Vitamin D-3, 2,000 IU

4. Ddrops, Liquid Vitamin D3, 2000 IU

5. Sports Research, Vitamin D3 with Coconut Oil, 1000 IU

1. Dr. Mercola, Vitamins D3 and K2

2. Solaray, Vitamin D3 + K2

3. Zhou Nutrition, K2 + D3, 2-in-1 Support

4. Sports Research, Vitamin K2 + D3, 100 mcg / 5000 IU

5. Thorne Research, D-5 000

Now Foods, Mega D-3 and MK-7, 5000 IU / 180 mcg

Dosage and analyzes

For proper absorption of calcium, a sufficient level of vitamin D is considered to be 30-60 ng / ml

A level of 70-80 ng / ml is required for the health of the body as a whole.Before preparing for pregnancy, doctors recommend that women raise their vitamin D levels to 80 ng / ml.

The prophylactic dosage of vitamin D is considered to be 600-1000 IU, some sources recommend taking 2000 IU in winter. The prophylactic dosage can be taken continuously without interruption.

If you decide to start taking vitamin D, it is recommended to donate blood for analysis “25-OH vitamin D” and, together with your doctor, calculate the dosage of the vitamin depending on the initial and desired level in the body.This table will help you calculate.

When taking therapeutic dosages of vitamin D, a control analysis is recommended every 3 months, with prophylactic doses once a year

If you are taking a multivitamin complex, be sure to recalculate your dosage of vitamin D, taking into account its content in multivitamins.

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90,000 Doctors warn of the dangers of vitamin D abuse in pandemic

Vitamin D not only helps to quickly cope with coronavirus infection, but is also a way to prevent this disease, according to doctors from different countries.In turn, its lack can lead to serious health problems – up to an increase in the risk of death in COVID-19. About what is the daily intake of vitamin D and what an overdose can lead to – in the material “Gazeta.Ru”.

Lack of vitamin D in the body poses a serious threat to health, said Elena Malysheva, MD, on her Instagram page. According to her, this vitamin is necessary for the maintenance of human bones and muscles, as well as for the proper functioning of the heart, memory and immune system.

Earlier, scientists from the Foundation of the Queen Elizabeth Hospital and the University of East Anglia also found that a lack of vitamin D can lead to increased risks of death in coronavirus infection.

In the course of the study, experts determined the average level of this vitamin in the population of 20 European countries, after which they compared the data obtained with the statistics of morbidity and mortality from coronavirus in these countries.

It turned out that the lower the average vitamin D level in the country, the higher the death rate from COVID-19.At the same time, scientists recorded a particularly low level of this microelement in residents of Italy, Spain and Switzerland.

Also, according to scientists from Northwestern University in Evanston (a city in the United States in the state of Illinois), an acute lack of vitamin D in the body increases the likelihood of developing a severe form of coronavirus infection by 15%.

In addition, the use of vitamin D can not only help to cope with coronavirus infection faster and easier, but also become a good way to prevent infection with COVID-19, Malysheva said.

“Antibodies are produced after meeting a virus, but if your lymphocytes are working well, then, having met a virus, these cells will simply eat it, devour it. Therefore, vitamin D is needed for this initial meeting of lymphocytes with coronavirus infection, ”Malysheva explained.

This assumption was confirmed by doctors from Trinity College Dublin. They made a conclusion about the preventive properties of this microelement by analyzing studies of vitamin D levels in adult Europeans over the past 20 years, and then comparing them with the number of coronavirus infections in European countries.

Taking vitamin D during a pandemic is especially important, as people now spend a lot of time indoors and are not exposed to direct sunlight, which is the main source of the substance, according to the UK Department of Health.

According to British experts, in order to improve health, it is necessary to take 10 micrograms of vitamin D a day. The Ministry of Health of the country clarified that in addition to sunlight, the main sources of this trace element are egg yolks, red meat, and fatty fish.

In turn, Elena Malysheva clarified that the daily intake of this vitamin can be obtained by consuming four grams of cod liver or one hundred grams of herring. In addition, synthesized vitamin D can be found in some yoghurts, breakfast cereals and margarine, the BBC reported.

