- What is Vitamin D
- How much vitamin D do you need?
- What foods provide vitamin D ?
- What kinds of vitamin D dietary supplements are available?
- Vitamin D2 versus Vitamin D3
- Are you getting enough vitamin D?
- Vitamin D Deficiency
- What are some effects of vitamin D on health?
- Can Excessive Vitamin D be harmful?
What is Vitamin D
Vitamin D also called Calciferol, is a fat-soluble vitamin that is naturally present in very few foods, added to others, and available as a dietary supplement. In foods and dietary supplements, vitamin D has two main forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol), that differ chemically only in their side-chain structures. Both forms are well absorbed in the small intestine. Absorption occurs by simple passive diffusion and by a mechanism that involves intestinal membrane carrier proteins 1). The concurrent presence of fat in the gut enhances vitamin D absorption, but some vitamin D is absorbed even without dietary fat. Neither aging nor obesity alters vitamin D absorption from the gut 2). Vitamin D is also produced endogenously when ultraviolet rays from sunlight strike your skin and trigger vitamin D synthesis. Vitamin D obtained from sun exposure, food, and supplements is biologically inert and must undergo two hydroxylations in the body for activation 3). The first occurs in the liver and converts vitamin D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol or 25-hydroxyvitamin D3 (25-hydroxycholecalciferol). The second occurs primarily in the kidney and forms the physiologically active 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol or vitamin D3 4). A manufactured calcitriol or vitamin D3 is used to treat kidney disease with low blood calcium, hyperparathyroidism due to kidney disease, low blood calcium due to hypoparathyroidism, osteoporosis, osteomalacia, and familial hypophosphatemia. It is taken by mouth or by injection into a vein.
Sunlight exposure is the primary source of vitamin D for most people. Solar ultraviolet-B radiation (UVB; wavelengths of 290 to 315 nanometers) stimulates the production of vitamin D3 from 7-dehydrocholesterol in the epidermis of the skin. Hence, vitamin D is actually more like a hormone than a vitamin, a substance that is required from the diet. Vitamin D enters the circulation and is transported to the liver, where it is hydroxylated to form 25-hydroxyvitamin D3 (calcidiol; the major circulating form of vitamin D). In the kidneys, the 1-α-hydroxylase enzyme catalyzes a second hydroxylation of 25-hydroxyvitamin D3, resulting in the formation of 1,25-dihydroxyvitamin D3 (calcitriol, 1,25-dihydroxyvitamin D3 or vitamin D3] — the most potent form of vitamin D 5). Most of the physiological effects of vitamin D in the body are related to the activity of 1,25-dihydroxyvitamin D3 (also known as calcitriol or vitamin D3). Keratinocytes in the epidermis possess hydroxylase enzymes that locally convert vitamin D to 1,25-dihydroxyvitamin D3, the form that regulates epidermal proliferation and differentiation 6).
Figure 1. Production of vitamin D3 in the skin
The plasma calcitriol (1,25-dihydroxyvitamin D3 or 1,25(OH)2D) or vitamin D3 concentration depends on the availability of calcidiol (25-hydroxyvitamin D3 or 25(OH)D) and the activities of the renal enzymes 1-α-hydroxylase and 24-α-hydroxylase 7). The renal 1-α-hydroxylase enzyme is primarily regulated by parathyroid hormone (PTH), serum calcium and phosphate concentrations, and fibroblast growth factor 23 (FGF23) 8). Increased parathyroid hormone (PTH), calcitonin, and hypophosphatemia (low blood phosphate) stimulate the renal enzymes 1-α-hydroxylase and enhance calcitriol [1,25(OH)2D] production, while high calcium, hyperphosphatemia (high blood phosphate) and calcitriol [1,25(OH)2D] inhibit the renal enzymes 1-α-hydroxylase 9). Calcitriol [1,25-dihydroxyvitamin D or 1,25(OH)2D] inhibits the synthesis and secretion of parathyroid hormone (PTH), providing negative feedback regulation of calcitriol production. Calcitriol [1,25-dihydroxyvitamin D or 1,25(OH)2D] synthesis may also be modulated by vitamin D receptors on the cell surface; downregulation of these receptors may play an important role in regulating vitamin D activation 10). Fibroblast growth factor 23 (FGF23), a newly described phosphaturic hormone, inhibits renal production of Calcitriol [1,25-dihydroxyvitamin D or 1,25(OH)2D] by inhibiting 1-α-hydroxylase in the renal proximal tubule and by simultaneously increasing the expression of 24-α-hydroxylase and production of 24,25(OH)2D (an inactive metabolite) 11). Calcitriol [1,25-dihydroxyvitamin D or 1,25(OH)2D] stimulates fibroblast growth factor 23 (FGF23), creating a feedback loop. Fibroblast growth factor 23 (FGF23) decreases renal reabsorption of phosphate, and thereby counteracts the increased gastrointestinal phosphate reabsorption induced by Calcitriol, maintaining phosphate homeostasis 12).
When hypocalcemia (low blood calcium) occurs, serum parathyroid hormone (PTH) concentration increases and enhances renal tubular reabsorption of calcium, as well as the activity of 1-α-hydroxylase in the kidney. This results in increased Calcitriol [1,25-dihydroxyvitamin D or 1,25(OH)2D] production, and in turn, intestinal calcium absorption. Parathyroid hormone (PTH) also stimulates bone osteoclast activity to mobilize bone calcium stores, thereby increasing serum calcium. Both Calcitriol and Calcidiol [25-hydroxyvitamin D or 25(OH)D] are degraded in part by being hydroxylated at the 24 position by a 24-hydroxylase. The activity of the 24-hydroxylase gene is increased by calcitriol (which therefore promotes its own inactivation) and reduced by parathyroid hormone (thereby allowing more active hormone to be formed) 13). Estrogen, placental growth hormone, and prolactin may also regulate vitamin D metabolism, playing a role during pregnancy to meet increased calcium demands. Calcitriol is also formed in some other tissues, but is used only within the tissues and not circulated. Parathyroid hormone (PTH)- independent extrarenal production of Calcitriol from Calcidiol is by activated macrophages in the lung and lymph nodes. The 1-α-hydroxylase enzyme is also expressed at other extrarenal sites, including the gastrointestinal tract, skin, vasculature, mammary epithelial cells, and in osteoblasts and osteoclasts 14).
Vitamin D is a nutrient found in some foods that is needed for health and to maintain strong bones. It does so by helping the body absorb calcium (one of bone’s main building blocks) from food and supplements. People who get too little vitamin D may develop soft, thin, and brittle bones, a condition known as rickets in children and osteomalacia in adults.
Vitamin D is important to the body in many other ways as well. Muscles need it to move, for example, nerves need it to carry messages between the brain and every body part, and the immune system needs vitamin D to fight off invading bacteria and viruses. Together with calcium, vitamin D also helps protect older adults from osteoporosis. Vitamin D is found in cells throughout the body.
Vitamin D promotes calcium absorption in the gut and maintains adequate serum calcium and phosphate concentrations to enable normal mineralization of bone and to prevent hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts 15), 16). Without sufficient vitamin D, bones can become thin, brittle, or misshapen. Vitamin D sufficiency prevents rickets in children and osteomalacia in adults 17). Together with calcium, vitamin D also helps protect older adults from osteoporosis.
Vitamin D has other roles in the body, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation 18), 19), 20). Many genes encoding proteins that regulate cell proliferation, differentiation, and apoptosis are modulated in part by vitamin D 21). Many cells have vitamin D receptors, and some convert 25-hydroxyvitamin D (25(OH)D or calcidiol) to calcitriol [1,25-dihydroxyvitamin D or 1,25(OH)2D].
Serum concentration of 25-hydroxyvitamin D (25(OH)D or calcidiol) is the best indicator of vitamin D status. It reflects vitamin D produced cutaneously and that obtained from food and supplements 22) and has a fairly long circulating half-life of 15 days 23). 25-hydroxyvitamin D (25(OH)D or calcidiol) functions as a biomarker of exposure, but it is not clear to what extent 25-hydroxyvitamin D (25(OH)D or calcidiol) levels also serve as a biomarker of effect (i.e., relating to health status or outcomes) 24). Serum 25-hydroxyvitamin D (25(OH)D or calcidiol) levels do not indicate the amount of vitamin D stored in body tissues.
In contrast to 25(OH)D, circulating Calcitriol [1,25-dihydroxyvitamin D or 1,25(OH)2D] is generally not a good indicator of vitamin D status because it has a short half-life of 15 hours and serum concentrations are closely regulated by parathyroid hormone, calcium, and phosphate 25). Levels of 1,25(OH)2D do not typically decrease until vitamin D deficiency is severe 26), 27).
There is considerable discussion of the serum concentrations of 25-hydroxyvitamin D (25(OH)D or calcidiol) associated with deficiency (e.g., rickets), adequacy for bone health, and optimal overall health, and cut points have not been developed by a scientific consensus process. Based on its review of data of vitamin D needs, a committee of the Institute of Medicine concluded that persons are at risk of vitamin D deficiency at serum 25(OH)D concentrations <30 nmol/L (<12 ng/mL). Some are potentially at risk for inadequacy at levels ranging from 30–50 nmol/L (12–20 ng/mL). Practically all people are sufficient at levels ≥50 nmol/L (≥20 ng/mL); the committee stated that 50 nmol/L is the serum 25(OH)D level that covers the needs of 97.5% of the population. Serum concentrations >125 nmol/L (>50 ng/mL) are associated with potential adverse effects 28) (Table 1).
An additional complication in assessing vitamin D status is in the actual measurement of 25-hydroxyvitamin D (25(OH)D or calcidiol) concentrations. Considerable variability exists among the various assays available (the two most common methods being antibody based and liquid chromatography based) and among laboratories that conduct the analyses 29), 30), 31). This means that compared with the actual concentration of 25-hydroxyvitamin D (25(OH)D or calcidiol) in a sample of blood serum, a falsely low or falsely high value may be obtained depending on the assay or laboratory used 32). A standard reference material for 25-hydroxyvitamin D (25(OH)D or calcidiol) became available in July 2009 that permits standardization of values across laboratories and may improve method-related variability 33), 34).
Table 1. Serum 25-Hydroxyvitamin D [25(OH)D] Concentrations and Health*
|<30||<12||Associated with vitamin D deficiency, leading to rickets|
in infants and children and osteomalacia in adults
|30 to <50||12 to <20||Generally considered inadequate for bone and overall health|
in healthy individuals
|≥50||≥20||Generally considered adequate for bone and overall health|
in healthy individuals
|>125||>50||Emerging evidence links potential adverse effects to such|
high levels, particularly >150 nmol/L (>60 ng/mL)
* Serum concentrations of 25(OH)D are reported in both nanomoles per liter (nmol/L) and nanograms per milliliter (ng/mL).
** 1 nmol/L = 0.4 ng/mL
How much vitamin D do you need?
Intake reference values for vitamin D and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine of The National Academies (formerly National Academy of Sciences) 36). DRI is the general term for a set of reference values used to plan and assess nutrient intakes of healthy people. These values, which vary by age and gender, include:
- Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy people.
- Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.
- Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects 37).
The FNB established an RDA for vitamin D representing a daily intake that is sufficient to maintain bone health and normal calcium metabolism in healthy people. RDAs for vitamin D are listed in both International Units (IUs) and micrograms (mcg); the biological activity of 40 IU is equal to 1 mcg (Table 2). Even though sunlight may be a major source of vitamin D for some, the vitamin D RDAs are set on the basis of minimal sun exposure 38).
Table 2. The amount of vitamin D you need each day depends on your age. Average daily recommended amounts from the Food and Nutrition Board (a national group of experts) for different ages are listed below in International Units (IU):
|Life Stage||Recommended Amount|
|Birth to 12 months||400 IU (10 mcg)|
|Children 1–13 years||600 IU (15 mcg)|
|Teens 14–18 years||600 IU (15 mcg)|
|Adults 19–70 years||600 IU (15 mcg)|
|Adults 71 years and older||800 IU (20 mcg)|
|Pregnant and breastfeeding women||600 IU (15 mcg)|
Footnote: The amount of vitamin D contained in supplements is sometimes expressed in international units (IU) where 40 IU is equal to one microgram (1 mcg) of vitamin D.[Source 39) ]
What foods provide vitamin D ?
Very few foods naturally have vitamin D. The flesh of fatty fish (such as salmon, tuna, and mackerel) and fish liver oils are among the best sources 40), 41). Small amounts of vitamin D are found in beef liver, cheese, and egg yolks. Vitamin D in these foods is primarily in the form of vitamin D3 and its metabolite 25(OH)D3 42). Some mushrooms provide vitamin D2 in variable amounts 43), 44). Mushrooms with enhanced levels of vitamin D2 from being exposed to ultraviolet light under controlled conditions are also available.
The U.S. Department of Agriculture’s (USDA’s) Nutrient Database website 45) lists the nutrient content of many foods with vitamin D arranged by nutrient content 46) and by food name 47). A growing number of foods are being analyzed for vitamin D content. Simpler and faster methods to measure vitamin D in foods are needed, as are food standard reference materials with certified values for vitamin D to ensure accurate measurements 48).
