|Use||Rickets, osteoporosis, vitamin D deficiency|
|Biological target||vitamin D receptor|
Vitamin D is a group of fat-soluble secosteroids responsible for enhancing intestinal absorption of calcium and phosphate. In humans, the most important compounds in this group are vitamin D3 (also known as cholecalciferol) and vitamin D2 (ergocalciferol). Cholecalciferol and ergocalciferol can be ingested from the diet and from supplements. The body can also synthesize vitamin D (specifically cholecalciferol) in the skin, from cholesterol, when sun exposure is adequate (hence its nickname, the "sunshine vitamin").
Although vitamin D is commonly called a vitamin, it is not actually an essential dietary vitamin in the strict sense, as it can be synthesized in adequate amounts by most mammals exposed to sunlight. A substance is only classified as an essential vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from its diet. In common with other compounds commonly called vitamins, vitamin D was nevertheless discovered in an effort to find the dietary substance lacking in a disease, namely rickets, the childhood form of osteomalacia. Additionally, like other compounds called vitamins, in the developed world, vitamin D is added to staple foods, such as milk, to avoid disease due to deficiency.
Synthesis from exposure to sunlight, as well as intake from the diet, generally contribute to the maintenance of adequate serum concentrations. Evidence indicates the synthesis of vitamin D from sun exposure is regulated by a negative feedback loop that prevents toxicity, but, because of uncertainty about the cancer risk from sunlight, no recommendations are issued by the Institute of Medicine, USA, for the amount of sun exposure required to meet vitamin D requirements. Accordingly, the Dietary Reference Intake for vitamin D assumes no synthesis occurs and all of a person's vitamin D is from food intake, although that will rarely occur in practice. Beyond its use to prevent osteomalacia or rickets, the evidence for other health effects of vitamin D supplementation in the general population is inconsistent. The best evidence of benefit is for bone health and a decrease in mortality in elderly women.
In the liver, cholecalciferol (vitamin D3) is converted to calcidiol, which is also known as calcifediol (INN), 25-hydroxycholecalciferol, or 25-hydroxyvitamin D3 — abbreviated 25(OH)D3. Ergocalciferol (vitamin D2) is converted in the liver to 25-hydroxyergocalciferol, also known as 25-hydroxyvitamin D2 — abbreviated 25(OH)D2. These are the two specific vitamin D metabolites that are measured in serum to determine a person's vitamin D status. Part of the calcidiol is converted by the kidneys to calcitriol, the biologically active form of vitamin D. Calcitriol circulates as a hormone in the blood, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone. Calcitriol also affects neuromuscular and immune function.
- 1 Effects
- 2 Types
- 3 Biosynthesis
- 4 Metabolic activation
- 5 Mechanism of action
- 6 Discovery
- 7 Recommendations
- 8 Industrial production
- 9 References
- 10 Further reading
- 11 External links
The effects of vitamin D supplementation on health are uncertain. A 2013 review did not find any effect from supplementation on the rates of disease, other than a tentative decrease in mortality in the old. Low vitamin D levels may result from disease rather than be cause by disease.
A United States Institute of Medicine, (IOM) report states: "Outcomes related to cancer, cardiovascular disease and hypertension, diabetes and metabolic syndrome, falls and physical performance, immune functioning and autoimmune disorders, infections, neuropsychological functioning, and preeclampsia could not be linked reliably with calcium or vitamin D intake and were often conflicting.":5 Some researchers claim the IOM was too definitive in its recommendations and made a mathematical mistake when calculating the blood level of vitamin D associated with bone health. Members of the IOM panel maintain that they used a "standard procedure for dietary recommendations" and that the report is solidly based on the data. Research on vitamin D supplements, including large scale clinical trials, is continuing.
Low blood levels of vitamin D are associated with increased mortality, and giving supplementary vitamin D3 to elderly women in institutional care seems to decrease the risk of death. Vitamin D2, alfacalcidol, and calcitriol do not appear to be effective. However, both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging. The relationship between serum calcidiol level and all-cause mortality is parabolic, Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population.:435
In 2013, the US Preventive Services Task Force found not enough evidence to determine if healthy women should use supplemental calcium and vitamin D to prevent fractures. Similarly, another 2013 meta-analysis did not find evidence that vitamin D supplementation increases bone density and thus did not recommended it general use to prevent osteoporosis.
In those with osteoporosis there does not appear to be a decreased risk of fractures from vitamin D except maybe among those in care homes where vitamin D with calcium may prevent hip fractures but causes stomach and kidney problems. Supplementation with higher doses of vitamin D, in those older than 65 years, may decrease fracture risk. This appears to apply more to people in institutions than those living independently. The quality of the evidence is, however, poor.
Vitamin D deficiency causes osteomalacia (called rickets when it occurs in children). Use of vitamin D in children with normal vitamin D levels does not appear to be improve bone density. Beyond that, low serum vitamin D levels have been associated with falls, and low bone mineral density.
Low vitamin D levels are associated with some cancers and with worse outcomes in other cancers, but taking supplements does not appear to help people with prostate cancer. Currently evidence is insufficient to support supplementation in those with cancer. Results for a protective or harmful effect of vitamin D supplementation in other types of cancer are inconclusive.
Evidence for health effects from vitamin D supplementation for cardiovascular health is poor. Moderate to high doses may reduce cardiovascular disease risk but are of questionable clinical significance.
In general, vitamin D functions to activate the innate and dampen the adaptive immune systems. Vitamin D deficiency has been linked to increased risk of viral infections. It has been postulated to play a role in influenza with lack of vitamin D synthesis during the winter as one explanation for high rates of influenza infection during the winter. For viral infections, other implicated factors include low relative humidities produced by indoor heating and low temperatures that favor virus spread.[not in citation given] Low levels of vitamin D appear to be a risk factor for tuberculosis, and historically it was used as a treatment. As of 2011, it is being investigated in controlled clinical trials. Vitamin D may also play a role in HIV. Although there are tentative data linking low levels of vitamin D to asthma, there is inconclusive evidence to support a beneficial effect from supplementation. Accordingly, supplementation is not currently recommended for treatment or prevention of asthma.
Low levels of vitamin D are associated with multiple sclerosis. Supplementation with vitamin D may have a protective effect, but there are uncertainties and unanswered questions. "The reasons why vitamin D deficiency is thought to be a risk factor for MS are as follows: (1) MS frequency increases with increasing latitude, which is strongly inversely correlated with duration and intensity of UVB from sunlight and vitamin D concentrations; (2) prevalence of MS is lower than expected at high latitudes in populations with high consumption of vitamin-D-rich fatty fish; and (3) MS risk seems to decrease with migration from high to low latitudes." A clinical trial sponsored by Charite University in Berlin, Germany, was begun in 2011, with the goal of examining the efficacy, safety, and tolerability of vitamin D3 in the treatment of multiple sclerosis.
Low levels of vitamin D in pregnancy are associated with gestational diabetes, pre-eclampsia, and small infants. The benefit of supplements, however, is unclear. Pregnant women who take an adequate amount of vitamin D during gestation may experience positive immune effects. Pregnant women often do not take the recommended amount of vitamin D. A trial of supplementation has found 4000 IU of vitamin D3 superior to lesser amount in pregnant women for achieving specific target blood levels.
A diet deficient in vitamin D in conjunction with inadequate sun exposure causes osteomalacia (or rickets when it occurs in children), which is a softening of the bones. In the developed world, this is a rare disease. However, vitamin D deficiency has become worldwide issue in the elderly and remains common in children and adults. Low blood calcidiol (25-hydroxy-vitamin D) can result from avoiding the sun. Deficiency results in impaired bone mineralization and bone damage which leads to bone-softening diseases including:
Rickets, a childhood disease, is characterized by impeded growth, soft, weak, deformity of the long bones that bend and bow under their weight as children start to walk. This condition is characterized by bow legs, which can be caused by calcium or phosphorus deficiency, as well as a lack of vitamin D; today, it is largely found in low-income countries in Africa, Asia, or the Middle East and in those with genetic disorders such as pseudovitamin D deficiency rickets. Rickets was first described in 1650 by Francis Glisson, who said it had first appeared about 30 years previously in the counties of Dorset and Somerset. In 1857, John Snow suggested that rickets, then widespread in Britain, was being caused by the adulteration of bakers' bread with alum. The role of diet in the development of rickets was determined by Edward Mellanby between 1918–1920. Nutritional rickets exists in countries with intense year-round sunlight such as Nigeria and can occur without vitamin D deficiency. Although rickets and osteomalacia are now rare in Britain, there have been outbreaks in some immigrant communities in which osteomalacia sufferers included women with seemingly adequate daylight outdoor exposure wearing Western clothing. Having darker skin and reduced exposure to sunshine did not produce rickets unless the diet deviated from a Western omnivore pattern characterized by high intakes of meat, fish, and eggs, and low intakes of high-extraction cereals. The dietary risk factors for rickets include abstaining from animal foods. Vitamin D deficiency remains the main cause of rickets among young infants in most countries, because breast milk is low in vitamin D and social customs and climatic conditions can prevent adequate UVB exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh, where the disease occurs among older toddlers and children, it has been attributed to low dietary calcium intakes, which are characteristic of cereal-based diets with limited access to dairy products. Rickets was formerly a major public health problem among the US population; in Denver, where ultraviolet rays are approximately 20% stronger than at sea level on the same latitude, almost two-thirds of 500 children had mild rickets in the late 1920s. An increase in the proportion of animal protein in the 20th century American diet coupled with increased consumption of milk fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases. Also, in the United States and Canada, vitamin D fortified milk, infant vitamin supplements, and vitamin supplements have helped to eradicate the majority of cases of rickets for children with fat malabsorption conditions.