Nevertheless, this substance should not be abused, warned Andrei Malyavin, chief freelance pulmonologist of the Russian Ministry of Health. According to him, this can lead to hypervitaminosis – an acute disorder as a result of intoxication with an ultra-high dose of one or more vitamins.

“I would like to warn against the unrestrained use of vitamin D, but we can talk about thousands of units of this trace element once a day, and not about 100 or 500 thousand. There is also such a thing as hypervitaminosis, it has very serious consequences”,

– he said on Wednesday on the air of the Doctor TV channel.

At the same time, Associate Professor of the Department of Clinical Pharmacology, Moscow State University of Medicine and Dentistry. Evdokimova Oleg Talibov clarified that this pathology practically does not occur in Russia due to the peculiarities of the climate.Nevertheless, it is still necessary to observe an adequate dose.

“Two thousand units of vitamin a day is the normal recommended dose. Among our fellow citizens, the number of people with vitamin D hypervitaminosis tends to zero, simply because the sun’s rays fall at the wrong angle and we generally have a low level of insolation (exposure of surfaces to sunlight – Gazeta.Ru). Another conversation that the recommendations to apply 50 thousand units are supernatural recommendations, ”he said in a conversation with the“ Doctor ”.

90,000 Reviews vitamin D 5000 IU Now Foods – the optimal dosage of D3: iherbnow – LiveJournal

In the review for vitamin D 5000 IU Nau Foods, we will briefly touch on the most pressing issues:

1) How to take vitamin D 5000 IU Nau Foods, instructions for use.

2) The benefits and harms of vitamin D-3 5000 Now Foods, what I found are the pros and cons.

3) Side effects and contraindications for taking Now Foods vitamin D-3 5000 IU.

Review vitamin D 5000 IU Now Foods – optimal dosage D3

I did not come to the conscious intake of vitamin complexes and supplements right away, but at first for a very long time I took various remedies from time to time, buying some advertised products or, for example, simply means for the eyesight of the skin and nails.

About the benefits of vitamin D3 for the body and the need for its regular intake, I learned everything in great detail at the moment when my mother was diagnosed with diabetes mellitus, and he was very insidious and diagnosed at an advanced stage: everyone knows how serious and complex this disease is, it very often manifests itself as hereditary, so I, like any person, would very much like to avoid it.

Review and Reviews for Vitamin D 5000 IU Nau Foods Now Foods

At the reception, the endocrinologist praised me for deciding to take preventive measures and besides all possible recommendations on proper nutrition, physical activity and regular monitoring of blood sugar (under my control, not just glucose, but glycated hemoglobin, which shows the average sugar level in the blood not at this time, but in the last month and a half), the doctor recommended that I be tested for vitamin D3 and monitor its level for life.

Review and Reviews for Vitamin D 5000 IU Nau Foods Now Foods

The benefits of vitamin D

It turned out that maintaining the level of vitamin D3 in the blood at the proper level works as an ideal prevention of diabetes and obesity (the risk of developing diabetes mellitus is reduced by at least 50%), and a very large percentage of the population suffers from a lack of this vitamin (some doctors call it almost a pandemic, especially in a not very sunny country like ours).Well, in general, this is almost the main vitamin (some consider it a hormone), which provides the foundation of health: strong bone tissue, good immunity, general tone, carbohydrate metabolism (and, accordingly, a good metabolism without fat deposits), and so on, the list is endless.

It was a surprise for me that in the list of recommended supplements a vitamin D3 preparation was prescribed to me by a cosmetologist (along with Omega-3, which is needed for everything and alpha-lipoic acid, and this was the first doctor who initiated me into the magical world of vitamin supplements): it turned out that with a deficiency of this vitamin, the condition of the skin deteriorates significantly, it participates in the process of renewing skin and hair cells, prevents the occurrence of skin diseases, thus the elasticity and freshness of the skin is also largely due to this vitamin.

Well, the gynecologist, during a discussion of female fertility, emphasized that vitamin D is needed not only in order to bear a baby well, to give birth to him healthy and on time, but also in order to successfully get pregnant (with which many girls, unfortunately, more and more problems have arisen lately), as well as maintain women’s health and a regular cycle.