Fortified foods provide most of the vitamin D in the American diet 49), 50). For example, almost all of the U.S. milk supply is voluntarily fortified with 100 IU/cup 51). (In Canada, milk is fortified by law with 35–40 IU/100 mL, as is margarine at ≥530 IU/100 g.) In the 1930s, a milk fortification program was implemented in the United States to combat rickets, then a major public health problem 52). Other dairy products made from milk, such as cheese and ice cream, are generally not fortified. Ready-to-eat breakfast cereals often contain added vitamin D, as do some brands of orange juice, yogurt, margarine and other food products.
Both the United States and Canada mandate the fortification of infant formula with vitamin D: 40–100 IU/100 kcal in the United States and 40–80 IU/100 kcal in Canada 53).
Fortified foods provide most of the vitamin D in American diets:
- Fatty fish such as salmon, tuna, and mackerel are among the best sources.
- Beef liver, cheese, and egg yolks provide small amounts.
- Mushrooms provide some vitamin D. In some mushrooms that are newly available in stores, the vitamin D content is being boosted by exposing these mushrooms to ultraviolet light.
- Almost all of the U.S. milk supply is fortified with 400 IU of vitamin D per quart. But foods made from milk, like cheese and ice cream, are usually not fortified.
- Vitamin D is added to many breakfast cereals and to some brands of orange juice, yogurt, margarine, and soy beverages; check the labels.
Table 3: Selected Food Sources of Vitamin D
|Food||IUs per serving*||Percent DV**|
|Cod liver oil, 1 tablespoon||1,360||340|
|Swordfish, cooked, 3 ounces||566||142|
|Salmon (sockeye), cooked, 3 ounces||447||112|
|Tuna fish, canned in water, drained, 3 ounces||154||39|
|Orange juice fortified with vitamin D, 1 cup (check product labels, as amount of added vitamin D varies)||137||34|
|Milk, nonfat, reduced fat, and whole, vitamin D-fortified, 1 cup||115-124||29-31|
|Yogurt, fortified with 20% of the DV for vitamin D, 6 ounces (more heavily fortified yogurts provide more of the DV)||80||20|
|Margarine, fortified, 1 tablespoon||60||15|
|Sardines, canned in oil, drained, 2 sardines||46||12|
|Liver, beef, cooked, 3 ounces||42||11|
|Egg, 1 large (vitamin D is found in yolk)||41||10|
|Ready-to-eat cereal, fortified with 10% of the DV for vitamin D, 0.75-1 cup (more heavily fortified cereals might provide more of the DV)||40||10|
|Cheese, Swiss, 1 ounce||6||2|
* IUs = International Units.
** DV = Daily Value. DVs were developed by the U.S. Food and Drug Administration to help consumers compare the nutrient contents among products within the context of a total daily diet. The DV for vitamin D is currently set at 400 IU for adults and children age 4 and older. Food labels, however, are not required to list vitamin D content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.
Note: The amount of vitamin D contained in supplements is sometimes expressed in international units (IU) where 40 IU is equal to one microgram (1 mcg) of vitamin D.[Source 54)]
Animal-based foods can provide some vitamin D in the form of 25(OH)D, which appears to be approximately five times more potent than the parent vitamin in raising serum 25(OH)D concentrations 55). One study finds that taking into account the serum 25(OH)D content of beef, pork, chicken, turkey, and eggs can increase the estimated levels of vitamin D in the food from two to 18 times, depending upon the food 56). At the present time, the USDA’s Nutrient Database does not include 25(OH)D when reporting the vitamin D content of foods. Actual vitamin D intakes in the U.S. population may be underestimated for this reason.
Can you get vitamin D from the sun?
Most people meet at least some of their vitamin D needs through exposure to sunlight 57), 58). Ultraviolet (UV) B radiation with a wavelength of 290–320 nanometers penetrates uncovered skin and converts cutaneous 7-dehydrocholesterol to previtamin D3, which in turn becomes vitamin D3 59). Season, time of day, length of day, cloud cover, smog, skin melanin content, and sunscreen are among the factors that affect UV radiation exposure and vitamin D synthesis 60). Perhaps surprisingly, geographic latitude does not consistently predict average serum 25(OH)D levels in a population. Ample opportunities exist to form vitamin D (and store it in the liver and fat) from exposure to sunlight during the spring, summer, and fall months even in the far north latitudes 61).
Complete cloud cover reduces UV energy by 50%; shade (including that produced by severe pollution) reduces it by 60% 62). UVB radiation does not penetrate glass, so exposure to sunshine indoors through a window does not produce vitamin D 63). Sunscreens with a sun protection factor (SPF) of 8 or more appear to block vitamin D-producing UV rays, although in practice people generally do not apply sufficient amounts, cover all sun-exposed skin, or reapply sunscreen regularly 64), 65). Therefore, skin likely synthesizes some vitamin D even when it is protected by sunscreen as typically applied.
The factors that affect UV radiation exposure and research to date on the amount of sun exposure needed to maintain adequate vitamin D levels make it difficult to provide general guidelines. It has been suggested by some vitamin D researchers, for example, that approximately 5–30 minutes of sun exposure between 10 AM and 3 PM at least twice a week to the face, arms, legs, or back without sunscreen usually lead to sufficient vitamin D synthesis and that the moderate use of commercial tanning beds that emit 2%–6% UVB radiation is also effective 66), 67). Individuals with limited sun exposure need to include good sources of vitamin D in their diet or take a supplement to achieve recommended levels of intake.
Despite the importance of the sun for vitamin D synthesis, it is prudent to limit exposure of skin to sunlight 68) and UV radiation from tanning beds 69). UV radiation is a carcinogen responsible for most of the estimated 1.5 million skin cancers and the 8,000 deaths due to metastatic melanoma that occur annually in the United States 70). Lifetime cumulative UV damage to skin is also largely responsible for some age-associated dryness and other cosmetic changes. The American Academy of Dermatology advises that photoprotective measures be taken, including the use of sunscreen, whenever one is exposed to the sun 71). Assessment of vitamin D requirements cannot address the level of sun exposure because of these public health concerns about skin cancer, and there are no studies to determine whether UVB-induced synthesis of vitamin D can occur without increased risk of skin cancer 72).
The body makes vitamin D when skin is directly exposed to the sun, and most people meet at least some of their vitamin D needs this way. Skin exposed to sunshine indoors through a window will not produce vitamin D. Cloudy days, shade, and having dark-colored skin also cut down on the amount of vitamin D the skin makes.
However, despite the importance of the sun to vitamin D synthesis, it is prudent to limit exposure of skin to sunlight in order to lower the risk for skin cancer. When out in the sun for more than a few minutes, wear protective clothing and apply sunscreen with an SPF (sun protection factor) of 15 or more. Tanning beds also cause the skin to make vitamin D, but pose similar risks for skin cancer.
People who avoid the sun or who cover their bodies with sunscreen or clothing should include good sources of vitamin D in their diets or take a supplement. Recommended intakes of vitamin D are set on the assumption of little sun exposure.
How long should you spend in the sun?
Most people can make enough vitamin D from being out in the sun daily for short periods with their forearms, hands or lower legs uncovered and without sunscreen from late March or early April to the end of September, especially from 11am to 3pm.
It’s not known exactly how much time is needed in the sun to make enough vitamin D to meet your body’s requirements. This is because there are a number of factors that can affect how vitamin D is made, such as your skin color or how much skin you have exposed. But you should be careful not to burn in the sun, so take care to cover up, or protect your skin with sunscreen, before your skin starts to turn red or burn.
Your risk of sunburn depends on 2 things. How sun-sensitive your skin is, and how strong the UV rays are you’re exposed to. Different people will have a different risk of sunburn on the same day, so it’s a good idea to know when your risk is high, so you can protect your skin.
In general people who have one or more of the following are at more risk:
- skin that burns easily
- light or fair colored skin, hair, or eyes
- lots of moles or freckles
- a history of sunburn
- a personal or family history of skin cancer
People with dark skin, such as those of African, African-Caribbean or south Asian origin, will need to spend longer in the sun to produce the same amount of vitamin D as someone with lighter skin.
- Children aged under six months should be kept out of direct strong sunlight. To ensure they get enough vitamin D, babies and children aged under five years should be given vitamin D supplements even if they do get out in the sun.
How long it takes for your skin to go red or burn varies from person to person. You’re the best person to know how your skin reacts in the sun. The more easily you get sunburnt, the more careful you need to be. Remember, you don’t need to peel – if your skin’s gone red or pink in the sun, that’s sunburn, and it’s dangerous. For people with darker skin it may feel irritated, tender or itchy. The longer you stay in the sun, especially for prolonged periods without sun protection, the greater your risk of skin cancer. Using sunbeds is not a recommended way of making vitamin D.
Other things that affect the strength of UV rays are the:
- Time of year – the highest risk months in the US are April to September. Near the equator, there are strong UV rays all year round.
- Altitude – UV rays are stronger the higher you go. So skiers and mountaineers can easily get caught out.
- Cloud cover – over 90% of UV can pass through light cloud.
- Reflection – up to 80% of UV rays are reflected back from snow, 15% from sand, 10% from concrete and up to 30% from water (depending on how choppy it is).
What kinds of vitamin D dietary supplements are available?
Vitamin D is found in supplements (and fortified foods) in two different forms: D2 (ergocalciferol) and D3 (cholecalciferol). Both increase vitamin D in the blood.
In supplements and fortified foods, vitamin D is available in two forms, D2 (ergocalciferol) and D3 (cholecalciferol) that differ chemically only in their side-chain structure. Vitamin D2 is manufactured by the UV irradiation of ergosterol in yeast, and vitamin D3 is manufactured by the irradiation of 7-dehydrocholesterol from lanolin and the chemical conversion of cholesterol 73). The two forms have traditionally been regarded as equivalent based on their ability to cure rickets and, indeed, most steps involved in the metabolism and actions of vitamin D2 and vitamin D3 are identical. Both forms (as well as vitamin D in foods and from cutaneous synthesis) effectively raise serum Calcidiol [25-hydroxyvitamin D or 25(OH)D] levels 74). Firm conclusions about any different effects of these two forms of vitamin D cannot be drawn. However, it appears that at nutritional doses vitamins D2 and D3 are equivalent, but at high doses vitamin D2 is less potent. Some studies suggest that cholecalciferol (Vitamin D3) increases serum Calcidiol [25(OH) D] more efficiently than does ergocalciferol (Vitamin D2) 75).
- Vitamin D3 (cholecalciferol) is available in 400, 800, 1000, 2000, 5000, 10,000, and 60,000 IU capsules. It is available in some countries as an intramuscular injection (Arachital 600,000 IU, which maintains vitamin D levels for 1 year). However, it can be extremely painful 76).
- Vitamin D2 (ergocalciferol) is available for oral use in 400 and 50,000 unit capsules or in a liquid form (8000 IU/mL) 77).
The American Academy of Pediatrics (AAP) recommends that exclusively and partially breastfed infants receive supplements of 400 IU/day of vitamin D shortly after birth and continue to receive these supplements until they are weaned and consume ≥1,000 mL/day of vitamin D-fortified formula or whole milk 78). Similarly, all non-breastfed infants ingesting <1,000 mL/day of vitamin D-fortified formula or milk should receive a vitamin D supplement of 400 IU/day 79). The American Academy of Pediatrics also recommends that older children and adolescents who do not obtain 400 IU/day through vitamin D-fortified milk and foods should take a 400 IU vitamin D supplement daily. However, this latter recommendation (issued November 2008) needs to be reevaluated in light of the Food and Nutrition Board’s vitamin D RDA of 600 IU/day for children and adolescents (issued November 2010 and which previously was an AI of 200 IU/day).
Vitamin D2 versus Vitamin D3
Vitamins D2 and D3, as described previously, differ only in their side chain structure. Physiological responses to both forms of the vitamin include regulation of calcium and phosphate homeostasis and regulation of cell proliferation and cell differentiation of specific cell types, as described above. Qualitatively, vitamins D2 and D3 exhibit virtually identical biological responses throughout the body (i.e., through gene expression) that are mediated by the vitamin D receptor 80).
Regarding the potency of the two forms of vitamin D, there are reports that certain animals, such as avian species and New World monkeys 81), discriminate against vitamin D2. However, it has been assumed for several decades that the two forms are essentially equipotent in humans 82). Recent reports involving human dietary studies have argued for 83) or against 84) a metabolic discrimination against vitamin D2, compared with vitamin D3. Part of the apparent conflict between these different studies 85) is almost certainly due to differences in size and frequency of dose (which have ranged from 1,000 IU daily doses to 50,000 IU in a single dose); the differences reported suggest a difference in pharmacokinetic parameters between vitamin D2 and vitamin D3.
This debate runs parallel to the suggestion that vitamin D2 is less toxic than its vitamin D3 counterpart. Experimental animal data from a number of mammalian species ranging from rodents to primates 86), support the concept that the D2 form is less toxic than D3, but there is no evidence available in humans. Nonetheless, the implication of these diverse studies in several mammalian species is that vitamin D2 compounds may show differences in pharmacokinetics that manifest as lower toxicity from high doses.