Osteomalacia is a disease in adults that results from vitamin D deficiency. Characteristics of this disease are softening of the bones, leading to bending of the spine, bowing of the legs, proximal muscle weakness, bone fragility, and increased risk for fractures. Osteomalacia reduces calcium absorption and increases calcium loss from bone, which increases the risk for bone fractures. Osteomalacia is usually present when 25-hydroxyvitamin D levels are less than about 10 ng/mL. The effects of osteomalacia are thought to contribute to chronic musculoskeletal pain, There is no persuasive evidence of lower vitamin D levels in chronic pain sufferers.
Influence of skin pigmentation
Some research shows that dark-skinned people living in temperate climates have lower vitamin D levels. It has been suggested that dark-skinned people are less efficient at making vitamin D because melanin in the skin hinders vitamin D synthesis; however, a recent study has found novel evidence that low vitamin D levels among Africans may be due to other reasons. Recent evidence implicates parathyroid hormone in adverse cardiovascular outcomes. Black women have an increase in serum PTH at a lower 25(OH)D level than white women. A large scale association study of the genetic determinants of vitamin D insufficiency in Caucasians found no links to pigmentation.
On the other hand, the uniform occurrence of low serum 25(OH)D in Indians living in India and Chinese in China, does not support the hypothesis that the low levels seen in the more pigmented are due to lack of synthesis from the sun at higher latitudes. The leader of the study has urged dark-skinned immigrants to take vitamin D supplements nonetheless, saying, "I see no risk, no downside, there's only a potential benefit. "
Vitamin D toxicity is rare. The threshold for vitamin D toxicity has not been established; however, the tolerable upper intake level (UL) is 4000 IU/day for ages 9–71. Vitamin D toxicity is not caused by sunlight exposure, but can be caused by supplementing with high doses of vitamin D. In healthy adults, sustained intake of more than 1250 micrograms/day (50,000 IU) can produce overt toxicity after several months and can increase serum 25-hydroxyvitamin D levels to 150 ng/mL and greater; those with certain medical conditions, such as primary hyperparathyroidism, are far more sensitive to vitamin D and develop hypercalcemia in response to any increase in vitamin D nutrition, while maternal hypercalcemia during pregnancy may increase fetal sensitivity to effects of vitamin D and lead to a syndrome of mental retardation and facial deformities.
Since hypercalcemia is a strong indication of vitamin D toxicity, this condition is noted with an increase in urination and thirst. If hypercalcemia is not treated, it results in excess deposits of calcium in soft tissues and organs such as the kidneys, liver, and heart, resulting in pain and organ damage. Pregnant or breastfeeding women should consult a doctor before taking a vitamin D supplement. The FDA advised manufacturers of liquid vitamin D supplements that droppers accompanying these products should be clearly and accurately marked for 400 international units (IU). In addition, for products intended for infants, the FDA recommends that the dropper hold no more than 400 IU. For infants (birth to 12 months), the tolerable upper limit (maximum amount that can be tolerated without harm) is set at 25 micrograms/day (1000 IU). One thousand micrograms (40,000 IU) per day in infants has produced toxicity within one month. After being commissioned by the Canadian and American governments, the Institute of Medicine (IOM) as of 30 November 2010[update], has increased the tolerable upper limit (UL) to 2500 IU per day for ages 1–3 years, 3000 IU per day for ages 4–8 years and 4000 IU per day for ages 9–71+ years (including pregnant or lactating women).
Vitamin D overdose causes hypercalcemia, and the main symptoms of vitamin D overdose are those of hypercalcemia: anorexia, nausea, and vomiting can occur, frequently followed by polyuria, polydipsia, weakness, insomnia, nervousness, pruritus, and, ultimately, renal failure. Proteinuria, urinary casts, azotemia, and metastatic calcification (especially in the kidneys) may develop. Other symptoms of vitamin D toxicity include mental retardation in young children, abnormal bone growth and formation, diarrhea, irritability, weight loss, and severe depression. Vitamin D toxicity is treated by discontinuing vitamin D supplementation and restricting calcium intake. Kidney damage may be irreversible. Exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity. Within about 20 minutes of ultraviolet exposure in light-skinned individuals (3–6 times longer for pigmented skin), the concentrations of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded.
Published cases of toxicity involving hypercalcemia in which the vitamin D dose and the 25-hydroxy-vitamin D levels are known all involve an intake of ≥40,000 IU (1000 μg) per day. Recommending supplementation, when those supposedly in need of it are labeled healthy, has proved contentious, and doubt exists concerning long term effects of attaining and maintaining high serum 25(OH)D by supplementation.
|Vitamin D1||molecular compound of ergocalciferol with lumisterol, 1:1|
|Vitamin D2||ergocalciferol (made from ergosterol)|
|Vitamin D3||cholecalciferol (made from 7-dehydrocholesterol in the skin).|
|Vitamin D5||sitocalciferol (made from 7-dehydrositosterol)|
Several forms (vitamers) of vitamin D exist (see table). The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol; vitamin D without a subscript refers to either D2 or D3 or both. These are known collectively as calciferol. Vitamin D2 was chemically characterized in 1931. In 1935, the chemical structure of vitamin D3 was established and proven to result from the ultraviolet irradiation of 7-dehydrocholesterol.
Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken. The structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.
Vitamin D3 (cholecalciferol) is produced through the action of ultraviolet irradiation (UV) on its precursor 7-dehydrocholesterol. Our skin makes vitamin D3 and supplies about 90 percent of our vitamin D. This molecule occurs naturally in the skin of animals and in milk. Vitamin D3 can be made by exposure of the skin to UV, or by exposing milk directly to UV (one commercial method). Vitamin D3 is also found in oily fish and cod liver oil.
Vitamin D2 is a derivative of ergosterol, a membrane sterol named for the ergot fungus, which is produced by some kinds of phytoplankton, invertebrates, yeasts, and higher fungi such as mushrooms. The vitamin ergocalciferol (D2) is produced in all of these organisms from ergosterol, in response to UV irradiation. Like all forms of vitamin D, it cannot be produced without UV irradiation. D2 is not produced by green land plants or vertebrates, because they lack the precursor ergosterol. The biological fate for producing 25(OH)D from vitamin D2 is expected to be the same as for 25(OH)D3, although some controversy exists over whether or not D2 can fully substitute for vitamin D3 in the human diet.
The transformation that converts 7-dehydrocholesterol to Vitamin D3 (cholecalciferol) occurs in two steps. First, 7-dehydrocholesterol, is photolyzed by ultraviolet light in a 6-electron conrotatory electrocyclic reaction. The product is previtamin D3. Second, previtamin D3 spontaneously isomerizes to vitamin D3 (cholecalciferol) in an antarafacial sigmatropic [1,7] hydride shift. At room temperature, the transformation of previtamin D3 to vitamin D3 takes about 12 days to complete.
Photosynthesis of vitamin D in the ocean by phytoplankton (such as coccolithophore and Emiliania huxleyi) has existed for more than 500 million years and continues to the present. Although primitive vertebrates in the ocean could absorb calcium from the ocean into their skeletons and eat plankton rich in vitamin D, land animals required another way to satisfy their vitamin D requirement for a calcified skeleton without relying on plants. Land vertebrates have been making their own vitamin D for more than 350 million years.