Review and Reviews for Vitamin D 5000 IU Nau Foods Now Foods

In addition to all this, vitamin D reduces the risks of developing oncology, vascular diseases, heart attacks, works as a prevention of tumors, and so on, it is one of the main vitamins, it regulates the production of calcium (without it, calcium, in principle, cannot be absorbed), therefore, the health of bones, teeth, muscles and joints, too, can not do without it (even the orthodontist, when we considered the issue of braces, emphasized that taking calcium and vitamin D3 will keep the enamel in good condition so that it can endure such a test).

Correct dosage of vitamin D

The cosmetologist’s recommendations were more modest (1000 IU per day), but the endocrinologist was more determined: the dose I needed was determined as 10,000 IU per day for a long time.

We made the choice of the drug together with the doctor: since the doctor trusted the companies Solgar and Now Foods, so I opted for Vitamin D-3 at a dosage of 5000 IU from Now Foods, in which a large dosage allows you to get the recommended rate without taking capsules in handfuls (it is enough to take two capsules a day), which is very convenient.

Vitamin D overdose from food additives

With this natural method of obtaining vitamin D from the sun, the body itself will produce the required amount. Do not be afraid of an overdose of vitamin D-3 from the sun and getting an excess of it in the body. However, prolonged skin exposure to ultraviolet light should be avoided for other reasons, in particular because of the risk of damage (burns) to the skin while sunbathing.

Therefore, let us consider how things are with the intake of vitamin D from food. In the modern world, dietary intake of vitamin D3 is relatively low. Therefore, it is necessary to introduce foods containing vitamin D into the diet, especially in the autumn-winter period. It is during this period that we spend little time in the sun, and the skin is covered with clothes or cosmetics with UV protection. Previously, it was believed that 5 micrograms per person per day is enough to cover the needs of the body, because our body will create the rest on its own as a result of irradiation of the skin with solar ultraviolet light.Modern research shows that in order to achieve the minimum concentration of vitamin D in the blood serum necessary for the body, it is necessary to take about 20 μg of vitamin D3 with food.

Vitamin D3 we get, for example, from fatty fish (herring, mackerel) and egg yolks, it is also possible to obtain it from milk, vegetable fats (flaxseed oil), cereals. Vitamin D retains its concentration up to 50-80% with short-term heating of the product to a temperature of 180 ℃, but oxidizes when interacting with air.

At a normal level of consumption of foods containing vitamin D (with a normal diet), there is no need to be afraid of its overdose, since the achievement of high concentrations is extremely unlikely.

How to take vitamin D Nau Foods

Let’s see the description of this product from the manufacturer:

Specialists of the American manufacturer of the best dietary supplements, mineral complexes and cosmetic preparations have developed an effective formula of a useful compound and created vitamin D3 5000 IU in an easily digestible capsule shell.Each tablet contains a high content of the active ingredient, which makes it possible to reduce the frequency of use and achieve positive changes in the functioning of the body after a short period of use. Vitamin D3 5000 IU is easily absorbed and has a list of beneficial properties that have a beneficial effect on various systems.

Features and physiological properties:
The American manufacturer offers a huge range of products that normalize the condition and functionality of the body.Despite the fact that the dietary supplement is not a drug, it can be used to treat various diseases as an additional agent. But supplements are mainly used for prevention.

Means Vitamin D 3 5000 units is a natural form of organic compound, but its activity is 25% higher. This component enters the body with food, and is also produced in the epidermis under ultraviolet rays. Despite this, deficiencies are very common, and Now Foods’ Vitamin D3 5000 IU Complex will make up for micronutrient deficiencies.The dietary supplement has a number of beneficial effects:
regulates the exchange of calcium and phosphorus;
helps to preserve the structure of bone tissue;
improves the functions of the parathyroid glands;
strengthens the immune system;
reduces susceptibility to the development of skin diseases;
normalizes blood clotting.
Vitamin D3 5000 IU in an American dietary supplement is supplemented with such a component as olive oil extract.This ingredient accelerates the absorption of organic compounds.