There is considerable evidence that most of the steps involved in the metabolism and actions of vitamin D2 and vitamin D3 are identical 87). The identification of the series of vitamin D3 metabolites in the late 1960s and early 1970s was followed by the identification of their vitamin D2 counterparts: 25OHD2, 1α,25(OH)2D2, and 24,25(OH)2D2 88). Noteworthy here is the fact that the structural features unique to the vitamin D2 side chain did not preclude either the 25- or 1α-hydroxylation steps in activation of the molecule or the first step of inactivation, namely 24-hydroxylation. Studies have also shown that the steps in the specific vitamin D signal transduction cascade do not appear to discriminate discernibly between the two vitamin D homologues at the molecular level (e.g., binding to the transport protein, vitamin D binding protein 89) or binding to the receptor, vitamin D receptor 90). Overall, it can be concluded that specific signal transduction systems designed to respond to vitamin D3 respond to physiological doses of vitamin D2 equally well.
At this time, firm conclusions about different effects of the two forms of vitamin D cannot be drawn; however, it would appear that at low doses, vitamin D2 and vitamin D3 are equivalent, but at high doses, vitamin D2 is less effective than vitamin D3. In essence, the potency of the two forms (as judged by the dose required to cure rickets) is assumed to be the same 91). Differences in toxicity for humans, as judged by the dose to cause hypervitaminosis D, are unclear, but there is evidence from experimental animal data to suggest that vitamin D2 is less toxic than vitamin D3.
Are you getting enough vitamin D?
Because vitamin D can come from sun, food, and supplements, the best measure of one’s vitamin D status is blood levels of a form known as 25-hydroxyvitamin D. Levels are described in either nanomoles per liter (nmol/L) or nanograms per milliliter (ng/mL), where 1 nmol/L = 0.4 ng/mL.
In general, levels below 30 nmol/L (12 ng/mL) are too low for bone or overall health, and levels above 125 nmol/L (50 ng/mL) are probably too high. Levels of 50 nmol/L or above (20 ng/mL or above) are sufficient for most people.
By these measures, some Americans are vitamin D deficient and almost no one has levels that are too high. In general, young people have higher blood levels of 25-hydroxyvitamin D than older people and males have higher levels than females. By race, non-Hispanic blacks tend to have the lowest levels and non-Hispanic whites the highest. The majority of Americans have blood levels lower than 75 nmol/L (30 ng/mL).
Certain other groups may not get enough vitamin D:
- Breastfed infants, because human milk is a poor source of the nutrient. Breastfed infants should be given a supplement of 400 IU of vitamin D each day.
- Older adults, because their skin doesn’t make vitamin D when exposed to sunlight as efficiently as when they were young, and their kidneys are less able to convert vitamin D to its active form.
- People with dark skin, because their skin has less ability to produce vitamin D from the sun.
- People with disorders such as Crohn’s disease or celiac disease who don’t handle fat properly, because vitamin D needs fat to be absorbed.
- Obese people, because their body fat binds to some vitamin D and prevents it from getting into the blood.
What happens if you don’t get enough vitamin D?
People can become deficient in vitamin D because they don’t consume enough or absorb enough from food, their exposure to sunlight is limited, or their kidneys cannot convert vitamin D to its active form in the body. In children, vitamin D deficiency causes rickets, where the bones become soft and bend. It’s a rare disease but still occurs, especially among African American infants and children. In adults, vitamin D deficiency leads to osteomalacia, causing bone pain and muscle weakness.
Vitamin D Deficiency
Nutrient deficiencies are usually the result of dietary inadequacy, impaired absorption and use, increased requirement, or increased excretion. A vitamin D deficiency can occur when usual intake is lower than recommended levels over time, exposure to sunlight is limited, the kidneys cannot convert calcidiol (25-hydroxyvitamin D3 or 25(OH)D) to its active form, or absorption of vitamin D from the digestive tract is inadequate. Vitamin D-deficient diets are associated with milk allergy, lactose intolerance, ovo-vegetarianism, and veganism 92).
Rickets and osteomalacia are the classical vitamin D deficiency diseases. In children, vitamin D deficiency causes rickets, a disease characterized by a failure of bone tissue to properly mineralize, resulting in soft bones and skeletal deformities 93). In the late 19th and early 20th centuries, German physicians noted that consuming 1–3 teaspoons/day of cod liver oil could reverse rickets 94). The fortification of milk and other staples, such as breakfast cereals and margarine, with vitamin D beginning in the 1930s has made rickets a rare disease in the United States, although it is still reported periodically, particularly among African American infants and children, immigrants from African, Middle-Eastern, and Asian countries 95), 96), 97). Possible explanations for this increase include genetic differences in vitamin D metabolism, dietary preferences, and behaviors that lead to less sun exposure 98).
Prolonged exclusive breastfeeding without the American Academy of Pediatrics-recommended vitamin D supplementation is a significant cause of rickets, particularly in dark-skinned infants breastfed by mothers who are not vitamin D replete 99). Additional causes of rickets include extensive use of sunscreens and placement of children in daycare programs, where they often have less outdoor activity and sun exposure 100), 101). Rickets is also more prevalent among immigrants from Asia, Africa, and the Middle East, possibly because of genetic differences in vitamin D metabolism and behavioral differences that lead to less sun exposure.
In adults, vitamin D deficiency can lead to osteomalacia, resulting in weak bones 102), 103). Symptoms of bone pain and muscle weakness can indicate inadequate vitamin D levels, but such symptoms can be subtle and go undetected in the initial stages.
Groups at Risk of Vitamin D Inadequacy
Obtaining sufficient vitamin D from natural food sources alone is difficult. For many people, consuming vitamin D-fortified foods and, arguably, being exposed to some sunlight are essential for maintaining a healthy vitamin D status. In some groups, dietary supplements might be required to meet the daily need for vitamin D.
- Breastfed infants
Vitamin D requirements cannot ordinarily be met by human milk alone 104), 105), which provides <25 IU/L to 78 IU/L 106). (The vitamin D content of human milk is related to the mother’s vitamin D status, so mothers who supplement with high doses of vitamin D may have correspondingly high levels of this nutrient in their milk 107).) A review of reports of nutritional rickets found that a majority of cases occurred among young, breastfed African Americans 108). A survey of Canadian pediatricians found the incidence of rickets in their patients to be 2.9 per 100,000; almost all those with rickets had been breast fed 109). While the sun is a potential source of vitamin D, the AAP advises keeping infants out of direct sunlight and having them wear protective clothing and sunscreen 110). As noted earlier, the AAP recommends that exclusively and partially breastfed infants be supplemented with 400 IU of vitamin D per day 111), the RDA for this nutrient during infancy.
- Older adults
Older adults are at increased risk of developing vitamin D insufficiency in part because, as they age, skin cannot synthesize vitamin D as efficiently, they are likely to spend more time indoors, and they may have inadequate intakes of the vitamin 112). As many as half of older adults in the United States with hip fractures could have serum 25(OH)D levels <30 nmol/L (<12 ng/mL) 113).
- People with limited sun exposure
Homebound individuals, women who wear long robes and head coverings for religious reasons, and people with occupations that limit sun exposure are unlikely to obtain adequate vitamin D from sunlight 114), 115). Because the extent and frequency of use of sunscreen are unknown, the significance of the role that sunscreen may play in reducing vitamin D synthesis is unclear 116). Ingesting RDA levels of vitamin D from foods and/or supplements will provide these individuals with adequate amounts of this nutrient.
- People with dark skin
Greater amounts of the pigment melanin in the epidermal layer result in darker skin and reduce the skin’s ability to produce vitamin D from sunlight 117). Various reports consistently show lower serum 25(OH)D levels in persons identified as black compared with those identified as white. It is not clear that lower levels of 25(OH)D for persons with dark skin have significant health consequences. Those of African American ancestry, for example, have reduced rates of fracture and osteoporosis compared with Caucasians (see section below on osteoporosis). Ingesting RDA levels of vitamin D from foods and/or supplements will provide these individuals with adequate amounts of this nutrient.
- People with inflammatory bowel disease and other conditions causing fat malabsorption
Because vitamin D is a fat-soluble vitamin, its absorption depends on the gut’s ability to absorb dietary fat. Individuals who have a reduced ability to absorb dietary fat might require vitamin D supplementation 118). Fat malabsorption is associated with a variety of medical conditions, including some forms of liver disease, cystic fibrosis, celiac disease, and Crohn’s disease, as well as ulcerative colitis when the terminal ileum is inflamed 119), 120), 121). In addition, people with some of these conditions might have lower intakes of certain foods, such as dairy products fortified with vitamin D.
- People who are obese or who have undergone gastric bypass surgery
A body mass index ≥30 is associated with lower serum 25(OH)D levels compared with non-obese individuals; people who are obese may need larger than usual intakes of vitamin D to achieve 25(OH)D levels comparable to those of normal weight 122). Obesity does not affect skin’s capacity to synthesize vitamin D, but greater amounts of subcutaneous fat sequester more of the vitamin and alter its release into the circulation. Obese individuals who have undergone gastric bypass surgery may become vitamin D deficient over time without a sufficient intake of this nutrient from food or supplements, since part of the upper small intestine where vitamin D is absorbed is bypassed and vitamin D mobilized into the serum from fat stores may not compensate over time 123), 124).
What are some effects of vitamin D on health?
Vitamin D is being studied for its possible connections to several diseases and medical problems, including diabetes, hypertension, and autoimmune conditions such as multiple sclerosis. Two of them discussed below are bone disorders and some types of cancer.
- Osteoporosis & Bone disorders
More than 40 million adults in the United States have or are at risk of developing osteoporosis, a disease characterized by low bone mass and structural deterioration of bone tissue that increases bone fragility and significantly increases the risk of bone fractures 125). Osteoporosis is most often associated with inadequate calcium intakes, but insufficient vitamin D contributes to osteoporosis by reducing calcium absorption 126). Although rickets and osteomalacia are extreme examples of the effects of vitamin D deficiency, osteoporosis is an example of a long-term effect of calcium and vitamin D insufficiency. Adequate storage levels of vitamin D maintain bone strength and might help prevent osteoporosis in older adults, non-ambulatory individuals who have difficulty exercising, postmenopausal women, and individuals on chronic steroid therapy 127).
Normal bone is constantly being remodeled. During menopause, the balance between these processes changes, resulting in more bone being resorbed than rebuilt. Hormone therapy with estrogen and progesterone might be able to delay the onset of osteoporosis. Several medical groups and professional societies support the use of HRT as an option for women who are at increased risk of osteoporosis or fractures 128), 129), 130). Such women should discuss this matter with their health care providers.
Most supplementation trials of the effects of vitamin D on bone health also include calcium, so it is difficult to isolate the effects of each nutrient. Among postmenopausal women and older men, supplements of both vitamin D and calcium result in small increases in bone mineral density throughout the skeleton. They also help to reduce fractures in institutionalized older populations, although the benefit is inconsistent in community-dwelling individuals 131), 132), 133). Vitamin D supplementation alone appears to have no effect on risk reduction for fractures nor does it appear to reduce falls among the elderly 134), 135), 136); one widely-cited meta-analysis suggesting a protective benefit of supplemental vitamin D against falls 137) has been severely critiqued 138). However, a large study of women aged ≥69 years followed for an average of 4.5 years found both lower (<50 nmol/L [<20 ng/mL]) and higher(≥75 nmol/L [≥30 ng/mL]) 25(OH)D levels at baseline to be associated with a greater risk of frailty 139). Women should consult their healthcare providers about their needs for vitamin D (and calcium) as part of an overall plan to prevent or treat osteoporosis.
As they get older, millions of people (mostly women, but men too) develop, or are at risk of, osteoporosis, where bones become fragile and may fracture if one falls. It is one consequence of not getting enough calcium and vitamin D over the long term. Supplements of both vitamin D3 (at 700–800 IU/day) and calcium (500–1,200 mg/day) have been shown to reduce the risk of bone loss and fractures in elderly people aged 62–85 years. Men and women should talk with their health care providers about their needs for vitamin D (and calcium) as part of an overall plan to prevent or treat osteoporosis.
Laboratory and animal evidence as well as epidemiologic data suggest that vitamin D status could affect cancer risk. Strong biological and mechanistic bases indicate that vitamin D plays a role in the prevention of colon, prostate, and breast cancers. Emerging epidemiologic data suggest that vitamin D may have a protective effect against colon cancer, but the data are not as strong for a protective effect against prostate and breast cancer, and are variable for cancers at other sites 140), 141), 142). Studies do not consistently show a protective or no effect, however. One study of Finnish smokers, for example, found that subjects in the highest quintile of baseline vitamin D status had a threefold higher risk of developing pancreatic cancer 143). A recent review found an increased risk of pancreatic cancer associated with high levels of serum 25(OH)D (≥100 nmol/L or ≥40 ng/mL) 144).