Vitamin D can be synthesized only via a photochemical process, so land vertebrates had to ingest foods that contained vitamin D or had to be exposed to sunlight to photosynthesize vitamin D in their skin to satisfy their body's vitamin D requirement.
Synthesis in the skin
Vitamin D3 (cholecalciferol) is produced photochemically in the skin from 7-dehydrocholesterol. The precursor of vitamin D3, 7-Dehydrocholesterol is produced in relatively large quantities, 10,000 to 20,000 IU of vitamin D are produced in 30 minutes of whole-body exposure, in the skin of most vertebrate animals, including humans. 7-dehydrocholesterol reacts with ultraviolet light of UVB type at wavelengths between 270 and 300 nm, with peak synthesis occurring between 295 and 297 nm. These wavelengths are present in sunlight when the UV index is greater than three, as well as in the light emitted by the UV lamps in tanning beds (which produce ultraviolet primarily in the UVA spectrum, but typically produce 4% to 10% of the total UV emissions as UVB). At a UV index greater than three, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, vitamin D3 can be made in the skin. Even if the UV index is high enough, exposure to light through windows is insufficient because glass almost completely blocks UVB light.
Depending on the intensity of UVB rays and the minutes of exposure, an equilibrium can develop in the skin, and vitamin D degrades as fast as it is generated.
The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer, thinner epidermis. Thick epidermis in the soles and palms consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Vitamin D is produced in the two innermost strata, the stratum basale and stratum spinosum.
The naked mole rat appears to be naturally cholecalciferol deficient, as serum 25-OH vitamin D levels are undetectable. In some animals, the presence of fur or feathers blocks the UV rays from reaching the skin. In birds and fur-bearing mammals, vitamin D is generated from the oily secretions of the skin deposited onto the feathers or fur and is obtained orally during grooming.
Sunscreen absorbs ultraviolet light and prevents it from reaching the skin. It has been reported that sunscreen with a sun protection factor (SPF) of 8 based on the UVB spectrum can decrease vitamin D synthetic capacity by 95 percent, whereas sunscreen with an SPF of 15 can reduce synthetic capacity by 98 percent.
Vitamin D is carried in the bloodstream to the liver, where it is converted into the prohormone calcidiol. Circulating calcidiol may then be converted into calcitriol, the biologically active form of vitamin D, in the kidneys. Following the final converting step in the kidney, calcitriol (the physiologically active form of vitamin D) is released into the circulation. By binding to vitamin D-binding protein (VDBP), a carrier protein in the plasma, calcitriol is transported to various target organs. In addition to the kidneys, calcitriol is also synthesized by monocyte-macrophages in the immune system. When synthesized by monocyte-macrophages, calcitriol acts locally as a cytokine, defending the body against microbial invaders by stimulating the innate immune system.
Whether it is made in the skin or ingested, cholecalciferol is hydroxylated in the liver at position 25 (upper right of the molecule) to form 25-hydroxycholecalciferol (calcidiol or 25(OH)D). This reaction is catalyzed by the microsomal enzyme vitamin D 25-hydroxylase, which is produced by hepatocytes. Once made, the product is released into the plasma, where it is bound to an α-globulin, vitamin D binding protein.
Calcidiol is transported to the proximal tubules of the kidneys, where it is hydroxylated at the 1-α position (lower right of the molecule) to form calcitriol (aka 1,25-dihydroxycholecalciferol and abbreviated to 1,25(OH)2D). This product is a potent ligand of the vitamin D receptor (VDR), which mediates most of the physiological actions of the vitamin. The conversion of calcidiol to calcitriol is catalyzed by the enzyme 25-hydroxyvitamin D3 1-alpha-hydroxylase, the levels of which are increased by parathyroid hormone (and additionally by low calcium or phosphate).
Mechanism of action
The active vitamin D metabolite calcitriol mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells. The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine. The vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDRs are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content.
One of the most important roles of vitamin D is to maintain skeletal calcium balance by promoting calcium absorption in the intestines, promoting bone resorption by increasing osteoclast number, maintaining calcium and phosphate levels for bone formation, and allowing proper functioning of parathyroid hormone to maintain serum calcium levels. Vitamin D deficiency can result in lower bone mineral density and an increased risk of reduced bone density (osteoporosis) or bone fracture because a lack of vitamin D alters mineral metabolism in the body. Thus, although it may initially appear paradoxical, vitamin D is also critical for bone remodeling through its role as a potent stimulator of bone resorption.
The VDR is known to be involved in cell proliferation and differentiation. Vitamin D also affects the immune system, and VDRs are expressed in several white blood cells, including monocytes and activated T and B cells. Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells. It also is involved in the biosynthesis of neurotrophic factors, synthesis of nitric oxide synthase, and increased glutathione levels.
Apart from VDR activation, various alternative mechanisms of action are known. An important one of these is its role as a natural inhibitor of signal transduction by hedgehog (a hormone involved in morphogenesis).
American researchers Elmer McCollum and Marguerite Davis in 1914 discovered a substance in cod liver oil which later was called "vitamin A". British doctor Edward Mellanby noticed dogs that were fed cod liver oil did not develop rickets and concluded vitamin A, or a closely associated factor, could prevent the disease. In 1922, Elmer McCollum tested modified cod liver oil in which the vitamin A had been destroyed. The modified oil cured the sick dogs, so McCollum concluded the factor in cod liver oil which cured rickets was distinct from vitamin A. He called it vitamin D because it was the fourth vitamin to be named. It was not initially realized that, unlike other vitamins, vitamin D can be synthesised by humans through exposure to UV light.
In 1925, it was established that when 7-dehydrocholesterol is irradiated with light, a form of a fat-soluble vitamin is produced (now known as D3). Alfred Fabian Hess showed "light equals vitamin D." Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928, for his work on the constitution of sterols and their connection with vitamins. In 1929 a group at NIMR in Hampstead, London, were working on the structure of vitamin D, which was still unknown, as well as the structure of steroids. A meeting took place with J.B.S. Haldane, J.D. Bernal and Dorothy Crowfoot to discuss possible structures, which contributed to bringing a team together. X-ray crystallography demonstrated that sterol molecules were flat, not as proposed by the German team led by Windaus. In 1932, Otto Rosenheim and Harold King published a paper putting forward structures for sterols and bile acids which found immediate acceptance. The informal academic collaboration between the team members Robert Benedict Bourdillon, Otto Rosenheim, Harold King and Kenneth Callow was very productive and led to the isolation and characterization of vitamin D. At this time the policy of the Medical Research Councilwas not to patent discoveries, believing that results of medical research should be open to everybody. In the 1930s Windaus clarified further the chemical structure of vitamin D.
In 1923, American biochemist Harry Steenbock at the University of Wisconsin demonstrated that irradiation by ultraviolet light increased the vitamin D content of foods and other organic materials. After irradiating rodent food, Steenbock discovered the rodents were cured of rickets. A vitamin D deficiency is a known cause of rickets. Using $300 of his own money, Steenbock patented his invention. His irradiation technique was used for foodstuffs, most memorably for milk. By the expiration of his patent in 1945, rickets had been all but eliminated in the US.
In 1971–72, the further metabolism of vitamin D to active forms was discovered. In the liver, vitamin D was found to be converted to calcidiol. Part of the calcidiol is then converted by the kidneys to calcitriol, the biologically active form of vitamin D. Calcitriol circulates as a hormone in the blood, regulating the concentration of calcium and phosphate in the bloodstream and promoting the healthy growth and remodeling of bone. Both calcidiol and calcitriol were identified by a team led by Michael F. Holick in the laboratory of Hector DeLuca.
Dietary reference intakes
Different institutions propose different recommendations concerning daily amounts of the vitamin.
Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited.
Australia and New Zealand
About a third of Australians have vitamin D deficiency. Australia and New Zealand have established average intakes for vitamin D, as follows: children 5.0 μg /day; adults 19–50 yr 5.0 μg/day, 51–70 yr 10.0 μg/day, >70 yr 15.0 μg/day.
|Age group||RDA (IU)||Tolerable Upper Intake (IU)|
|Infants 0–6 months||400*||1000|
|Infants 7–12 months||400*||1500|
|Children 1–3 years||600||2500|
|Children 4–8 years||600||3000|
|Children and Adults 9–70 years||600||4000|
|Adults > 70 years||800||4000|
|Pregnancy & Lactation||600||4000|
Note*: Adequate Intake rather than Recommended Dietary Allowance.
The recommended daily amount for vitamin D in the European Union is 5 µg.