Recommended dosage and precautions
Vitamin D3 5000 IU is indicated for use in case of disorders in the gastrointestinal tract and liver, micronutrient deficiency, diseases of the skeletal system. It is advisable to use the drug for the prevention and treatment of rickets, osteoporosis, psoriasis, eczema and other skin problems. Vitamin D3 NOW 5000 is taken 1 capsule every 2 days, or as directed by a physician.It is recommended to take it during meals with plenty of liquid.
The additive is contraindicated for persons with hypersensitivity to the components of the product, urolithiasis, renal insufficiency, high calcium levels in the blood. An overdose of the active substance is accompanied by dizziness, muscle and joint pain.

The preparation is in a very small plastic jar of the recognizable Now Foods color, a plastic cap that opens upwards is sealed with a plastic rim before use, a protective membrane under the lid protects the freshness of the product before the first opening and guarantees the originality of the contents.The country of origin of the product is the USA.

The capsules are very small gel capsules, pretty bright yellow, very convenient and absolutely hassle-free to take: it is advisable to take them with food with foods containing fats for better absorption. It is worth emphasizing right away that the dose of 10,000 IU recommended by the doctor is therapeutic, not prophylactic, I do not think that it is worth taking vitamin D3 in such a dosage for a long time without consulting a doctor and taking preliminary tests.

In addition to the 5,000 IU dosage, Now Foods has supplements with a dosage of 2,000 IU and many others (vitamin D with added vitamin K and so on). I always order the drug on IHerb, because there are always good prices and I believe that the products are original.

The results of analyzes of the level of vitamin D3 at first were 55 ng / ml, after half a year 84 ng / ml, after another half a year 108 ng / ml. These results clearly demonstrate how quickly and visibly the said Now Foods drug works, how effective it really is, is not a dummy and does not work like a placebo.

The doctor adjusted the dosage for me first to 10,000 IU except weekends (Saturday and Sunday), then to 5,000 IU daily, and then we switched to the level recommended by the manufacturer – 5,000 IU every other day. At the same time, at one point after a year of taking, my vitamin D level was even slightly exceeded, the doctor did not take into account my frequent and long trips to hot countries, when, despite all the protection, the vitamin is produced thanks to solar radiation (while I interrupted the intake for three months and resumed it already according to the recommended scheme).

In the past two years, I have been taking the drug exclusively for the prevention and maintenance of vitamin D3 at the proper level (I perform the analysis about once every six months and it stays at around 80-90 ng / ml, that is, an almost ideal level), simultaneously with it on a regular basis I take Solgar’s Omega-3 and Alpha Lipoic Acid (everything else periodically).

A great achievement for me personally – this is a stable and quite decent blood sugar level for my absolutely wrong lifestyle and even more unhealthy diet: all tests show a glycated hemoglobin level of no more than 4.9 (for me this is very cool, given my bad heredity and not very good analyzes earlier, I have always previously almost balanced on the brink, and now everything is relatively under control).

In addition, I definitely consider my strong immunity to be the merit of taking vitamin D: for the entire time of admission, I not only did not receive a single sick leave, but I did not even feel any mild symptoms of ODS, for example, even during the height of epidemics, off-season, with hypothermia and in any other situations, that is, I just don’t get sick and that’s it.

Hair, skin, nails – their condition has definitely improved significantly, but I think that this is the merit of all the drugs I take in the complex, because they work perfectly together, complementing each other, but vitamin D is definitely not useless, because it works as a complete an antioxidant that reduces UV damage to the skin (which is, in principle, the main cause of aging) and protects cell membranes from destruction.

My vitamin favorites

For those for whom the condition of the hair, their rapid growth and well-groomed appearance is especially important, as well as those suffering from hair loss, I can definitely recommend the coolest French remedies that give just an ideal effect after a course of application (although they are not very budgetary): this is a complex for hair from the Phyto company. From time to time I gather my spirit and buy myself these products as an intensive therapy for hair, a certain shake-up and reboot, and the result is simply stunning every time, the hair begins to grow very intensively, and the loss practically stops.

The cosmetologist confirms that now the results from any cosmetic procedures are more noticeable, the skin reacts better and faster to any care (and this is very important at my age 35+, no one wants to grow old).