Vitamin D emerged as a protective factor in a prospective, cross-sectional study of 3,121 adults aged ≥50 years (96% men) who underwent a colonoscopy. The study found that 10% had at least one advanced cancerous lesion. Those with the highest vitamin D intakes (>645 IU/day) had a significantly lower risk of these lesions 145). However, the Women’s Health Initiative, in which 36,282 postmenopausal women of various races and ethnicities were randomly assigned to receive 400 IU vitamin D plus 1,000 mg calcium daily or a placebo, found no significant differences between the groups in the incidence of colorectal cancers over 7 years 146). More recently, a clinical trial focused on bone health in 1,179 postmenopausal women residing in rural Nebraska found that subjects supplemented daily with calcium (1,400–1,500 mg) and vitamin D3 (1,100 IU) had a significantly lower incidence of cancer over 4 years compared with women taking a placebo 147). The small number of cancers (50) precludes generalizing about a protective effect from either or both nutrients or for cancers at different sites. This caution is supported by an analysis of 16,618 participants in NHANES III (1988–1994), in which total cancer mortality was found to be unrelated to baseline vitamin D status 148). However, colorectal cancer mortality was inversely related to serum 25(OH)D concentrations. A large observational study with participants from 10 western European countries also found a strong inverse association between prediagnostic 25(OH)D concentrations and risk of colorectal cancer 149).
Further research is needed to determine whether vitamin D inadequacy in particular increases cancer risk, whether greater exposure to the nutrient is protective, and whether some individuals could be at increased risk of cancer because of vitamin D exposure 150), 151). The United States Preventive Services Task Force stated that, due to insufficient evidence, it was unable to assess the balance of benefits and harms of supplemental vitamin D to prevent cancer 152). Taken together, studies to date do not indicate that vitamin D with or without calcium supplementation reduces the incidence of cancer, but adequate or higher 25(OH)D levels might reduce cancer mortality rates. Further research is needed to determine whether vitamin D inadequacy increases cancer risk, whether greater exposure to the nutrient can prevent cancer, and whether some individuals could have an increased risk of cancer because of their vitamin D status over time.
- Prostate cancer
Can vitamin D reduce your risk of prostate cancer ? It’s too early to say, but it’s a possibility that requires additional study 153). Vitamin D has an important role in regulating cell growth. Laboratory experiments suggest that it helps prevent the unrestrained cell multiplication that characterizes cancer by reducing cell division, restricting tumor blood supply (angiogenesis), increasing the death of cancer cells (apoptosis), and limiting the spread of cancer cells (metastasis). Like many human tissues, the prostate has an abundant supply of vitamin D receptors. And, like some other tissues, it also contains enzymes that convert biologically inactive 25(OH)D into the active form of the vitamin, 1,25(OH)2D. These enzymes are much more active in normal prostate cells than in prostate cancer cells.
Research to date provides mixed evidence on whether levels of 25(OH)D are associated with the development of prostate cancer. Several studies published in 2014 suggested that high levels of 25(OH)D might increase the risk of prostate cancer. For example, a meta-analysis of 21 studies that included 11,941 men with prostate cancer and 13,870 controls found a 17% higher risk of prostate cancer for participants with higher levels of 25(OH)D 154). What constituted a “higher” level varied by study but was typically at least 75 nmol/L (30 ng/mL). In a cohort of 4,733 men, of which 1,731 had prostate cancer, those with 25(OH)D levels of 45–70 nmol/L (18–28 ng/mL) had a significantly lower risk of the disease than men with either lower or higher values 155). This U-shaped association was most pronounced for men with the most aggressive forms of prostate cancer. A case-control analysis of 1,695 cases of prostate cancer and 1,682 controls found no associations between 25(OH)D levels and prostate cancer risk 156). However, higher serum 25(OH)D levels (at a cut point of 75 nmol/L [30 ng/mL]) were linked to a modestly higher risk of slow-growth prostate cancer and a more substantial lower risk of aggressive disease.
Since 2014, however, several published studies and meta-analyses have found no relationship between 25(OH)D levels and prostate cancer risk 157). For example, an analysis was conducted of 19 prospective studies that provided data on prediagnostic levels of 25(OH)D for 13,462 men who developed prostate cancer and 20,261 control participants 158). Vitamin D deficiency or insufficiency did not increase the risk of prostate cancer, and higher 25(OH)D concentrations were not associated with a lower risk.
Several studies have examined whether levels of 25(OH)D in men with prostate cancer are associated with a lower risk of death from the disease or from any cause. One study included 1,119 men treated for prostate cancer whose plasma 25(OH)D levels were measured 4.9 to 8.6 years after their diagnosis. Among the 198 participants who died (41 deaths were due to prostate cancer), 25(OH)D levels were not associated with risk of death from prostate cancer or any cause 159). However, a meta-analysis of 7 cohort studies that included 7,808 men with prostate cancer found higher 25(OH)D levels to be significantly associated with lower mortality rates from prostate cancer or any other cause 160). A dose-response analysis found that each 20 nmol/L [8 ng/mL] increase in 25(OH)D was associated with a 9% lower risk of both all-cause and prostate cancer-specific mortality.
For men with prostate cancer, whether vitamin D supplementation lengthens cancer-related survival is not clear. A meta-analysis of 3 randomized controlled trials in 1,273 men with prostate cancer found no significant differences in total mortality rates between those receiving vitamin D supplementation (from 10 mcg [400 IU]/day for 28 days to 45 mcg [1,800 IU] given in three doses total at 2-week intervals) and those receiving a placebo 161).
- Weight loss
Observational studies indicate that greater body weights are associated with lower vitamin D status, and obese individuals frequently have marginal or deficient circulating 25(OH)D levels 162). However, clinical trials do not support a cause-and-effect relationship between vitamin D and weight loss.
A systematic review and meta-analysis of 15 weight-loss intervention studies that used caloric restriction, exercise, or both, but not necessarily vitamin D supplementation or other treatments, found that people who lost weight had significantly greater increases in serum 25(OH)D levels than those who maintained their weight 163). In another study, 10 mcg (400 IU)/day vitamin D and 1,000 mg/day calcium supplementation slightly, but significantly, reduced weight gain amounts in comparison with placebo in postmenopausal women, especially those with a baseline total calcium intake of less than 1,200 mg/day 164). However, a meta-analysis of 12 vitamin D supplementation trials (including 5 in which body composition measurements were primary outcomes) found that vitamin D supplements without calorie restriction did not affect body weight or fat mass when the results were compared with those of placebo 165).
Overall, the available research suggests that consuming higher amounts of vitamin D or taking vitamin D supplements does not promote weight loss.
- Other conditions
A growing body of research suggests that vitamin D might play some role in the prevention and treatment of type 1 166) and type 2 diabetes 167), hypertension 168), glucose intolerance 169), multiple sclerosis 170), and other medical conditions 171), 172). However, most evidence for these roles comes from in vitro, animal, and epidemiological studies, not the randomized clinical trials considered to be more definitive 173). Until such trials are conducted, the implications of the available evidence for public health and patient care will be debated. One meta-analysis found use of vitamin D supplements to be associated with a statistically significant reduction in overall mortality from any cause 174), 175), but a reanalysis of the data found no association 176). A systematic review of these and other health outcomes related to vitamin D and calcium intakes, both alone and in combination, was published in August 2009 177).
Vitamin D and Cardiovascular Disease
Vitamin D helps regulate the renin-angiotensin-aldosterone system (and thereby blood pressure), vascular cell growth, and inflammatory and fibrotic pathways 178). Vitamin D deficiency is associated with vascular dysfunction, arterial stiffening, left ventricular hypertrophy, and hyperlipidemia 179). For these reasons, vitamin D has been linked to heart health and risk of vardiovascular disease.
Observational studies support an association between higher serum 25(OH)D levels and a lower risk of vardiovascular disease incidence and mortality. For example, a meta-analysis included 34 observational studies that followed 180,667 participants (mean age greater than 50 years) for 1.3 to more than 32 years. The results showed that baseline serum 25(OH)D levels were inversely associated with total number of vardiovascular disease events (including myocardial infarction, ischemic heart disease, heart failure, and stroke) and mortality risk 180). Overall, the risk of vardiovascular disease events was 10% lower for each 25 nmol/L (10 ng/mL) increase in serum 25(OH)D.
Another large observational study that followed 247,574 adults from Denmark for 0–7 years found that levels of 25(OH)D that were low (about 12.5 nmol/L [5 ng/mL]) and high (about 125 nmol/L [50 ng/mL]) were associated with a greater risk of mortality from vardiovascular disease, stroke, and acute myocardial infarction 181). Other meta-analyses of prospective studies have found associations between lower vitamin D status measured by serum 25(OH)D levels or vitamin D intakes and an increased risk of ischemic stroke, ischemic heart disease, myocardial infarction, and early death 182).
In contrast to the observational studies, clinical trials have provided little support for the hypothesis that supplemental vitamin D reduces the risk of vardiovascular disease or vardiovascular disease mortality. For example, a 3-year trial in New Zealand randomized 5,110 adults (mean age 65.9 years) to a single dose of 5,000 mcg (200,000 IU) vitamin D3 followed by 2,500 mcg (100,000 IU) each month or a placebo for a median of 3.3 years 183). Vitamin D supplementation had no effect on the incidence rate of myocardial infarction, angina, heart failure, arrhythmia, arteriosclerosis, stroke, venous thrombosis, or death from vardiovascular disease. Similarly, the VITAL clinical trial described above found that vitamin D supplements did not significantly decrease rates of heart attacks, strokes, coronary revascularization, or deaths from cardiovascular causes 184). Moreover, the effects did not vary by baseline serum 25(OH)D levels or whether participants took the trial’s omega-3 supplement in addition to vitamin D.
However, another clinical trial designed to investigate bone fracture risk found that 800 IU/day vitamin D3 (with or without calcium) or a placebo in 5,292 adults aged 70 years and older for a median of 6.2 years offered protection from cardiac failure, but not myocardial infarction or stroke 185).
High serum cholesterol levels and hypertension are two of the main risk factors for vardiovascular disease. The data on supplemental vitamin D and cholesterol levels are mixed, as shown in one meta-analysis of 41 clinical trials in a total of 3,434 participants (mean age 55 years). The results of this analysis showed that 0.5 mcg (20 IU) to 214 mcg (8,570 IU)/day vitamin D supplementation (mean of 2,795 IU) for 6 weeks to 3 years reduced serum total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels, but not high-density lipoprotein cholesterol levels 186).
Studies of the effects of vitamin D supplements on hypertension have also had mixed findings. In one meta-analysis of 46 clinical trials that included 4,541 participants, vitamin D supplements (typically 40 mcg [1,600 IU]/day or less) for a minimum of 4 weeks had no significant effects on systolic or diastolic blood pressure 187). In contrast, another meta-analysis of 30 clinical trials in 4,744 participants (mean age 54.5 years) that administered 5 mcg (200 IU) to 300 mcg (12,000 IU)/day vitamin D3 for a mean of 5.6 months showed that more than 20 mcg (800 IU)/day significantly reduced systolic and diastolic blood pressure in normal-weight participants who had hypertension 188). However, more than 20 mcg (800 IU)/day vitamin D3, when taken with calcium supplements, significantly increased blood pressure in overweight and obese participants. Another meta-analysis of genetic studies in 146,581 participants (primarily adults) found that a low vitamin D status increased blood pressure and hypertension risk in people with genetic variants associated with low endogenous production of 25(OH)D 189).
Overall, clinical trials show that vitamin D supplementation does not reduce vardiovascular disease risk, even for people with low 25(OH)D status (below 20 nmol/L [12 ng/mL]) at baseline 190).
Vitamin D and Multiple Sclerosis
Many epidemiological and genetic studies have shown an association between multiple sclerosis (MS) and low 25(OH)D levels before and after the disease begins 191). Vitamin D appears to have no effect on recurrence of multiple sclerosis (MS) relapse, worsening of disability measured by the Expanded Disability Status Scale (EDSS), and MRI lesions 192). Effects on health‐related quality of life and fatigue are unclear. Vitamin D₃ at the doses and treatment durations used in the included trials appears to be safe, although available data are limited. Observational studies suggest that adequate vitamin D levels might reduce the risk of contracting multiple sclerosis (MS) and, once MS is present, decrease the risk of relapse and slow the disease’s progression 193). One study, for example, tested 25(OH)D levels in 1,092 women in Finland an average of 9 years before their MS diagnosis and compared their outcomes with those of 2,123 similar women who did not develop MS 194). More than half the women who developed MS had deficient or insufficient vitamin D levels. Women with 25(OH)D levels of less than 30 nmol/L (12 ng/mL) had a 43% higher MS risk than women with levels of 50 nmol/L (20 ng/mL) or higher. Among the women with two or more serum 25(OH)D samples taken before diagnosis (which reduced random measurement variation), a 50 nmol/L increase in 25(OH)D was associated with a 41% reduced risk of MS, and 25(OH)D levels less than 30 nmol/L were associated with an MS risk that was twice as high as levels of 50 nmol/L or higher.
Two earlier prospective studies of similar design—one in the United States with 444 non-Hispanic White individuals 195) and the other with 576 individuals in northern Sweden 196) found that levels of 25(OH)D greater than 99.1 nmol/L (39.6 ng/mL) and at least 75 nmol/L (30 ng/mL), respectively, were associated with a 61–62% lower risk of MS.
No clinical trials have examined whether vitamin D supplementation can prevent the onset of MS, but several have investigated whether supplemental vitamin D can help manage the disease. A 2018 Cochrane review analyzed 12 such trials that had a total of 933 participants with MS; the reviewers judged all of these trials to be of low quality 197). Overall, vitamin D supplementation, when compared with placebo administration, had no effect on relevant clinical outcomes, such as recurrent relapse or worsened disability.