The European Menopause and Andropause Society (EMAS) recommended 15 µg (600 IU) until age 70, and 20 µg (800 IU) in older than 71 years, in postmenopausal women. This dose should be increased up to 4,000 IU/day in some patients with very low vitamin D status or in case of co-morbid conditions.
The Director General of Research and Development and Chief Scientific Adviser for the UK Department of Health and NHS said that children aged six months to five years should be given vitamin D supplements, particularly during the winter. However, vitamin D supplements are not recommended for people who get enough vitamin D from their diets and from sunlight.
According to the United States Institute of Medicine, the recommended dietary allowances of vitamin D are:
- Infants 0–6 months: 400 IU/day*
- Infants 6–12 months: 400 IU/day*
- 1–70 years of age: 600 IU/day (15 μg/day)
- 71+ years of age: 800 IU/day (20 μg/day)
- Pregnant/lactating: 600 IU/day (15 μg/day)
- Asterisk for infants indicates Adequate Intake (AI) for infants, as an RDA has yet to be established for infants.
Upper intake levels
The Tolerable Upper Intake Level is defined as "the highest average daily intake of a nutrient that is likely to pose no risk of adverse health effects for nearly all persons in the general population.:403 " Although tolerable upper intake levels are believed to be safe, information on the long-term effects is incomplete and these levels of intake are not recommended::403:433
- 0–6 months of age: 1,000 IU (25 µg/day)
- 6–12 months of age: 1,500 IU (37.5 µg/day)
- 1–3 years of age: 2,500 IU (62.5 µg/day)
- 4–8 years of age: 3,000 IU (75 µg/day)
- 9–71+ years of age: 4,000 IU (100 µg/day)
- Pregnant/lactating: 4,000 IU:5(100 µg/day)
The Dietary Reference Intake for vitamin D issued by the American (U.S.) Institute of Medicine (IOM) in 2010 superseded a previous recommendation which had Adequate Intake status. The recommendations were formed assuming the individual has no skin synthesis of vitamin D because of inadequate sun exposure. The reference intake for vitamin D refers to total intake from food, beverages and supplements, is intended for the North American population, and assumes that calcium requirements are being met.:5
One school of thought contends that human physiology is fine tuned to an intake of 4000–12,000 IU/day from sun exposure with concomitant serum 25-hydroxyvitamin D levels of 40 to 80 ng/mL and that this is required for optimal health. Proponents of this view, who include some members of the panel that drafted a now superseded 1997 report on vitamin D from the Institute of Medicine, contend that the IOM's warning about serum concentrations above 50 ng/mL lacks biological plausibility. They suggest that for some people reducing the risk of preventable disease requires a higher level of vitamin D than that recommended by the IOM.
According to the European Food Safety Authority the Tolerable Upper Intake Levels are:
- 0–12 months: 25 µg/day (1000 IU)
- 1–10 years: 50 µg/day (2000 IU)
- 11–17 years: 100 µg/day (4000 IU)
- 17+: 100 µg/day (4,000 IU)
- Pregnant/lactating women: 100 µg/day (4,000 IU)
Serum 25-hydroxyvitamin D
US labs generally report 25(OH)D levels as ng/mL. Other countries often use nmol/L.
A U.S. Institute of Medicine committee concluded that a serum 25-hydroxyvitamin D level of 20 ng/mL (50 nmol/L) is desirable for bone and overall health. The Dietary Reference Intakes for vitamin D are chosen with a margin of safety and 'overshoot' the targeted serum value to ensure that the specified levels of intake achieve the desired serum 25-hydroxyvitamin D levels in almost all persons. It is assumed there are no contributions to serum 25-hydroxyvitamin D level from sun exposure and the recommendations are fully applicable to people with dark skin or negligible exposure to sunlight.:1
The Institute found that serum 25-hydroxyvitamin D concentrations above 30 ng/mL (75 nmol/L) are "not consistently associated with increased benefit". Serum 25-hydroxyvitamin D levels above 50 ng/mL (125 nmol/L) may be cause for concern. However, the desired range of serum 25-hydroxyvitamin D is between 20-50 ng/mL.
There is a lower risk of cardiovascular disease when vitamin D ranged from 20 to 60 nmol/L (8 to 24 ng/mL). There appears to be a "threshold effect" once 60 nmol/L (24 ng/mL) have been reached i.e., levels of vitamin D over 60 nmol/L did not show added benefit.
Allowable health claims
Apart from the above discussion on health effects or scientific evidence for lowering disease risk, governmental regulatory agencies stipulate for the food industry health claims allowable as statements on packaging.
- normal function of the immune system
- normal inflammatory response
- normal muscle function
- reduced risk of falling in people over age 60
US Food and Drug Administration (FDA)
- may reduce the risk of osteoporosis
- adequate calcium and regular exercise may help to achieve strong bones in children and adolescents and may reduce the risk of osteoporosis in older adults. An adequate intake of vitamin D is also necessary
- Mushrooms, portabella, exposed to ultraviolet light, raw: Vitamin D2: 11.2 μg (446 IU)
- Mushrooms, portabella, exposed to ultraviolet light, grilled: Vitamin D2: 13.1 μg (524 IU)
- Mushrooms, shiitake, dried: Vitamin D2: 3.9 μg (154 IU)
- Mushrooms, shiitake, raw: Vitamin D2: 0.4 μg (18 IU)
- Mushrooms, portabella, raw: Vitamin D2: 0.3 μg (10 IU)
- Mushroom powder, any species, illuminated with sunlight or artificial ultraviolet light sources
Human bioavailability of vitamin D2 from vitamin D2-enhanced button mushrooms via UV-B irradiation is effective in improving vitamin D status and not different from a vitamin D2 supplement. from UV-irradiated yeast baked into bread is bioavailable. By visual assessment or using a chromometer, no significant discoloration of irradiated mushrooms, as measured by the degree of "whiteness", was observed. Claims have been made that a normal serving (approx. 3 oz or 1/2 cup, or 60 grams) of fresh mushrooms treated with ultraviolet light have increased vitamin D content to levels up to 80 micrograms, or 2700 IU if exposed to just 5 minutes of UV light after being harvested.
- Alfalfa (Medicago sativa subsp. sativa), shoot: 4.8 μg (192 IU) vitamin D2, 0.1 μg (4 IU) vitamin D3 (per 100 g).
- Vegan sources
- Animal sources
- Fish liver oils, such as cod liver oil, 1 Tablespoon (15 ml) provides 1,360 IU (90.6 IU/ml)
- Fatty fish species, such as:
- Catfish (wild), 85 g (3 oz) provides 425 IU (5 IU/g)
- Salmon, cooked, 100 g (3.5 oz) provides 360 IU (3.6 IU/g)
- Mackerel, cooked, 100 g, 345 IU (3.45 IU/g)
- Sardines, canned in oil, drained, 50 g (1.75 oz), 250 IU (5 IU/g)
- Tuna, canned in oil, 100 g, 235 IU (2.35 IU/g)
- Eel, cooked, 100 g, 200 IU (2.00 IU/g)
- A whole egg provides 20 IU if egg weighs 60 g (0.333 IU/g)
- Beef liver, cooked, 100 g, provides 15 IU (0.15 IU/g)
Vitamin D3 (cholecalciferol) is produced industrially by exposing 7-dehydrocholesterol to UVB light, followed by purification. The 7-dehydrocholesterol is a natural substance in wool grease (lanolin) from sheep or other woolly animals. Vitamin D2 (ergocalciferol) is produced in a similar way using ergosterol from yeast or mushrooms as a starting material.
- Holick MF (March 2006). "High prevalence of vitamin D inadequacy and implications for health". Mayo Clin. Proc. 81 (3): 353–73. doi:10.4065/81.3.353. PMID 16529140.
- Calvo MS, Whiting SJ, Barton CN (February 2005). "Vitamin D intake: a global perspective of current status". J. Nutr. 135 (2): 310–6. PMID 15671233.
- Norman AW (August 2008). "From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health". Am. J. Clin. Nutr. 88 (2): 491S–499S. PMID 18689389.
- Wolf G (June 2004). "The discovery of vitamin D: the contribution of Adolf Windaus". J Nutr 134 (6): 1299–302. PMID 15173387.
- Pittas AG, Chung, M, Trikalinos, T, Mitri, J, Brendel, M, Patel, K, Lichtenstein, AH, Lau, J, Balk, EM (Mar 2010). "Vitamin D and Cardiometabolic Outcomes: A Systematic Review". Annals of internal medicine 152 (5): 307–14. doi:10.1059/0003-4819-152-5-201003020-00009. PMC 3211092. PMID 20194237.