Review and Reviews for Vitamin D 5000 IU Nau Foods Now Foods

Provided that taking vitamin D regulates a huge number of processes in the body, helps in the prevention and treatment of a huge number of diseases, and a large number of people have a deficiency of it (in countries with little sun, almost everyone), I sincerely believe that if If as many people as possible knew about its value and necessity, then most likely problems with serious illnesses would happen much less often.

In my personal opinion, Vitamin D-3 at a dosage of 5000 IU from Now Foods is a very cool, working, active product that can help prevent many diseases, improve the condition of hair, nails, skin, teeth, bones and muscles, and revitalize. tone and performance. I think that for a very modest price, such a drug is just a godsend and it definitely requires consideration (especially in the current realities, when there are a lot of suspicious dietary supplements on the market, from which at best there will be no harm, and at worst, their reception can end in failure).

Review and Reviews for Vitamin D 5000 IU Nau Foods Now Foods

It is probably worth emphasizing that taking any vitamins and supplements must be coordinated with your doctor, monitor test readings, pay attention to your health, and then taking them will definitely have a beneficial effect and allow you to live a more active, pleasant and full life.

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Vitamin D3 capsules Reviews

Work D3

5

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Efficiency:

From my own experience, I was convinced of the effectiveness of this product.I was tested for vitamin D (calciferol, 25-OH), the indicator turned out to be much lower than normal – 19.5 ng / ml. After four months of taking two capsules a day, I passed the test again, the result was 38.73 ng / ml, which is already getting into the norm. Now I take it permanently. For myself (weight 105 kg., + – 2 kg.) I realized that in the autumn-winter period it is better to take 3 capsules a day, and in the spring and summer 1-2. This product goes well with: With food.

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Just not put in the order !!

1

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Efficiency:

I made a big order.As usual, a bunch of offers, promotions and the like. had to put in these vitamins, shaker and bars as a bonus. The parcel arrived without all this, and I also had to pay taxes, since the cost in the parcel was higher than the passing limit. no reaction to the manager’s question, as if it should be. when they nevertheless admitted their mistake and the problem with the application, they refused to send it at all. The correspondence was simply endless, and almost zero sense. The products became just awful, almost all. Prices on the plan with normal eminent brands, as well as services with quality of service, none.Don’t mess with myprotein !!! This product goes well with: No idea, not even sent.

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Excellent quality as always!

5

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Efficiency:

I recommend excellent vitamins to everyone!

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My Review

5

Miscibility:

Efficiency:

Received the order, the service is on top! On the scales, everything that should be, the product is effective, I took 8 mini caps 30 minutes before training.During the training I felt cheerful, the training was more productive. From myself I will say, you will not regret this product from this company!) This product goes well with: With water

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Vitamin that can be obtained from the sun

5

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Efficiency:

Excellent vitamins that we can get from the sun, good dosage, you can drink in principle with anything you want This product goes well with: We can

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Excellent vitamins

5

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Efficiency:

Quality vitamins, I take 1-2 pcs every day.Perfectly support immunity, for the whole year (2020) and the beginning of 2021 I did not even catch a cold. 5 stars This product goes well with: It goes well with water, omega 3, multivitamins💪🔥

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D3 not D2

5

Miscibility:

Efficiency:

The jar is small, the capsules in the gel are spherical, too small, not all even (not critical).The drawing of the can does not fully correspond to the original. I drink three times a day, it is possible with food, but better with Omega 3 or Omega 3,6,9 after meals for 10-15 minutes. The vitamin is not water-soluble, but fat-soluble, so it is preferable with omega together or with more or less fatty foods. Overdose based on research is unlikely or unlikely. This product works well with: Omega 3 or Omega 3,6,9

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Best Buy

5

Miscibility:

Efficiency:

We got into a good action, we live in the westernmost point of Russia.There is a parcel by Poniexspress from England! They ask for passport data and TIN, it is not very clear what the TIN is for, but it must be given, or the parcel will be returned to the sender. They brought us right up to the apartment. A good dose in the 1st tablet. Looks like fish oil, but slightly smaller in size. Tasteless This product goes well with: Calcium from the same company

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Great product

5

Miscibility:

Efficiency:

Good vitamins.This is not the first time we order. Very satisfied with all myprotein products. Delivery to Kiev 5 days, but it happened 7-8. I give 5 points out of 5. This product goes well with: Food.

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