Experts have reached no firm consensus on whether vitamin D can help prevent MS given the lack of clinical trial evidence 198). In addition, studies have not consistently shown that vitamin D supplementation tempers the signs and symptoms of active MS or reduces rates of relapse.
A study conducted by researchers at the University of Oxford and another conducted at the New Jersey Medical School have suggested that maintaining adequate levels of vitamin D may have a protective effect and lower the risk of developing multiple sclerosis (MS) 199).
Another study conducted at Maastricht University in the Netherlands and others suggest that for people who already have MS, vitamin D may lessen the frequency and severity of their symptoms. More research is needed to assess these findings.
When a person has MS, his or her immune system attacks the coating that protects the nerve cells. Research suggests that a connection between vitamin D and MS could be tied to the positive effects vitamin D has on the immune system.
The link between vitamin D and MS is strengthened by the association between sunlight and the risk of MS. The farther away from the equator a person lives, the higher the risk of MS. Sunlight is the body’s most efficient source for vitamin D — suggesting that exposure to sunlight may offer protection from MS. In addition, in studies of a group of nurses, the risk of developing MS was substantially less for women taking 400 international units (IUs) or more of vitamin D a day.
Screening for vitamin D deficiency is important for African-Americans and other ethnic groups with dark skin, due to decreased natural production of vitamin D from sun exposure.
The Institute of Medicine recommends 600 IUs of vitamin D a day for adults ages 19 to 70. The recommendation increases to 800 IUs a day for adults age 71 and older.
Some doctors question whether these levels are adequate and think that getting more vitamin D would benefit many people. However, the Institute of Medicine recommends that adults avoid taking more than 4,000 IUs a day.
If you are diagnosed with vitamin D deficiency, it may be appropriate to use up to 50,000 IUs weekly for up to three months until your vitamin D levels become normal, and then switch to a maintenance dose
Very large doses of vitamin D over an extended period can result in vitamin D toxicity. Signs and symptoms include nausea, vomiting, constipation, poor appetite, weakness and weight loss. In addition, vitamin D toxicity can lead to elevated levels of calcium in your blood, which can result in kidney stones.
Vitamin D and Depression
Vitamin D is involved in various brain processes, and vitamin D receptors are present on neurons and glia in areas of the brain thought to be involved in the pathophysiology of depression 200)].
A systematic review and meta-analysis of 14 observational studies that included a total of 31,424 adults (mean age ranging from 27.5 to 77 years) found an association between deficient or low levels of 25(OH)D and depression 201).
Clinical trials, however, do not support these findings. For example, a meta-analysis of 9 trials with a total of 4,923 adult participants diagnosed with depression or depressive symptoms found no significant reduction in symptoms after supplementation with vitamin D 202). The trials administered different amounts of vitamin D (ranging from 10 mcg [400 IU]/day to 1,000 mcg [40,000 IU]/week). They also had different study durations (5 days to 5 years), mean participant ages (range, 22 years to 75 years), and baseline 25(OH)D levels; furthermore, some but not all studies administered concurrent antidepressant medications.
Three trials conducted since that meta-analysis also found no effect of vitamin D supplementation on depressive symptoms. One trial included 206 adults (mean age 52 years) who were randomized to take a bolus dose of 2,500 mcg (100,000 IU) vitamin D3 followed by 500 mcg (20,000 IU)/week or a placebo for 4 months 203). Most participants had minimal or mild depression, had a low mean baseline 25(OH) level of 33.8 nmol/L (13.5 ng/mL), and were not taking antidepressants. The second trial included 155 adults aged 60–80 years who had clinically relevant depressive symptoms, no major depressive disorder, and serum 25(OH)D levels less than 50 to 70 nmol/L (20 to 28 ng/mL) depending on the season; in addition, they were not taking antidepressants 204). Participants were randomized to take either 30 mcg (1,200 IU)/day vitamin D3 or a placebo for 1 year. In the VITAL trial described above, 16,657 men and women 50 years of age and older with no history of depression and 1,696 with an increased risk of recurrent depression (that had not been medically treated for the past 2 years) were randomized to take 50 mcg (2,000 IU)/day vitamin D3 (with or without fish oil) or a placebo for a median of 5.3 years 205). The groups showed no significant differences in the incidence and recurrent rates of depression, clinically relevant depressive symptoms, or changes in mood scores.
Overall, clinical trials did not find that vitamin D supplements helped prevent or treat depressive symptoms or mild depression, especially in middle-aged to older adults who were not taking prescription antidepressants. No studies have evaluated whether vitamin D supplements may benefit individuals under medical care for clinical depression who have low or deficient 25(OH)D levels and are taking antidepressant medication.
Can Vitamin D prevent Alzheimer’s & Dementia?
Maybe. But it’s too soon to say for certain. New research suggests people with very low levels of vitamin D in their blood, known as vitamin D deficiency, are more likely to develop Alzheimer’s disease and other forms of dementia 206).
For example, a large 2014 study published in Neurology showed people with extremely low blood levels of vitamin D were more than twice as likely to develop Alzheimer’s disease or other types of dementia than those with normal vitamin D levels. But it’s important to point out that the association between vitamin D deficiency and dementia risk is only observational at this point. More research is needed to show cause and effect.
Vitamin D is vital to bone metabolism, calcium absorption and other metabolic processes in the body. Its role in brain function, cognition and the aging process is still unclear. Some studies suggest vitamin D may be involved in a variety of processes related to cognition, but more research is needed to better understand this relationship.
Most of our vitamin D is produced within the body in response to sunlight exposure. Vitamin D occurs naturally in only a few foods, including fatty fish and fish liver oils. The biggest dietary sources of vitamin D are fortified foods, such as milk, breakfast cereals and orange juice. Vitamin D supplements are also widely available.
Vitamin D deficiency is common among older adults, partially because the skin’s ability to synthesize vitamin D from the sun decreases with age.
It’s too early to recommend increasing your daily dose of vitamin D in hopes of preventing dementia or Alzheimer’s disease. But maintaining healthy vitamin D levels can’t hurt and may pay off in other ways, such as reducing the risk of osteoporosis. According to the Institute of Medicine, the recommended daily dose of Vitamin D is 600 International Units (IU) per day for adults under age 70 and 800 IU per day for adults over 70.
More studies are needed to determine if vitamin D deficiency is indeed a risk factor for Alzheimer’s disease and dementia, and if treatment with vitamin D supplements or sun exposure can prevent or treat these conditions.
Vitamins D and type 2 diabetes
Vitamin D plays a role in glucose metabolism. Vitamin D stimulates insulin secretion via the vitamin D receptor on pancreatic beta cells and reduces peripheral insulin resistance through vitamin D receptors in the muscles and liver 207). Vitamin D might be involved in the pathophysiology of type 2 diabetes through its effects on glucose metabolism and insulin signaling as well as its ability to reduce inflammation and improve pancreatic beta-cell function 208).
Observational studies have linked lower serum 25(OH)D levels to an increased risk of diabetes, but their results might have been confounded by the fact that many participants were overweight or obese and were therefore more predisposed to developing diabetes and having lower 25(OH)D levels 209). A review of 71 observational studies in adults with and without type 2 diabetes from 16 countries found a significant inverse relationship between vitamin D status and blood sugar levels in participants who did and did not have diabetes 210).
In contrast to observational studies, clinical trials provide little support for the benefits of vitamin D supplementation for glucose homeostasis. One trial included 65 overweight or obese adult men and women (mean age 32 years) who were otherwise healthy, did not have diabetes, and had low serum vitamin D levels (at or below 50 nmol/L [20 ng/mL]) 211). The investigators randomly assigned participants to receive either a bolus oral dose of 2,500 mcg (100,000 IU) vitamin D3 followed by 100 mcg (4,000 IU)/day or a placebo for 16 weeks. In the 54 participants who completed the study, vitamin D supplementation did not improve insulin sensitivity or insulin secretion in comparison with placebo.
One systematic review and meta-analysis evaluated 35 clinical trials that included 43,407 adults with normal glucose tolerance, prediabetes, or type 2 diabetes who received a median of 83 mcg (3,332 IU)/day vitamin D supplements or placebo for a median of 16 weeks 212). Vitamin D had no significant effects on glucose homeostasis, insulin secretion or resistance, or hemoglobin A1c levels (a measure of average blood sugar levels over the previous 2–3 months), irrespective of the study population, vitamin D dose, or trial quality.
Several trials have investigated whether vitamin D supplementation can prevent the transition from prediabetes to diabetes in patients with adequate 25(OH)D levels, and all have had negative results. In a trial in Norway, 511 men and women aged 25–80 years (mean age 62 years) with prediabetes received 500 mcg (20,000 IU) vitamin D3 or a placebo each week for 5 years 213). The results showed no significant differences in rates of progression to type 2 diabetes; in serum glucose, insulin, or hemoglobin A1c levels; or in measures of insulin resistance. At baseline, participants had an adequate mean serum 25(OH)D level of 60 nmol/L (24 ng/mL).
The largest trial to date of vitamin D supplements for diabetes prevention randomized 2,423 men and women aged 25 years and older (mean age 60 years) with prediabetes who were overweight or obese (mean BMI of 32.1) to 100 mcg (4,000 IU)/day vitamin D3 or placebo for a median of 2.5 years 214). Most participants (78%) had adequate serum levels of vitamin D at baseline (at least 50 nmol/L [20 ng/mL]). Vitamin D did not significantly prevent the development of diabetes in comparison with placebo. However, a post hoc analysis showed a 62% lower incidence of diabetes among participants with low baseline serum 25(OH)D levels (less than 30 nmol/L [12 ng/mL]) who took the vitamin D supplement than among those who took the placebo 215).
Studies have also assessed the value of vitamin D supplementation for managing diabetes, and they have found that the vitamin offers limited benefits. One meta-analysis of 20 clinical trials compared the effects of 0.5 mcg (20 IU)/day to 1,250 mcg (50,000 IU)/week vitamin D supplementation for 2–6 months with those of placebo on glycemic control in 2,703 adults from around the world who had diabetes 216). The vitamin D reduced insulin resistance to a small but significant degree, especially in people taking more than 50 mcg (2,000 IU)/day who were vitamin D deficient at baseline, had good glycemic control, were not obese, and were of Middle Eastern ethnicity. However, the supplementation had no significant effects on fasting blood glucose, hemoglobin A1c, or fasting insulin levels.
Clinical trials to date provide little evidence that vitamin D supplementation helps maintain glucose homeostasis, reduces the risk of progression from prediabetes to type 2 diabetes, or helps manage the disease, particularly in vitamin D-replete individuals.
Can Excessive Vitamin D be harmful?
Yes, excess amounts of vitamin D are toxic. Because vitamin D increases calcium absorption in the gastrointestinal tract, vitamin D toxicity results in marked hypercalcemia (total calcium greater than 11.1 mg/dL, beyond the normal range of 8.4 to 10.2 mg/dL), hypercalciuria, and high serum 25(OH)D levels (typically greater than 375 nmol/l [150 ng/mL]) 217). Hypercalcemia (high blood calcium), in turn, can lead to nausea, poor appetite, vomiting, constipation, muscle weakness, weight loss, neuropsychiatric disturbances, pain, loss of appetite, dehydration, polyuria, excessive thirst, and kidney stones. And by raising blood levels of calcium, too much vitamin D can cause confusion, disorientation, and problems with heart rhythm. Excess vitamin D can also damage the kidneys.
In extreme cases, vitamin D toxicity causes renal failure, calcification of soft tissues throughout the body (including in coronary vessels and heart valves), cardiac arrhythmias, and even death. Vitamin D toxicity has been caused by consumption of dietary supplements that contained excessive vitamin D amounts because of manufacturing errors, that were taken inappropriately or in excessive amounts, or that were incorrectly prescribed by physicians 218).
Vitamin D toxicity can cause non-specific symptoms such as anorexia, weight loss, polyuria, and heart arrhythmias. More seriously, it can also raise blood levels of calcium which leads to vascular and tissue calcification, with subsequent damage to the heart, blood vessels, and kidneys 219). The use of supplements of both calcium (1,000 mg/day) and vitamin D (10 mcg (400 IU)/day vitamin D) by postmenopausal women was associated with a 17% increase in the risk of kidney stones over 7 years in the Women’s Health Initiative 220). A serum 25(OH)D concentration consistently >500 nmol/L (>200 ng/mL) is considered to be potentially toxic 221). However, other, shorter (from 24 weeks to 5 years) clinical trials of vitamin D supplementation alone or with calcium in adults found greater risks of hypercalcemia and hypercalciuria, but not of kidney stones 222).
Experts do not believe that excessive sun exposure does not result in vitamin D toxicity because the sustained heat on the skin is thought to photodegrade previtamin D3 and vitamin D3 as it is formed 223). In addition, thermal activation of previtamin D3 in the skin gives rise to various non-vitamin D forms that limit formation of vitamin D3 itself. Some vitamin D3 is also converted to nonactive forms 224). Intakes of vitamin D from food that are high enough to cause toxicity are very unlikely. Toxicity is much more likely to occur from high intakes of dietary supplements containing vitamin D. However, frequent use of tanning beds, which provide artificial UV radiation, can lead to 25(OH)D levels well above 375–500 nmol/L (150–200 ng/mL) 225).