- Chung M, Balk, EM, Brendel, M, Ip, S, Lau, J, Lee, J, Lichtenstein, A, Patel, K, Raman, G, Tatsioni, A, Terasawa, T, Trikalinos, TA (August 2009). "Vitamin D and calcium: a systematic review of health outcomes". Evidence report/technology assessment (183): 1–420. PMID 20629479.
- Ross AC, Taylor CL, Yaktine AL Del Valle HB (2011). Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C: National Academies Press. p. 435. ISBN 0-309-16394-3.
- Bjelakovic G, Gluud, LL, Nikolova, D, Whitfield, K, Wetterslev, J, Simonetti, RG, Bjelakovic, M, Gluud, C (July 2011). "Vitamin D supplementation for prevention of mortality in adults". In Bjelakovic, Goran. Cochrane database of systematic reviews (Online) (7): CD007470. doi:10.1002/14651858.CD007470.pub2. PMID 21735411.
- "Vitamin D Tests". Lab Tests Online (USA). American Association for Clinical Chemistry. Retrieved 23 June 2013.
- Hollis BW (January 1996). "Assessment of vitamin D nutritional and hormonal status: what to measure and how to do it". Calcif. Tissue Int. 58 (1): 4–5. doi:10.1007/BF02509538. PMID 8825231.
- Holick MF, Schnoes HK, Deluca HF, Suda T, Cousins RJ (1971). "Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine". Biochemistry 10 (14): 2799–804. doi:10.1021/bi00790a023. PMID 4326883.
- "Dietary Supplement Fact Sheet: Vitamin D". Office of Dietary Supplements (ODS). National Institutes of Health (NIH). Retrieved 2010-04-11.
- Autier P, Boniol M, Pizot C, Mullie P (December 2013). "Vitamin D status and ill health: a systematic review". The Lancet Diabetes & Endocrinology. doi:10.1016/S2213-8587(13)70165-7.
- Maxmen A (2011). "Nutrition advice: the vitamin D-lemma". Nature 475 (7354): 23–5. doi:10.1038/475023a. PMID 21734684.
- Zittermann A, Gummert, JF, Börgermann, J (Nov 2009). "Vitamin D deficiency and mortality". Current opinion in clinical nutrition and metabolic care 12 (6): 634–9. doi:10.1097/MCO.0b013e3283310767. PMID 19710612.
- Tuohimaa P (March 2009). "Vitamin D and aging". The Journal of Steroid Biochemistry and Molecular Biology 114 (1–2): 78–84. doi:10.1016/j.jsbmb.2008.12.020. PMID 19444937.
- Tuohimaa P, Keisala T, Minasyan A, Cachat J, Kalueff A (2009). "Vitamin D, nervous system and aging". Psychoneuroendocrinology 34: S278–86. doi:10.1016/j.psyneuen.2009.07.003. PMID 19660871.
- Manya H, Akasaka-Manya K, Endo T (July 2010). "Klotho protein deficiency and aging". Geriatr Gerontol Int 10 (Suppl 1): S80–7. doi:10.1111/j.1447-0594.2010.00596.x. PMID 20590845.
- U.S. Preventive Services Task Force (June 2012-06-12). "Vitamin D and Calcium Supplementation to Prevent Cancer and Osteoporotic Fractures". Health. U.S. Preventive Services Task Force.
- "Vitamin D and Calcium Supplementation to Prevent Fractures". USPSTF. Feb 2013. Retrieved 12 October 2013.
- Reid IR, Bolland MJ, Grey A (October 2013). "Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis". Lancet. doi:10.1016/S0140-6736(13)61647-5. PMID 24119980.
- Avenell A, Gillespie WJ, Gillespie LD, O'Connell D (2009). "Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis". In Avenell, Alison. Cochrane Database Syst Rev (2): CD000227. doi:10.1002/14651858.CD000227.pub3. PMID 19370554.
- Bischoff-Ferrari HA, Willett WC, Orav EJ, Oray EJ, Lips P, Meunier PJ, Lyons RA, Flicker L, Wark J, Jackson RD, Cauley JA, Meyer HE, Pfeifer M, Sanders KM, Stähelin HB, Theiler R, Dawson-Hughes B (July 2012). "A pooled analysis of vitamin D dose requirements for fracture prevention". N. Engl. J. Med. 367 (1): 40–9. doi:10.1056/NEJMoa1109617. PMID 22762317.
- Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA (2011). "Vitamin D with or Without Calcium Supplementation for Prevention of Cancer and Fractures: An Updated Meta-analysis for the U.S. Preventive Services Task Force". Annals of internal medicine 155 (12): 827–38. doi:10.1059/0003-4819-155-12-201112200-00005. PMID 22184690.
- Cranney A, Weiler HA, O'Donnell S, Puil L (August 2008). "Summary of evidence-based review on vitamin D efficacy and safety in relation to bone health". Am. J. Clin. Nutr. 88 (2): 513S–519S. PMID 18689393.
- Winzenberg T, Powell S, Shaw KA, Jones G (2011). "Effects of vitamin D supplementation on bone density in healthy children: systematic review and meta-analysis". BMJ 342: c7254. doi:10.1136/bmj.c7254. PMC 3026600. PMID 21266418.
- Cranney A, Horsley, T, O'Donnell, S, Weiler, H, Puil, L, Ooi, D, Atkinson, S, Ward, L, Moher, D, Hanley, D, Fang, M, Yazdi, F, Garritty, C, Sampson, M, Barrowman, N, Tsertsvadze, A, Mamaladze, V (August 2007). "Effectiveness and safety of vitamin D in relation to bone health". Evidence report/technology assessment (158): 1–235. PMID 18088161.
- Buttigliero C, Monagheddu, C, Petroni, P, Saini, A, Dogliotti, L, Ciccone, G, Berruti, A (2011). "Prognostic role of vitamin d status and efficacy of vitamin d supplementation in cancer patients: a systematic review". The oncologist 16 (9): 1215–27. doi:10.1634/theoncologist.2011-0098. PMC 3228169. PMID 21835895.
- "Vitamin D and Cancer Prevention — National Cancer Institute". Cancer.gov. 2010-06-16. Retrieved 2012-06-13.
- Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM (March 2010). "Vitamin D and Cardiometabolic Outcomes: A Systematic Review". Annals of Internal Medicine 152 (5): 307–14. doi:10.1059/0003-4819-152-5-201003020-00009. PMC 3211092. PMID 20194237.
- McGreevy C, Williams D (2011). "New insights about vitamin d and cardiovascular disease: A narrative review". Annals of internal medicine 155 (12): 820–6. doi:10.1059/0003-4819-155-12-201112200-00004. PMID 22184689.
- Wang L, Manson, JE, Song, Y, Sesso, HD (Mar 2010). "Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events". Annals of internal medicine 152 (5): 315–23. doi:10.1059/0003-4819-152-5-201003020-00010. PMID 20194238.
- Hewison M (2011). "Vitamin D and innate and adaptive immunity". Vitam. Horm. Vitamins & Hormones 86: 23–62. doi:10.1016/B978-0-12-386960-9.00002-2. ISBN 9780123869609. PMID 21419266.
- Beard JA, Bearden, A, Striker, R (Mar 2011). "Vitamin D and the anti-viral state". Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 50 (3): 194–200. doi:10.1016/j.jcv.2010.12.006. PMC 3308600. PMID 21242105.
- Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E (2006). "Epidemic influenza and vitamin D". Epidemiology and Infection 134 (6): 1129–40. doi:10.1017/S0950268806007175. PMC 2870528. PMID 16959053.
- Bruce D, Ooi JH, Yu S, Cantorna MT (2010). "Vitamin D and host resistance to infection? Putting the cart in front of the horse". Experimental biology and medicine (Maywood, N.J.) 235 (8): 921–7. doi:10.1258/ebm.2010.010061. PMC 3138330. PMID 20660091.
- Nnoaham KE, Clarke, A (Feb 2008). "Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis". International Journal of Epidemiology 37 (1): 113–9. doi:10.1093/ije/dym247. PMID 18245055.
- Luong K, Nguyen, LT (Jun 2011). "Impact of vitamin D in the treatment of tuberculosis". The American journal of the medical sciences 341 (6): 493–8. doi:10.1097/MAJ.0b013e3182070f47. PMID 21289501.
- Spector SA, Nguyen, LT (Feb 2011). "Vitamin D and HIV: letting the sun shine in". Topics in antiviral medicine 19 (1): 6–10. PMID 21852710.