Long-term intakes above the upper limit (UL) increase the risk of adverse health effects 226) (Table 4). Most reports suggest a toxicity threshold for vitamin D of 10,000 to 40,000 IU/day and serum 25(OH)D levels of 500–600 nmol/L (200–240 ng/mL). While symptoms of toxicity are unlikely at daily intakes below 10,000 IU/day, the FNB pointed to emerging science from national survey data, observational studies, and clinical trials suggesting that even lower vitamin D intakes and serum 25(OH)D levels might have adverse health effects over time. The FNB concluded that serum 25(OH)D levels above approximately 125–150 nmol/L (50–60 ng/mL) should be avoided, as even lower serum levels (approximately 75–120 nmol/L or 30–48 ng/mL) are associated with increases in all-cause mortality, greater risk of cancer at some sites like the pancreas, greater risk of cardiovascular events, and more falls and fractures among the elderly. The FNB committee cited research which found that vitamin D intakes of 5,000 IU/day achieved serum 25(OH)D concentrations between 100–150 nmol/L (40–60 ng/mL), but no greater. Applying an uncertainty factor of 20% to this intake value gave a UL of 4,000 IU which the FNB applied to children aged 9 and older and adults, with corresponding lower amounts for younger children.
The upper limit for vitamin D is 1,000 to 1,500 IU/day for infants, 2,500 to 3,000 IU/day for children 1-8 years, and 4,000 IU/day for children 9 years and older, adults, and pregnant and lactating teens and women. Vitamin D toxicity almost always occurs from overuse of supplements. Excessive sun exposure doesn’t cause vitamin D poisoning because the body limits the amount of this vitamin it produces.
Table 4: Tolerable Upper Intake Levels (ULs) for Vitamin D
|0–6 months||1,000 IU|
|7–12 months||1,500 IU|
|1–3 years||2,500 IU|
|4–8 years||3,000 IU|
|9–18 years||4,000 IU|
|19+ years||4,000 IU|
Vitamin D Side Effects and Warnings
Vitamin D is likely safe when taken by mouth in doses of 100 micrograms of vitamin D3 daily (4,000 IU) and when applied to the skin alone or in combination with corticosteroids for up to three months 228).
Vitamin D is possibly safe when taken by mouth or injected into the muscle in doses of 300,000 IU three times a year for vitamin D deficiency.
Vitamin D may cause allergic skin reactions (inflammation, irritation, rash, and thinning), build-up of calcium in the arteries, changes in cholesterol levels, daytime sleepiness, excessive vitamin D levels, hardening of the arteries, headaches, increased calcium excretion or levels, increased risk of falls and fractures, increased risk of heart attack and stroke, increased risk of high blood pressure during pregnancy, increased risk of urinary tract infection, kidney or urinary stones, muscle pain, respiratory tract infection, and stomach problems (constipation, cramps, diarrhea, upset stomach, and vomiting).
Vitamin D may affect blood sugar levels. Caution is advised in people with diabetes or low blood sugar, and in those taking drugs, herbs, or supplements that affect blood sugar. Blood sugar levels may need to be monitored by a qualified healthcare professional, including a pharmacist, and medication adjustments may be necessary.
Vitamin D may affect blood pressure. Caution is advised in people with blood pressure disorders or those taking drugs or herbs and supplements that affect blood pressure.
Use cautiously in people with headaches, heart disease, immune disorders (including lymph cancer and tuberculosis), kidney disease, liver disease, lung disorders, musculoskeletal disorders, skin disorders, stomach disorders, and thyroid disorders.
Use cautiously in pregnant women at risk of high blood pressure associated with pregnancy.
Use cautiously in breastfeeding women.
Avoid in people with known allergy or sensitivity to vitamin D, any similar compounds, or any part of the formula.
Avoid in people with abnormal calcium excretion or levels.
Pregnancy and Breastfeeding
Use cautiously in pregnant women at risk of high blood pressure associated with pregnancy. The recommended adequate intake for pregnant women is the same as for non-pregnant adults. Most prenatal vitamins provide 400 IU of vitamin D daily as cholecalciferol, while high-risk populations may benefit from higher amounts (2,000-4,000 IU daily).
Use cautiously in breastfeeding women. The daily recommended intake for vitamin D during breastfeeding is 400 IU (10 micrograms) daily. Vitamin D2 in doses of 2,000 IU daily or 60,000 IU monthly for three months has been found to be safe and effective. Exclusively breastfed babies may be supplemented with 400-2,000 IU daily.
References [ + ]
|1, 2.||↵||Silva MC, Furlanetto TW. Intestinal absorption of vitamin D: a systematic review. Nutr Rev. 2018 Jan 1;76(1):60-76. doi: 10.1093/nutrit/nux034|
|3.||↵||National Institute of Health. Vitamin D. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/|
|4, 15, 17, 18, 21, 22, 24, 28, 29, 33, 35, 36, 37, 38, 40, 49, 51, 52, 53.||↵||Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010|
|5.||↵||Brunette MG, Chan M, Ferriere C, Roberts KD. Site of 1,25(OH)2 vitamin D3 synthesis in the kidney. Nature. 1978 Nov 16;276(5685):287-9. doi: 10.1038/276287a0|
|6.||↵||Abramovits W. Calcitriol 3 microg/g ointment: an effective and safe addition to the armamentarium in topical psoriasis therapy. J Drugs Dermatol. 2009 Aug;8(8 Suppl):s17-22.|
|7, 75, 76, 77.||↵||Sahay M, Sahay R. Rickets–vitamin D deficiency and dependency. Indian Journal of Endocrinology and Metabolism. 2012;16(2):164-176. doi:10.4103/2230-8210.93732. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313732/|
|8, 13.||↵||Christakos S, Ajibade dV, dhawan P, Fechner AJ, Mady LJ. vitamin D: Metabolism. Endocrinol Metab Clin North Am. 2010;39:243. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879391/|
|9.||↵||Portale AA, Halloran BP, Morris RC., Jr Physiologic regulation of the serum concentration of 1,25-dihydroxyvitamin D by phosphorus in normal men. J Clin Invest. 1989;83:1494. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC303852/|
|10.||↵||Iida K, Shinki T, Yamaguchi A, DeLuca HF, Kurokawa K, Suda T. A possible role of vitamin D receptors in regulating vitamin D activation in the kidney. Proc Natl Acad Sci U S A. 1995;92:6112. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC41652/|
|11.||↵||Prié D, Friedlander G. Reciprocal control of 1,25-dihydroxyvitamin D and FGF23 formation involving the FGF23/Klotho system. Clin J Am Soc Nephrol. 2010;5:1717. http://cjasn.asnjournals.org/content/5/9/1717.long|
|12.||↵||Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol. 2006;17:1305–15. http://jasn.asnjournals.org/content/17/5/1305.long|
|14.||↵||Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab. 2009;94:26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630868/|
|16, 26, 58, 74, 113, 132, 135.||↵||Cranney C, Horsely T, O’Donnell S, Weiler H, Ooi D, Atkinson S, et al. Effectiveness and safety of vitamin D. Evidence Report/Technology Assessment No. 158 prepared by the University of Ottawa Evidence-based Practice Center under Contract No. 290-02.0021. AHRQ Publication No. 07-E013. Rockville, MD: Agency for Healthcare Research and Quality, 2007. https://www.ncbi.nlm.nih.gov/pubmed/18088161?dopt=Abstract|
|19, 95, 120.||↵||Holick MF. Vitamin D. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease, 10th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.|
|20.||↵||Norman AW, Henry HH. Vitamin D. In: Bowman BA, Russell RM, eds. Present Knowledge in Nutrition, 9th ed. Washington DC: ILSI Press, 2006.|
|23, 25, 103.||↵||Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008;88:582S-6S. https://www.ncbi.nlm.nih.gov/pubmed/18689406?dopt=Abstract|
|27, 66, 73, 223.||↵||Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81. https://www.ncbi.nlm.nih.gov/pubmed/17634462?dopt=Abstract|
|30.||↵||Carter GD. 25-hydroxyvitamin D assays: the quest for accuracy. Clin Chem 2009;55:1300-02.|
|31.||↵||Hollis BW. Editorial: the determination of circulating 25-hydroxyvitamin D: no easy task. J. Clin Endocrinol Metab 2004;89:3149-3151.|
|32.||↵||Binkley N, Krueger D, Cowgill CS, Plum L, Lake E, Hansen KE, et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab 2004;89:3152-57. https://www.ncbi.nlm.nih.gov/pubmed/15240586?dopt=Abstract|
|34.||↵||National Institute of Standards and Technology. NIST releases vitamin D standard reference material, 2009. https://www.nist.gov/news-events/news/2009/07/nist-releases-vitamin-d-standard-reference-material|
|39.||↵||Vitamin D. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional|
|41.||↵||U.S. Department of Agriculture, Agricultural Research Service. 2011. USDA National Nutrient Database for Standard Reference, Release 24. Nutrient Data Laboratory Home Page. https://www.ars.usda.gov/northeast-area/beltsville-md/beltsville-human-nutrition-research-center/nutrient-data-laboratory/|
|42.||↵||Ovesen L, Brot C, Jakobsen J. Food contents and biological activity of 25-hydroxyvitamin D: a vitamin D metabolite to be reckoned with? Ann Nutr Metab 2003;47:107-13. https://www.ncbi.nlm.nih.gov/pubmed/12743460?dopt=Abstract|
|43.||↵||Mattila PH, Piironen VI, Uusi-Rauva EJ, Koivistoinen PE. Vitamin D contents in edible mushrooms. J Agric Food Chem 1994;42:2449-53.|
|44, 50.||↵||Calvo MS, Whiting SJ, Barton CN. Vitamin D fortification in the United States and Canada: current status and data needs. Am J Clin Nutr 2004;80:1710S-6S. https://www.ncbi.nlm.nih.gov/pubmed/15585792?dopt=Abstract|
|45.||↵||The USDA Food Composition Databases. https://ndb.nal.usda.gov/ndb/|
|46.||↵||The USDA Food Composition Databases. Vitamin D Content. https://ods.od.nih.gov/pubs/usdandb/VitaminD-Content.pdf|
|47.||↵||The USDA Food Composition Databases. Foods Vitamin D Content. https://ods.od.nih.gov/pubs/usdandb/VitaminD-Food.pdf|
|48.||↵||Byrdwell WC, DeVries J, Exler J, Harnly JM, Holden JM, Holick MF, et al. Analyzing vitamin D in foods and supplements: methodologic challenges. Am J Clin Nutr 2008;88:554S-7S. https://www.ncbi.nlm.nih.gov/pubmed/18689401?dopt=Abstract|
|54.||↵||U.S. Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 27. Nutrient Data Laboratory home page, 2014. https://ndb.nal.usda.gov/ndb/|
|55, 56.||↵||Taylor CL, Patterson KY, Roseland JM, Wise SA, Merkel JM, Pehrsson PR, Yetley EA. Including food 25-hydroxyvitamin D in intake estimates may reduce the discrepancy between dietary and serum measures of vitamin D status. J Nutr 2014;144:654-9. https://www.ncbi.nlm.nih.gov/pubmed/24623845?dopt=Abstract|
|57, 59, 60, 61, 64, 72, 92, 102, 104, 112, 116, 117, 119, 122, 131, 134, 138, 140, 173, 209, 219, 224, 226, 227.||↵||Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.|
|62, 93, 96, 100.||↵||Wharton B, Bishop N. Rickets. Lancet 2003;362:1389-400. https://www.ncbi.nlm.nih.gov/pubmed/14585642?dopt=Abstract|
|63.||↵||Holick MF. Photobiology of vitamin D. In: Feldman D, Pike JW, Glorieux FH, eds. Vitamin D, Second Edition, Volume I. Burlington, MA: Elsevier, 2005.|
|65, 68, 70.||↵||Wolpowitz D, Gilchrest BA. The vitamin D questions: how much do you need and how should you get it? J Am Acad Dermatol 2006;54:301-17. https://www.ncbi.nlm.nih.gov/pubmed/16443061?dopt=Abstract|
|67.||↵||Holick MF. Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health. Curr Opin Endocrinol Diabetes 2002;9:87-98.|
|69.||↵||International Agency for Research on Cancer Working Group on ultraviolet (UV) light and skin cancer. The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: a systematic review. Int J Cancer 2006;120:1116-22. https://www.ncbi.nlm.nih.gov/pubmed/17131335?dopt=Abstract|
|71, 97.||↵||American Academy of Dermatology. Position statement on vitamin D. November 1, 2008. https://www.aad.org/Forms/Policies/Uploads/PS/PS-Vitamin%20D.pdf|
|78, 79, 106, 107, 111.||↵||Wagner CL, Greer FR; American Academy of Pediatrics Section on Breastfeeding; American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122:1142-1152. https://www.ncbi.nlm.nih.gov/pubmed/18977996?dopt=Abstract|
|80.||↵||Jurutka PW, Whitfield GK, Hsieh JC, Thompson PD, Haussler CA, Haussler MR. Molecular nature of the vitamin D receptor and its role in regulation of gene expression. Reviews in Endocrinology and Metabloic Disorders. 2001;2(2):203–16.|
|81.||↵||Drescher D, Deluca HF, Imrie MH. On the site of discrimination of chicks against vitamin D. Archives of Biochemistry and Biophysics. 1969;130(1):657–61.|
|82.||↵||Christiansen C, Rodbro P, Munck O. Actions of vitamins D2 and D3 and 25-OHD3 in anticonvulsant osteomalacia. British Medical Journal. 1975;2(5967):363–5.|
|83.||↵||Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. Journal of Clinical Endocrinology and Metabolism. 2004;89(11):5387–91.|
|84, 85.||↵||Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, Ameri A, Tannenbaum AD. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. Journal of Clinical Endocrinology and Metabolism. 2008;93(3):677–81|
|86.||↵||Weber K, Goldberg M, Stangassinger M, Erben RG. 1Alpha-hydroxyvitamin D2 is less toxic but not bone selective relative to 1alpha-hydroxyvitamin D3 in ovariectomized rats. Journal of Bone and Mineral Research. 2001;16(4):639–51.|
|87.||↵||Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiological Reviews. 1998;78(4):1193–231.|
|88, 89.||↵||Jones G, Byrnes B, Palma F, Segev D, Mazur Y. Displacement potency of vitamin D2 analogs in competitive protein-binding assays for 25-hydroxyvitamin D3, 24,25-dihydroxyvitamin D3, and 1,25-dihydroxyvitamin D3. Journal of Clinical Endocrinology and Metabolism. 1980;50(4):773–5.|
|90.||↵||Reinhardt TA, Ramberg CF, Horst RL. Comparison of receptor binding, biological activity, and in vivo tracer kinetics for 1,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D2, and its 24 epimer. Archives of Biochemistry and Biophysics. 1989;273(1):64–71|
|91.||↵||Park EA. The therapy of rickets. JAMA. 1940;94:370–9.|
|94, 101.||↵||Chesney R. Rickets: an old form for a new century. Pediatr Int 2003;45: 509-11. https://www.ncbi.nlm.nih.gov/pubmed/14521522?dopt=Abstract|
|98.||↵||Uday S, Högler W. Erratum to: Nutritional Rickets and Osteomalacia in the Twenty-first Century: Revised Concepts, Public Health, and Prevention Strategies. Curr Osteoporos Rep. 2017;15(5):507. doi:10.1007/s11914-017-0395-7|
|99.||↵||Goldring SR, Krane S, Avioli LV. Disorders of calcification: osteomalacia and rickets. In: DeGroot LJ, Besser M, Burger HG, Jameson JL, Loriaux DL, Marshall JC, et al., eds. Endocrinology. 3rd ed. Philadelphia: WB Saunders, 1995:1204-27.|
|105.||↵||Picciano MF. Nutrient composition of human milk. Pediatr Clin North Am 2001;48:53-67. https://www.ncbi.nlm.nih.gov/pubmed/11236733?dopt=Abstract|
|108.||↵||Weisberg P, Scanlon KS, Li R, Cogswell ME. Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003. Am J Clin Nutr 2004;80:1697S-705S. https://www.ncbi.nlm.nih.gov/pubmed/15585790?dopt=Abstract|
|109.||↵||Ward LM, Gaboury I, Ladhani M, Zlotkin S. Vitamin D-deficiency rickets among children in Canada. CMAJ 2007;177:161-166. https://www.ncbi.nlm.nih.gov/pubmed/17600035?dopt=Abstract|
|110.||↵||American Academy of Pediatrics Committee on Environmental Health. Ultraviolet light: a hazard to children. Pediatrics 1999;104:328-33. https://www.ncbi.nlm.nih.gov/pubmed/10429020?dopt=Abstract|
|114.||↵||Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitamin D3: Exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 1988;67:373-8. https://www.ncbi.nlm.nih.gov/pubmed/2839537?dopt=Abstract|
|115.||↵||Webb AR, Pilbeam C, Hanafin N, Holick MF. An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr 1990;51:1075-81. https://www.ncbi.nlm.nih.gov/pubmed/2349922?dopt=Abstract|
|118, 121.||↵||Pappa HM, Bern E, Kamin D, Grand RJ. Vitamin D status in gastrointestinal and liver disease. Curr Opin Gastroenterol 2008;24:176-83. https://www.ncbi.nlm.nih.gov/pubmed/18301268?dopt=Abstract|
|123.||↵||Malone M. Recommended nutritional supplements for bariatric surgery patients. Ann Pharmacother 2008;42:1851-8. https://www.ncbi.nlm.nih.gov/pubmed/19017827?dopt=Abstract|
|124.||↵||Compher CW, Badellino KO, Boullata JI. Vitamin D and the bariatric surgical patient: a review. Obes Surg 2008;18:220-4. https://www.ncbi.nlm.nih.gov/pubmed/18176832?dopt=Abstract|
|125.||↵||National Institutes of Health Osteoporosis and Related Bone Diseases National Research Center. Osteoporosis overview. October 2010. https://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/overview.asp|
|126.||↵||Heaney RP. Long-latency deficiency disease: insights from calcium and vitamin D. Am J Clin Nutr 2003;78:912-9. https://www.ncbi.nlm.nih.gov/pubmed/14594776?dopt=Abstract|
|127.||↵||LeBoff MS, Kohlmeier L, Hurwitz S, Franklin J, Wright J, Glowacki J. Occult vitamin D deficiency in postmenopausal US women with acute hip fracture. JAMA 1999;251:1505-11. https://www.ncbi.nlm.nih.gov/pubmed/10227320?dopt=Abstract|
|128.||↵||National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. Osteoporosis Handout on Health. NIH Publication No. 11-5158; 2011.|
|129.||↵||American College of Obstetricians and Gynecologists. Hormone Therapy, April 2013. https://www.acog.org/~/media/For%20Patients/pfs003.pdf|
|130.||↵||North American Menopause Society. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012;19:257-71. www.ncbi.nlm.nih.gov/pubmed/22367731?dopt=Abstract|
|133, 136.||↵||Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al. Vitamin D and calcium: a systematic review of health outcomes. Evidence Report/Technology Assessment No. 183 prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I. AHRQ Publication No. 09-E015. Rockville, MD: Agency for Healthcare Research and Quality, 2009.|
|137.||↵||Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 2009;339:b3692. https://www.ncbi.nlm.nih.gov/pubmed/19797342?dopt=Abstract|
|139.||↵||Ensrud KE, Ewing SK, Fredman L, Hochberg MC,Cauley JA, Hillier TA, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J ClinEndocrinolMetab 2010;95:5266-5273. https://www.ncbi.nlm.nih.gov/pubmed/21131545?dopt=Abstract|
|141, 150.||↵||Davis CD. Vitamin D and cancer: current dilemmas and future research needs. Am J Clin Nutr 2008;88:565S-9S. https://www.ncbi.nlm.nih.gov/pubmed/18689403?dopt=Abstract|
|142.||↵||Davis CD, Hartmuller V, Freedman M, Hartge P, Picciano MF, Swanson CA, Milner JA. Vitamin D and cancer: current dilemmas and future needs. Nutr Rev 2007;65:S71-S74. https://www.ncbi.nlm.nih.gov/pubmed/17867373?dopt=Abstract|
|143.||↵||Stolzenberg-Solomon RZ, Vieth R, Azad A, Pietinen P, Taylor PR, Virtamo J, et al. A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res 2006;66:10213-9. https://www.ncbi.nlm.nih.gov/pubmed/17047087?dopt=Abstract|
|144.||↵||Kathy J. Helzlsouer for the VDPP Steering Committee. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol 2010;172:4-9. https://www.ncbi.nlm.nih.gov/pubmed/20562193?dopt=Abstract|
|145, 149.||↵||Jenab M, Bueno-de-Mesquita HB, Ferrari P, van Duijnhoven FJB, Norat T, Pischon T, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. BMJ 2010;340:b5500. https://www.ncbi.nlm.nih.gov/pubmed/20093284?dopt=Abstract|
|146.||↵||Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sullivan MJ, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-96. https://www.ncbi.nlm.nih.gov/pubmed/16481636?dopt=Abstract|
|147.||↵||Parfitt AM. Osteomalacia and related disorders. In: Avioli LV, Krane SM, eds. Metabolic bone disease and clinically related disorders. 2nd ed. Philadelphia: WB Saunders, 1990:329-96.|
|148.||↵||Freedman DM, Looker AC, Chang S-C, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 2007;99:1594-602. https://www.ncbi.nlm.nih.gov/pubmed/17971526?dopt=Abstract|
|151.||↵||Davis CD, Dwyer JT. The ‘sunshine vitamin’: benefits beyond bone? J Natl Cancer Inst 2007;99:1563-5. https://www.ncbi.nlm.nih.gov/pubmed/17971523?dopt=Abstract|
|152.||↵||Moyer VA; U.S. Preventive Services Task Force. Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: U.S. Preventive services Task Force recommendation statement. Ann Intern Med. 2014 Apr 15;160(8):558-64. doi: 10.7326/M14-0198|
|153.||↵||Harvard University. Harvard Medical Publication. http://www.health.harvard.edu/newsletter_article/vitamin-d-and-your-health-breaking-old-rules-raising-new-hopes|
|154.||↵||Xu Y, Shao X, Yao Y, Xu L, Chang L, Jiang Z, Lin Z. Positive association between circulating 25-hydroxyvitamin D levels and prostate cancer risk: new findings from an updated meta-analysis. J Cancer Res Clin Oncol. 2014 Sep;140(9):1465-77. doi: 10.1007/s00432-014-1706-3|
|155.||↵||Kristal AR, Till C, Song X, Tangen CM, Goodman PJ, Neuhauser ML, Schenk JM, Thompson IM, Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL, Klein EA. Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2014 Aug;23(8):1494-504. doi: 10.1158/1055-9965.EPI-14-0115|
|156.||↵||Schenk JM, Till CA, Tangen CM, Goodman PJ, Song X, Torkko KC, Kristal AR, Peters U, Neuhouser ML. Serum 25-hydroxyvitamin D concentrations and risk of prostate cancer: results from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev. 2014 Aug;23(8):1484-93. doi: 10.1158/1055-9965.EPI-13-1340|
|157.||↵||Heath AK, Hodge AM, Ebeling PR, Eyles DW, Kvaskoff D, Buchanan DD, Giles GG, Williamson EJ, English DR. Circulating 25-Hydroxyvitamin D Concentration and Risk of Breast, Prostate, and Colorectal Cancers: The Melbourne Collaborative Cohort Study. Cancer Epidemiol Biomarkers Prev. 2019 May;28(5):900-908. doi: 10.1158/1055-9965.EPI-18-1155|
|158.||↵||Travis RC, Perez-Cornago A, Appleby PN, et al. A Collaborative Analysis of Individual Participant Data from 19 Prospective Studies Assesses Circulating Vitamin D and Prostate Cancer Risk. Cancer Res. 2019;79(1):274-285. doi:10.1158/0008-5472.CAN-18-2318|
|159.||↵||Nair-Shalliker V, Bang A, Egger S, Clements M, Gardiner RA, Kricker A, Seibel MJ, Chambers SK, Kimlin MG, Armstrong BK, Smith DP. Post-treatment levels of plasma 25- and 1,25-dihydroxy vitamin D and mortality in men with aggressive prostate cancer. Sci Rep. 2020 May 8;10(1):7736. doi: 10.1038/s41598-020-62182-w|
|160.||↵||Song ZY, Yao Q, Zhuo Z, Ma Z, Chen G. Circulating vitamin D level and mortality in prostate cancer patients: a dose-response meta-analysis. Endocr Connect. 2018 Dec 1;7(12):R294-R303. doi: 10.1530/EC-18-0283|
|161.||↵||Shahvazi S, Soltani S, Ahmadi SM, de Souza RJ, Salehi-Abargouei A. The Effect of Vitamin D Supplementation on Prostate Cancer: A Systematic Review and Meta-Analysis of Clinical Trials. Horm Metab Res. 2019 Jan;51(1):11-21. doi: 10.1055/a-0774-8809|
|162.||↵||Earthman CP, Beckman LM, Masodkar K, Sibley SD. The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications. Int J Obes (Lond). 2012 Mar;36(3):387-96. doi: 10.1038/ijo.2011.119|
|163.||↵||Mallard SR, Howe AS, Houghton LA. Vitamin D status and weight loss: a systematic review and meta-analysis of randomized and nonrandomized controlled weight-loss trials. Am J Clin Nutr. 2016 Oct;104(4):1151-1159. doi: 10.3945/ajcn.116.136879|