- Hart, PH (2012 Jun). "Vitamin D supplementation, moderate sun exposure, and control of immune Diseases". Discovery medicine 13 (73): 397–404. PMID 22742645.
- Paul G, Brehm, JM, Alcorn, JF, Holguín, F, Aujla, SJ, Celedón, JC (Jan 2012). "Vitamin D and asthma". American Journal of Respiratory and Critical Care Medicine 185 (2): 124–32. doi:10.1164/rccm.201108-1502CI. PMC 3297088. PMID 22016447.
- Ascherio A, Munger, KL, Simon, KC (Jun 2010). "Vitamin D and multiple sclerosis". Lancet neurology 9 (6): 599–612. doi:10.1016/S1474-4422(10)70086-7. PMID 20494325.
- Pierrot-Deseilligny C, Souberbielle, JC (Jul 2010). "Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis?". Brain : a journal of neurology 133 (Pt 7): 1869–88. doi:10.1093/brain/awq147. PMID 20584945.
- Pierrot-Deseilligny C, Souberbielle, JC (Apr 2011). "Widespread vitamin D insufficiency: A new challenge for primary prevention, with particular reference to multiple sclerosis". Presse medicale (Paris, France : 1983) 40 (4 Pt 1): 349–56. doi:10.1016/j.lpm.2011.01.003. PMID 21333483.
- ClinicalTrials.gov NCT01440062 Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS)
- Dörr J, Ohlraun S, Skarabis H, Paul F (2012). "Efficacy of vitamin D supplementation in multiple sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial". Trials 13 (1): 15. doi:10.1186/1745-6215-13-15. PMC 3298796. PMID 22316314.
- Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O'Beirne M, Rabi DM (2013). "Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies". BMJ 346: f1169. doi:10.1136/bmj.f1169. PMID 23533188.
- Wagner CL, Taylor SN, Dawodu A, Johnson DD, Hollis BW (March 2012). "Vitamin D and its role during pregnancy in attaining optimal health of mother and fetus". Nutrients 4 (3): 208–30. doi:10.3390/nu4030208. PMC 3347028. PMID 22666547.
- "Rickets". National Health Service. Last reviewed 08/03/2012. Retrieved 2012-07-09.
- MedlinePlus Encyclopedia Rickets
- Eriksen EF, Glerup H (2002). "Vitamin D deficiency and aging: implications for general health and osteoporosis". Biogerontology 3 (1–2): 73–7. doi:10.1023/A:1015263514765. PMID 12014847.
- Holick MF (July 2007). "Vitamin D deficiency". N. Engl. J. Med. 357 (3): 266–81. doi:10.1056/NEJMra070553. PMID 17634462.
- Schoenmakers I, Goldberg GR, Prentice A (2008). "Abundant sunshine and vitamin D deficiency". British Journal of Nutrition 99 (6): 1171–3. doi:10.1017/S0007114508898662. PMC 2758994. PMID 18234141.
- Grant WB, Holick MF (2005). "Benefits and requirements of vitamin D for optimal health: a review". Alternative medicine review 10 (2): 94–111. PMID 15989379.
- Brown JE (2008). Nutrition through the life cycle. Belmont, CA: Thomson/Wadsworth. ISBN 0-495-11637-8.
- Lerch C, Meissner T, Lerch C (2007). "Interventions for the prevention of nutritional rickets in term born children". In Lerch, Christian. Cochrane database of systematic reviews (Online) (4): CD006164. doi:10.1002/14651858.CD006164.pub2. PMID 17943890.
- Zargar AH, Mithal A, Wani AI, Laway BA, Masoodi SR, Bashir MI, Ganie MA (June 2000). "Pseudovitamin D deficiency rickets—a report from the Indian subcontinent". Postgraduate Medical Journal 76 (896): 369–72. doi:10.1136/pmj.76.896.369. PMC 1741602. PMID 10824056.
- Gibbs D (1994). "Rickets and the crippled child: an historical perspective". Journal of the Royal Society of Medicine 87 (12): 729–32. PMC 1294978. PMID 7503834.
- Dunnigan M (2003). "Commentary: John Snow and alum-induced rickets from adulterated London bread: an overlooked contribution to metabolic bone disease". International Journal of Epidemiology 32 (3): 340–1. doi:10.1093/ije/dyg160. PMID 12777415.
- Pileggi V, De Luca HF, Steenbock H (September 1955). "The role of vitamin D and intestinal phytase in the prevention of rickets in rats on cereal diets". Archives of Biochemistry and Biophysics 58 (1): 194–204. doi:10.1016/0003-9861(55)90106-5. PMID 13259690.
- Ford JA, Colhoun EM, McIntosh WB, Dunnigan MG (1972). "Biochemical Response of Late Rickets and Osteomalacia to a Chupatty-free Diet". British Medical Journal 3 (5824): 446–7. doi:10.1136/bmj.3.5824.446. PMC 1786011. PMID 5069221.
- Rajakumar K (2003). "Vitamin D, cod-liver oil, sunlight, and rickets: a historical perspective". Pediatrics 112 (2): e132–5. doi:10.1542/peds.112.2.e132. PMID 12897318.
- Oramasionwu GE, Thacher TD, Pam SD, Pettifor JM, Abrams SA (2008). "Adaptation of calcium absorption during treatment of nutritional rickets in Nigerian children". The British journal of nutrition 100 (2): 387–92. doi:10.1017/S0007114507901233. PMID 18197991.
- Fischer PR, Rahman A, Cimma JP, Kyaw-Myint TO, Kabir AR, Talukder K, Hassan N, Manaster BJ, Staab DB (1999). "Nutritional rickets without vitamin D deficiency in Bangladesh". Journal of tropical pediatrics 45 (5): 291–3. doi:10.1093/tropej/45.5.291. PMID 10584471.
- Dunnigan MG, Henderson JB (1997). "An epidemiological model of privational rickets and osteomalacia". The Proceedings of the Nutrition Society 56 (3): 939–56. doi:10.1079/PNS19970100. PMID 9483661.
- Robertson I, Ford JA, McIntosh WB, Dunnigan MG (1981). "The role of cereals in the aetiology of nutritional rickets: the lesson of the Irish National Nutrition Survey 1943–8". The British journal of nutrition 45 (1): 17–22. doi:10.1079/BJN19810073. PMID 6970590.
- Clements MR (1989). "The problem of rickets in UK Asians". Journal of Human Nutrition and Dietetics 2 (2): 105. doi:10.1111/j.1365-277X.1989.tb00015.x.
- Pettifor JM (2004). "Nutritional rickets: deficiency of vitamin D, calcium, or both?". The American Journal of Clinical Nutrition 80 (6 Suppl): 1725S–9S. PMID 15585795.
- Dunnigan MG, Henderson JB, Hole DJ, Mawer EB, Berry JL (2007). "Meat consumption reduces the risk of nutritional rickets and osteomalacia". British Journal of Nutrition 94 (6): 983–91. doi:10.1079/BJN20051558. PMID 16351777.
- "US National Institutes Of Health, National Cancer Institute". Science.education.nih.gov. Retrieved 2010-08-24.
- Weick MT (1967). "A history of rickets in the United States". The American Journal of Clinical Nutrition 20 (11): 1234–41. PMID 4862158.
- Garrison RH, Somer E (1997). The Nutrition Desk Reference. McGraw-Hill. ISBN 978-0-87983-826-3.
- DuPuis EM (2002). Nature's Perfect Food: How Milk Became America's Drink. ISBN 978-0-8147-1938-1.
- Teegarden D, Lyle RM, Proulx WR, Johnston CC, Weaver CM (1999). "Previous milk consumption is associated with greater bone density in young women". The American Journal of Clinical Nutrition 69 (5): 1014–7. PMID 10232644.
- Holick MF (2004). "Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease". The American Journal of Clinical Nutrition 80 (6 Suppl): 1678S–88S. PMID 15585788.
- Insel PM, Turner ER, Ross D (2006). Discovering nutrition (2nd ed.). Boston: Jones and Bartlett Publishers. ISBN 0-7637-3555-8.
- Holick MF (2003). "Vitamin D: A millenium perspective". Journal of Cellular Biochemistry 88 (2): 296–307. doi:10.1002/jcb.10338. PMID 12520530.
- Stewart B. Leavitt. "Vitamin D – A Neglected 'Analgesic' for Chronic Musculoskeletal Pain". Pain-Topics.org. Retrieved 2009-03-25.
- Straube S, Andrew Moore R, Derry S, McQuay HJ (2009). "Vitamin D and chronic pain". Pain 141 (1–2): 10–3. doi:10.1016/j.pain.2008.11.010. PMID 19084336.
- Azmina Govindji RD (1 July 2010). "When it's sunny, top up your vitamin D". TheIsmaili.org. Retrieved 2010-07-01.
- Ford L, Graham V, Wall A, Berg J (November 2006). "Vitamin D concentrations in an UK inner-city multicultural outpatient population". Annals of Clinical Biochemistry 43 (6): 468–73. doi:10.1258/000456306778904614. PMID 17132277.
- Signorello LB, Williams SM, Zheng W, Smith JR, Long J, Cai Q, Hargreaves MK, Hollis BW, Blot WJ (2010). "Blood vitamin D levels in relation to genetic estimation of African ancestry". Cancer Epidemiology, Biomarkers & Prevention 19 (9): 2325–31. doi:10.1158/1055-9965.EPI-10-0482. PMC 2938736. PMID 20647395.
- Aloia JF, Chen DG, Chen H (2010). "The 25(OH)D/PTH Threshold in Black Women". The Journal of Clinical Endocrinology and Metabolism 95 (11): 5069–73. doi:10.1210/jc.2010-0610. PMC 2968726. PMID 20685862.
- Wang TJ, Zhang F, Richards JB, Kestenbaum B, Van Meurs JB, Berry D, Kiel DP, Streeten EA, Ohlsson C (2010). "Common genetic determinants of vitamin D insufficiency: a genome-wide association study". Lancet 376 (9736): 180–8. doi:10.1016/S0140-6736(10)60588-0. PMC 3086761. PMID 20541252.
- Bouillon R (2010). "Genetic and environmental determinants of vitamin D status". Lancet 376 (9736): 148–9. doi:10.1016/S0140-6736(10)60635-6. PMID 20541253.
- Harinarayan CV, Joshi SR (2009). "Vitamin D status in India—its implications and remedial measures". The Journal of the Association of Physicians of India 57: 40–8. PMID 19753759.
- Lips P (2010). "Worldwide status of vitamin D nutrition". The Journal of Steroid Biochemistry and Molecular Biology 121 (1–2): 297–300. doi:10.1016/j.jsbmb.2010.02.021. PMID 20197091.
- CBC "Dark-skinned immigrants urged to take vitamin D". February 16, 2010. CBC News.[unreliable medical source?]
- Stephen Strauss."The vitamin D debate"[dead link]. February 13, 2008.CBC News.[unreliable medical source?]
- Vitamin D at Merck Manual of Diagnosis and Therapy Professional Edition
- Vieth R (May 1999). "Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety". The American Journal of Clinical Nutrition 69 (5): 842–56. PMID 10232622.
- Tolerable Upper Intake Limits for Vitamins And Minerals (PDF). European Food Safety Authority. December 2006. ISBN 92-9199-014-0.
- DeLancey S (2010-06-15). "FDA Cautions on Accurate Vitamin D Supplementation for Infants". Press Announcement. U.S. Food and Drug Administration.
- Holick MF (March 1995). "Environmental factors that influence the cutaneous production of vitamin D" (PDF). The American Journal of Clinical Nutrition 61 (3 Suppl): 638S–645S. PMID 7879731.
- Tseng L, Brehm, JM, Alcorn, JF, Holguín, F, Aujla, SJ, Celedón, JC (2003). "Controversies in Vitamin D Supplementation". Nutrition Bytes 9 (1).
- Dorland's Illustrated Medical Dictionary, under Vitamin (Table of Vitamins)
- History of Vitamin D University of California, Riverside, Vitamin D Workshop.
- About Vitamin D Including Sections: History, Nutrition, Chemistry, Biochemistry, and Diseases. University of California Riverside
- Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society (2011). "Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline". J Clin Endocrinol Metab 96 (7): 1911–30. doi:10.1210/jc.2011-0385. PMID 21646368.
- Houghton LA, Vieth R (October 2006). "The case against ergocalciferol (vitamin D2) as a vitamin supplement" (PDF). The American Journal of Clinical Nutrition 84 (4): 694–7. PMID 17023693.
- Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, Ameri A, Tannenbaum AD (March 2008). "Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D". J. Clin. Endocrinol. Metab. 93 (3): 677–81. doi:10.1210/jc.2007-2308. PMC 2266966. PMID 18089691.
- Holick MF (March 2004). "Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis". The American Journal of Clinical Nutrition 79 (3): 362–71. PMID 14985208.
- Holick MF (2011). The Vitamin D Solution: A 3-Step Strategy to Cure Our Most Common Health Problems. New York: Plume. p. 27. ISBN 0-452-29688-9.
- Crissey SD, Ange KD, Jacobsen KL, Slifka KA, Bowen PE, Stacewicz-Sapuntzakis M, Langman CB, Sadler W, Kahn S (2003). "Serum concentrations of lipids, vitamin D metabolites, retinol, retinyl esters, tocopherols and selected carotenoids in twelve captive wild felid species at four zoos". The Journal of nutrition 133 (1): 160–6. PMID 12514284.
- Hume EM, Lucas NS, Smith HH (1927). "On the Absorption of vitamin D from the Skin". Biochemical Journal 21 (2): 362–367. PMC 1251921. PMID 16743844.
- C. Claiborne Ray (2005-05-17). "Sunshine Vitamin D". The New York Times. Retrieved 2013-03-08.
- Bolton J. "UV FAQs". Info. International Ultraviolet Association.
- Yahav S, Buffenstein R (1993). "Cholecalciferol supplementation alters gut function and improves digestibility in an underground inhabitant, the naked mole rat (Heterocephalus glaber), when fed on a carrot diet". The British journal of nutrition 69 (1): 233–41. doi:10.1079/BJN19930025. PMID 8384476.
- Stout SD, Agarwal SC (2003). Bone loss and osteoporosis: an anthropological perspective. New York: Kluwer Academic/Plenum Publishers. ISBN 0-306-47767-X.
- Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium (2011). "8, Implications and Special Concerns". In Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary Reference Intakes for Calcium and Vitamin D. Washington DC: National Academies Press. ISBN 0-309-16394-3. PMID 21796828.
- Walter F., PhD. Boron (2003). "The Parathyroid Glands and Vitamin F". Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1094. ISBN 978-1-4160-2328-9.
- Adams JS, Hewison M (2010). "Update in Vitamin D". Journal of Clinical Endocrinology & Metabolism 95 (2): 471–8. doi:10.1210/jc.2009-1773. PMC 2840860. PMID 20133466.
- Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (May 2004). "Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase". Proc Natl Acad Sci U S A 101 (20): 7711–7715. Bibcode:2004PNAS..101.7711C. doi:10.1073/pnas.0402490101. PMC 419671. PMID 15128933.
- Laing CJ, Cooke NE (2004). "Section I: Ch. 8: Vitamin D Binding Protein". In Feldman D, Glorieux FH, Pike JW. Vitamin D 1 (2 ed.). Academic Press. pp. 117–134. ISBN 0122526872.
- Bouillon R, Van Cromphaut S, Carmeliet G (2003). "Intestinal calcium absorption: Molecular vitamin D mediated mechanisms". Journal of Cellular Biochemistry 88 (2): 332–9. doi:10.1002/jcb.10360. PMID 12520535.
- Bell TD, Demay MB, Burnett-Bowie SAM (April 2010). "The biology and pathology of vitamin D control in bone". Journal of Cellular Biochemistry 111 (1): 7–13. doi:10.1002/jcb.22661. PMID 20506379.
- American Academy of Periodontology 2010 In-Service Exam, question A-27
- Vitamin D[dead link] The Physicians Desk Reference. 2006 Thompson Healthcare.
- Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK (February 1996). "Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells". Molecular Brain Research 36 (1): 193–6. doi:10.1016/0169-328X(95)00314-I. PMID 9011759.
- Sarkar FH, Li Y, Wang Z, Kong D (2010). "The role of nutraceuticals in the regulation of Wnt and Hedgehog signaling in cancer". Cancer Metastasis Reviews 29 (3): 383–64. doi:10.1007/s10555-010-9233-4. PMC 2974632. PMID 20711635.
- "Hedgehog signaling and Vitamin D". Medscape.com. 2009-12-18. Retrieved 2010-03-25.
- "Age-old children's disease back in force". Thestar.com. 2007-07-25. Retrieved 2010-08-24.
- Elena Conis (2006-07-24). "Fortified foods took out rickets". Los Angeles Times. Retrieved 2010-08-24.