|164.||↵||Caan B, Neuhouser M, Aragaki A, Lewis CB, Jackson R, LeBoff MS, Margolis KL, Powell L, Uwaifo G, Whitlock E, Wylie-Rosett J, LaCroix A. Calcium plus vitamin D supplementation and the risk of postmenopausal weight gain. Arch Intern Med. 2007 May 14;167(9):893-902. doi: 10.1001/archinte.167.9.893|
|165.||↵||Pathak K, Soares MJ, Calton EK, Zhao Y, Hallett J. Vitamin D supplementation and body weight status: a systematic review and meta-analysis of randomized controlled trials. Obes Rev. 2014 Jun;15(6):528-37. doi: 10.1111/obr.12162|
|166.||↵||Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500-3. https://www.ncbi.nlm.nih.gov/pubmed/11705562?dopt=Abstract|
|167.||↵||Pittas AG, Dawson-Hughes B, Li T, Van Dam RM, Willett WC, Manson JE, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care 2006;29:650-6. https://www.ncbi.nlm.nih.gov/pubmed/16505521?dopt=Abstract|
|168.||↵||Krause R, Bühring M, Hopfenmüller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet 1998;352:709-10. https://www.ncbi.nlm.nih.gov/pubmed/9728997?dopt=Abstract|
|169.||↵||Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79:820-5. https://www.ncbi.nlm.nih.gov/pubmed/15113720?dopt=Abstract|
|170.||↵||Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006;296:2832-8. https://www.ncbi.nlm.nih.gov/pubmed/17179460?dopt=Abstract|
|171.||↵||Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag K. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis Rheum 2004;50:72-7. https://www.ncbi.nlm.nih.gov/pubmed/14730601?dopt=Abstract|
|172.||↵||Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2006;83:754-9. https://www.ncbi.nlm.nih.gov/pubmed/16600924?dopt=Abstract|
|174.||↵||Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007;167:1730-7. https://www.ncbi.nlm.nih.gov/pubmed/17846391?dopt=Abstract|
|175.||↵||Giovannucci E. Can vitamin D reduce total mortality? Arch Intern Med 2007;167:1709-10. https://www.ncbi.nlm.nih.gov/pubmed/17846388?dopt=Abstract|
|176, 177.||↵||Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al. Vitamin D and calcium: a systematic review of health outcomesexternal link disclaimer. Evidence Report/Technology Assessment No. 183 prepared by the Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I. AHRQ Publication No. 09-E015. Rockville, MD: Agency for Healthcare Research and Quality, 2009.|
|178.||↵||Kassi E, Adamopoulos C, Basdra EK, Papavassiliou AG. Role of vitamin D in atherosclerosis. Circulation. 2013 Dec 3;128(23):2517-31. doi: 10.1161/CIRCULATIONAHA.113.002654|
|179.||↵||Al Mheid I, Quyyumi AA. Vitamin D and Cardiovascular Disease: Controversy Unresolved. J Am Coll Cardiol. 2017 Jul 4;70(1):89-100. doi: 10.1016/j.jacc.2017.05.031|
|180.||↵||Zhang R, Li B, Gao X, Tian R, Pan Y, Jiang Y, Gu H, Wang Y, Wang Y, Liu G. Serum 25-hydroxyvitamin D and the risk of cardiovascular disease: dose-response meta-analysis of prospective studies. Am J Clin Nutr. 2017 Apr;105(4):810-819. doi: 10.3945/ajcn.116.140392|
|181.||↵||Durup D, Jørgensen HL, Christensen J, Tjønneland A, Olsen A, Halkjær J, Lind B, Heegaard AM, Schwarz P. A Reverse J-Shaped Association Between Serum 25-Hydroxyvitamin D and Cardiovascular Disease Mortality: The CopD Study. J Clin Endocrinol Metab. 2015 Jun;100(6):2339-46. doi: 10.1210/jc.2014-4551|
|182.||↵||Zhou R, Wang M, Huang H, Li W, Hu Y, Wu T. Lower Vitamin D Status Is Associated with an Increased Risk of Ischemic Stroke: A Systematic Review and Meta-Analysis. Nutrients. 2018 Feb 28;10(3):277. doi: 10.3390/nu10030277|
|183.||↵||Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J, Murphy J, Khaw KT, Camargo CA Jr. Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study : A Randomized Clinical Trial. JAMA Cardiol. 2017 Jun 1;2(6):608-616. doi: 10.1001/jamacardio.2017.0175|
|184, 190.||↵||Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, Gibson H, Gordon D, Copeland T, D’Agostino D, Friedenberg G, Ridge C, Bubes V, Giovannucci EL, Willett WC, Buring JE; VITAL Research Group. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019 Jan 3;380(1):33-44. doi: 10.1056/NEJMoa1809944|
|185.||↵||Ford JA, MacLennan GS, Avenell A, Bolland M, Grey A, Witham M; RECORD Trial Group. Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis. Am J Clin Nutr. 2014 Sep;100(3):746-55. doi: 10.3945/ajcn.113.082602|
|186.||↵||Dibaba DT. Effect of vitamin D supplementation on serum lipid profiles: a systematic review and meta-analysis. Nutr Rev. 2019 Dec 1;77(12):890-902. doi: 10.1093/nutrit/nuz037|
|187.||↵||Beveridge LA, Struthers AD, Khan F, Jorde R, Scragg R, Macdonald HM, Alvarez JA, Boxer RS, Dalbeni A, Gepner AD, Isbel NM, Larsen T, Nagpal J, Petchey WG, Stricker H, Strobel F, Tangpricha V, Toxqui L, Vaquero MP, Wamberg L, Zittermann A, Witham MD; D-PRESSURE Collaboration. Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data. JAMA Intern Med. 2015 May;175(5):745-54. doi: 10.1001/jamainternmed.2015.0237|
|188.||↵||Golzarand M, Shab-Bidar S, Koochakpoor G, Speakman J R, Djafarian K. Effect of vitamin D3 supplementation on blood pressure in adults: An updated meta-analysis. Nutr Metab Cardiovasc Dis. 2016 Aug;26(8):663-73. doi: 10.1016/j.numecd.2016.04.011|
|189.||↵||Vimaleswaran KS, Cavadino A, Berry DJ, et al. Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study. Lancet Diabetes Endocrinol. 2014;2(9):719-729. doi:10.1016/S2213-8587(14)70113-5|
|191, 192, 197.||↵||Jagannath VA, Filippini G, Di Pietrantonj C, Asokan GV, Robak EW, Whamond L, Robinson SA. Vitamin D for the management of multiple sclerosis. Cochrane Database of Systematic Reviews 2018, Issue 9. Art. No.: CD008422. DOI: 10.1002/14651858.CD008422.pub3 https://doi.org/10.1002/14651858.CD008422.pub3|
|193.||↵||Sintzel MB, Rametta M, Reder AT. Vitamin D and Multiple Sclerosis: A Comprehensive Review. Neurol Ther. 2018 Jun;7(1):59-85. doi: 10.1007/s40120-017-0086-4|
|194.||↵||Munger KL, Hongell K, Åivo J, Soilu-Hänninen M, Surcel HM, Ascherio A. 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. Neurology. 2017 Oct 10;89(15):1578-1583. doi: 10.1212/WNL.0000000000004489|
|195.||↵||Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8. doi: 10.1001/jama.296.23.2832|
|196.||↵||Salzer J, Hallmans G, Nyström M, Stenlund H, Wadell G, Sundström P. Vitamin D as a protective factor in multiple sclerosis. Neurology. 2012 Nov 20;79(21):2140-5. doi: 10.1212/WNL.0b013e3182752ea8|
|198.||↵||Marrie RA, Beck CA. Preventing multiple sclerosis: To (take) vitamin D or not to (take) vitamin D? Neurology. 2017 Oct 10;89(15):1538-1539. doi: 10.1212/WNL.0000000000004506|
|199.||↵||Mayo Foundation for Medical Education and Research. Vitamin D and MS: Is there any connection ? – http://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/expert-answers/vitamin-d-and-ms/faq-20058258|
|200, 201.||↵||Anglin RE, Samaan Z, Walter SD, McDonald SD. Vitamin D deficiency and depression in adults: systematic review and meta-analysis. Br J Psychiatry. 2013 Feb;202:100-7. doi: 10.1192/bjp.bp.111.106666|
|202.||↵||Gowda U, Mutowo MP, Smith BJ, Wluka AE, Renzaho AM. Vitamin D supplementation to reduce depression in adults: meta-analysis of randomized controlled trials. Nutrition. 2015 Mar;31(3):421-9. doi: 10.1016/j.nut.2014.06.017|
|203.||↵||Jorde R, Kubiak J. No improvement in depressive symptoms by vitamin D supplementation: results from a randomised controlled trial. J Nutr Sci. 2018 Nov 22;7:e30. doi: 10.1017/jns.2018.19|
|204.||↵||de Koning EJ, Lips P, Penninx BWJH, Elders PJM, Heijboer AC, den Heijer M, Bet PM, van Marwijk HWJ, van Schoor NM. Vitamin D supplementation for the prevention of depression and poor physical function in older persons: the D-Vitaal study, a randomized clinical trial. Am J Clin Nutr. 2019 Nov 1;110(5):1119-1130. doi: 10.1093/ajcn/nqz141|
|205.||↵||Okereke OI, Reynolds CF 3rd, Mischoulon D, Chang G, Vyas CM, Cook NR, Weinberg A, Bubes V, Copeland T, Friedenberg G, Lee IM, Buring JE, Manson JE. Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2020 Aug 4;324(5):471-480. doi: 10.1001/jama.2020.10224|
|206.||↵||Mayo Foundation for Medical Education and Research. Vitamin D: Can it prevent Alzheimer’s & dementia ? – http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/expert-answers/vitamin-d-alzheimers/faq-20111272|
|207, 216.||↵||Li X, Liu Y, Zheng Y, Wang P, Zhang Y. The Effect of Vitamin D Supplementation on Glycemic Control in Type 2 Diabetes Patients: A Systematic Review and Meta-Analysis. Nutrients. 2018 Mar 19;10(3):375. doi: 10.3390/nu10030375|
|208, 214.||↵||Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, Brodsky I, Ceglia L, Chadha C, Chatterjee R, Desouza C, Dolor R, Foreyt J, Fuss P, Ghazi A, Hsia DS, Johnson KC, Kashyap SR, Kim S, LeBlanc ES, Lewis MR, Liao E, Neff LM, Nelson J, O’Neil P, Park J, Peters A, Phillips LS, Pratley R, Raskin P, Rasouli N, Robbins D, Rosen C, Vickery EM, Staten M; D2d Research Group. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019 Aug 8;381(6):520-530. doi: 10.1056/NEJMoa1900906|
|210.||↵||Rafiq S, Jeppesen PB. Is Hypovitaminosis D Related to Incidence of Type 2 Diabetes and High Fasting Glucose Level in Healthy Subjects: A Systematic Review and Meta-Analysis of Observational Studies. Nutrients. 2018 Jan 10;10(1):59. doi: 10.3390/nu10010059|
|211.||↵||Mousa A, Naderpoor N, de Courten MP, Teede H, Kellow N, Walker K, Scragg R, de Courten B. Vitamin D supplementation has no effect on insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults: a randomized placebo-controlled trial. Am J Clin Nutr. 2017 Jun;105(6):1372-1381. doi: 10.3945/ajcn.117.152736|
|212.||↵||Seida JC, Mitri J, Colmers IN, Majumdar SR, Davidson MB, Edwards AL, Hanley DA, Pittas AG, Tjosvold L, Johnson JA. Clinical review: Effect of vitamin D3 supplementation on improving glucose homeostasis and preventing diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2014 Oct;99(10):3551-60. doi: 10.1210/jc.2014-2136. Epub 2014 Jul 25. Erratum in: J Clin Endocrinol Metab. 2015 Aug;100(8):3219|
|213.||↵||Jorde R, Sollid ST, Svartberg J, Schirmer H, Joakimsen RM, Njølstad I, Fuskevåg OM, Figenschau Y, Hutchinson MY. Vitamin D 20,000 IU per Week for Five Years Does Not Prevent Progression From Prediabetes to Diabetes. J Clin Endocrinol Metab. 2016 Apr;101(4):1647-55. doi: 10.1210/jc.2015-4013|
|215.||↵||Pittas A, Dawson-Hughes B, Staten M. Vitamin D Supplementation and Prevention of Type 2 Diabetes. Reply. N Engl J Med. 2019 Oct 31;381(18):1785-1786. doi: 10.1056/NEJMc1912185|
|217.||↵||Galior K, Grebe S, Singh R. Development of Vitamin D Toxicity from Overcorrection of Vitamin D Deficiency: A Review of Case Reports. Nutrients. 2018 Jul 24;10(8):953. doi: 10.3390/nu10080953|
|218.||↵||Auguste BL, Avila-Casado C, Bargman JM. Use of vitamin D drops leading to kidney failure in a 54-year-old man. CMAJ. 2019 Apr 8;191(14):E390-E394. doi: 10.1503/cmaj.180465|
|220.||↵||Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-83. DOI: 10.1056/NEJMoa055218|
|221.||↵||Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr 2008;88:582S-6S. https://www.ncbi.nlm.nih.gov/pubmed/18689406|
|222.||↵||Malihi Z, Lawes CMM, Wu Z, Huang Y, Waayer D, Toop L, Khaw KT, Camargo CA, Scragg R. Monthly high-dose vitamin D supplementation does not increase kidney stone risk or serum calcium: results from a randomized controlled trial. Am J Clin Nutr. 2019 Jun 1;109(6):1578-1587. doi: 10.1093/ajcn/nqy378|
|225.||↵||Laurent MR, Gielen E, Pauwels S, Vanderschueren D, Bouillon R. Hypervitaminosis D Associated With Tanning Bed Use: A Case Report. Ann Intern Med. 2017 Jan 17;166(2):155-156. doi: 10.7326/L16-0138|
|228.||↵||Mayo Foundation for Medical Education and Research. Vitamin D Safety. http://www.mayoclinic.org/drugs-supplements/vitamin-d/safety/hrb-20060400|