- McClean FC, Budy AM (28 January 1964). "Vitamin A, Vitamin D, Cartilage, Bones, and Teeth". Vitamins and Hormones 21. Academic Press. pp. 51–52. ISBN 978-0-12-709821-0.
- "Unraveling The Enigma Of Vitamin D" United States National Academy of Sciences
- "Adolf Windaus – Biography". Nobelprize.org. 2010-03-25. Retrieved 2010-03-25.
- Rosenheim O, King H (1932). "The Ring-system of sterols and bile acids. Part II". J. Chem. Technol. Biotechnol. 51 (47): 954–7. doi:10.1002/jctb.5000514702.
- Askew FA, Bourdillon RB, Bruce HM, Callow RK, St. L. Philpot J, and Webster TA (1932). "Crystalline Vitamin D". Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character 109 (764): 488–506. doi:10.1098/rspb.1932.0008. JSTOR 81571.
- Hirsch AL (2011). "Industrial aspects of vitamin D". In Feldman DJ, Pike JW, Adams JS. Vitamin D. London; Waltham, MA: Academic Press. p. 73. ISBN 978-0-12-387035-3.
- Ziedonis AA, Mowery DC, Nelson RR, Bhaven NS (2004). Ivory tower and industrial innovation: university-industry technology transfer before and after the Bayh-Dole Act in the United States. Stanford, Calif: Stanford Business Books. pp. 39–40. ISBN 0-8047-4920-5.
- Marshall J (2005). Elbridge A. Stuart Founder of the Carnation Company. Kessinger Publishing. p. 235. ISBN 978-1-4179-8883-9.
- "25-hydroxy vitamin D test". MedlinePlus Medical Encyclopedia. U.S. National Library of Medicine.
- Holick MF, Deluca HF, Avioli LV (1972). "Isolation and identification of 25-hydroxycholecalciferol from human plasma". Archives of Internal Medicine 129 (1): 56–61. doi:10.1001/archinte.1972.00320010060005. PMID 4332591.
- Glerup H, Mikkelsen K, Poulsen L, Hass E, Overbeck S, Thomsen J, Charles P, Eriksen EF (February 2000). "Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited". J. Intern. Med. 247 (2): 260–8. doi:10.1046/j.1365-2796.2000.00595.x. PMID 10692090.
- "Dietary Reference Intakes Tables [Health Canada, 2005]". Retrieved 21 July 2011.
- Salleh, A. (12 June 2012). "Vitamin D food fortification on the table". Australian Broadcasting Corporation.
- "Nutrient reference values for Australia and New Zealand" (PDF). National Health and Medical Research Council. 2005-09-09. Retrieved 2010-12-11.
- "Vitamin D and Calcium: Updated Dietary Reference Intakes". Nutrition and Healthy Eating. Health Canada. Retrieved 2012-06-13.
- "Vitamins: what they do and where to find them (EUFIC)". European Food Information Council. 10-12-2010. Retrieved 2010-12-11. "Vitamin D"
- Pérez-López FR, Brincat M, Erel CT, Tremollieres F, Gambacciani M, Lambrinoudaki I, Moen MH, Schenck-Gustafsson K, Vujovic S, Rozenberg S, Rees M (January 2012). "EMAS position statement: Vitamin D and postmenopausal health". Maturitas 71 (1): 83–8. doi:10.1016/j.maturitas.2011.11.002. PMID 22100145.
- "All under-fives should take vitamin D pills to avoid rickets, says Government's health chief". Daily Mail. 27 January 2011.
- Heaney RP, Holick MF (2011). "Perspective: Why the IOM Recommendations for Vitamin D are Deficient". Journal of Bone and Mineral Research 26 (3): 455–7. doi:10.1002/jbmr.328. PMID 21337617.
- EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) (2012). "Scientific Opinion on the Tolerable Upper Intake Level of vitamin D". EFSA Journal 10 (7): 2813. doi:10.2903/j.efsa.2012.2813.
- Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD (November 2012). "Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies". Circ Cardiovasc Qual Outcomes 5 (6): 819–29. doi:10.1161/CIRCOUTCOMES.112.967604. PMC 3510675. PMID 23149428.
- European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA) (2010). "Scientific opinion on the substantiation of health claims related to vitamin D and normal function of the immune system and inflammatory response (ID 154, 159), maintenance of normal muscle function (ID 155) and maintenance of normal cardiovascular function (ID 159) pursuant to Article 13(1) of Regulation (EC) No 1924/2006". EFSA Journal 8 (2): 1468–85. doi:10.2903/j.efsa.2010.1468.
- European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA) (2011). "Scientific opinion on the substantiation of a health claim related to vitamin D and risk of falling pursuant to Article 14 of Regulation (EC) No 1924/2006". EFSA Journal 9 (9): 2382–2400. doi:10.2903/j.efsa.2011.2382.
- "Guidance for Industry: Food Labeling: Health Claims; Calcium and Osteoporosis, and Calcium, Vitamin D, and Osteoporosis". US Food and Drug Administration. 2009-05-01.
- "Health Canada Scientific Summary on the U. S. Health Claim Regarding Calcium and Osteoporosis". Bureau of Nutritional Sciences Food Directorate, Health Products and Food Branch Health Canada. 2000-05-01.
- "Regulatory Systems of Health Claims in Japan". Japan Consumer Affairs Agency, Food Labelling Division. 2011-06-01.
- "Vitamin D". Nutrient Reference Values for Australia and New Zealand. Australian Ministry of Health. 2005-09-09.
- "USDA nutrient database". National Nutrient Database for Standard Reference. U.S. Agricultural Research Service, Nutrient Data Laboratory. "use the keyword 'portabella' and then click submit"
- "Access". Medscape. Retrieved 2012-06-13.
- Urbain P, Singler F, Ihorst G, Biesalski HK, Bertz H (August 2011). "Bioavailability of vitamin D₂ from UV-B-irradiated button mushrooms in healthy adults deficient in serum 25-hydroxyvitamin D: a randomized controlled trial". Eur J Clin Nutr 65 (8): 965–71. doi:10.1038/ejcn.2011.53. PMID 21540874.
- Hohman EE, Martin BR, Lachcik PJ, Gordon DT, Fleet JC, Weaver CM (March 2011). "Bioavailability and efficacy of vitamin D2 from UV-irradiated yeast in growing, vitamin D-deficient rats". J. Agric. Food Chem. 59 (6): 2341–6. doi:10.1021/jf104679c. PMC 3235799. PMID 21332187.
- Koyyalamudi SR, Jeong SC, Song CH, Cho KY, Pang G (2009). "Vitamin D2 formation and bioavailability from Agaricus bisporus button mushrooms treated with ultraviolet irradiation". J Agric Food Chem 57 (8): 3351–5. doi:10.1021/jf803908q. PMID 19281276.
- Using Fresh Mushrooms as a Source of Vitamin D. "Using Fresh Mushrooms as a Source of Vitamin D / Nutrition / Healthy Eating". Fitday.com. Retrieved 2012-06-13.
- "Bringing Mushrooms Out of the Dark". MSNBC. April 18, 2006. Retrieved 2007-08-06.
- Duke J. "Dr. Duke's Phytochemical and Ethnobotanical Databases". U.S. Agricultural Research Service.
- DRI, Dietary reference intakes: for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, D.C: National Academy Press. 1997. p. 250. ISBN 0-309-06350-7.
- Wang T, Bengtsson G, Kärnefelt I, Björn LO (September 2001). "Provitamins and vitamins D₂and D₃in Cladina spp. over a latitudinal gradient: possible correlation with UV levels". J. Photochem. Photobiol. B, Biol. 62 (1–2): 118–22. doi:10.1016/S1011-1344(01)00160-9. PMID 11693362.
- Holick MF, Brehm, JM, Alcorn, JF, Holguín, F, Aujla, SJ, Celedón, JC (2005). "The Vitamin D Epidemic and its Health Consequences". Journal of Nutrition 135 (11): 2739S–48S. PMID 16251641.
- Rubin, A.L. (2011). Vitamin D for Dummies. Wiley Publishing. ISBN 978-0-470-89175-9
- Dietary Supplement Fact Sheet: Vitamin D from the U.S. National Institutes of Health
- Disagreement among experts about the correct vitamin D dose. (Nature News, July 6, 2011)
- Vitamin D: analyte monograph; The Association for Clinical Biochemistry and Laboratory Medicine
- Vitamin D from Mayo Foundation for Medical Education and Research
- Calcitriol Drug monograph from West-ward Pharmaceutical Corp
- Vitamin D in children from Royal National Orthopaedic Hospital Trust
- Vitamin D at Lab Tests Online