Vitamin D

Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol).

The major natural source of the vitamin is synthesis of cholecalciferol in the lower layers of epidermis of the skin through a chemical reaction that is dependent on sun exposure (specifically UVB radiation). Cholecalciferol and ergocalciferol can be ingested from the diet and supplements. Only a few foods, such as the flesh of fatty fish, naturally contain significant amounts of vitamin D. In the U.S. and other countries, cow's milk and plant-derived milk substitutes are fortified with vitamin D, as are many breakfast cereals. Mushrooms exposed to ultraviolet light contribute useful amounts of vitamin D₂. Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, because sun exposure in the population is variable and recommendations about the amount of sun exposure that is safe are uncertain in view of the skin cancer risk.

Vitamin D from the diet, or from skin synthesis, is biologically inactive. It is activated by two protein enzyme hydroxylation steps, the first in the liver and the second in the kidneys. Because vitamin D can be synthesized in adequate amounts by most mammals if they get enough sunlight, it is not essential and therefore is technically not a vitamin. Instead it can be considered a hormone, with activation of the vitamin D pro-hormone resulting in the active form, calcitriol, which then produces effects via a nuclear receptor in multiple locations.

Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol); ergocalciferol is converted to 25-hydroxyergocalciferol. These two vitamin D metabolites (called 25-hydroxyvitamin D or 25(OH)D) are measured in serum to determine a person's vitamin D status. Calcifediol is further hydroxylated by the kidneys and some of the immune system cells to form calcitriol (1,25-dihydroxycholecalciferol), the biologically active form of vitamin D. Calcitriol circulates as a hormone in the blood, having a major role regulating the concentration of calcium and phosphate, and promoting the healthy growth and remodeling of bone. Calcitriol also has other effects, including some on cell growth, neuromuscular and immune functions, and reduction of inflammation.

Vitamin D has a significant role in calcium homeostasis and metabolism. Its discovery was due to effort to find the dietary substance lacking in children with rickets (the childhood form of osteomalacia). Vitamin D supplements are given to treat or to prevent osteomalacia and rickets. The evidence for other health effects of vitamin D supplementation in vitamin D-replete individuals is inconsistent. The effect of vitamin D supplementation on mortality is not clear, with one meta-analysis finding a small decrease in mortality in elderly people. Except for the prevention of rickets and osteomalacia in high-risk groups, any benefit of vitamin D supplements to musculoskeletal or general health may be small.

Types

Several forms (vitamers) of vitamin D exist. 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, and is known collectively as calciferol.

Vitamin D₂ was chemically characterized in 1931. In 1935, the chemical structure of vitamin D₃ was defined and shown to result from the ultraviolet irradiation of 7-dehydrocholesterol. A chemical nomenclature for vitamin D forms was recommended in 1981, but alternative names remain in common use.

Chemically, the various forms of vitamin D are secosteroids, that is, steroids in which one of the bonds in the steroid rings is broken. The structural difference between vitamin D₂ and vitamin D₃ is in the side chain, which contains a double bond, between carbons 22 and 23, and a methyl group on carbon 24 in vitamin D₂.

Many vitamin D analogues have been synthesized.

Biology

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, vitamin D is also critical for bone remodeling through its role as a potent stimulator of bone resorption.

The VDR regulates 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. In vitro, vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells, and affects the synthesis of neurotrophic factors, nitric oxide synthase, and glutathione.

Vitamin D receptor expression decreases with age and findings suggest that vitamin D is directly related to muscle strength, mass and function.

Deficiency

An estimated one billion people worldwide are either vitamin D insufficient or deficient. Vitamin D deficiency is widespread in the European population. A diet with insufficient vitamin D in conjunction with inadequate sun exposure causes vitamin D deficiency. Severe vitamin D deficiency in children causes rickets, a softening and weakening of bones, which is a rare disease in the developed world.

Vitamin D deficiency is found worldwide in the elderly and remains common in children and adults. Deficiency results in impaired bone mineralization and bone damage which leads to bone-softening diseases, including rickets in children and osteomalacia in adults. Low blood calcifediol (25-hydroxy-vitamin D) can result from avoiding the sun. Being deficient in vitamin D can cause intestinal absorption of dietary calcium to fall to 15%. When not deficient, an individual usually absorbs between 60 and 80%.

Bone health

Rickets

Rickets, a childhood disease, is characterized by impeded growth and soft, weak, deformed long bones that bend and bow under their weight as children start to walk. Rickets typically appears between 3 and 18 months of age. Cases continue to be reported in North American and other Western Countries and is primarily seen in breastfed infants and those with darker skin complexions. This condition is characterized by bow legs, which can be caused by calcium or phosphorus deficiency, as well as a lack of vitamin D; in the 21st century, 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.

Maternal vitamin D deficiency may cause overt bone disease from before birth and impairment of bone quality after birth. 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 the UK, outbreaks have happened in some immigrant communities in which osteomalacia patients 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. 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 sun exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh, where rickets 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 about 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 and osteoporosis

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 10ng/mL. Although 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 or that supplementation alleviates chronic nonspecific musculoskeletal pain.

Osteoporosis is a condition of reduced bone mineral density with increased bone fragility and risk of bone fractures. Osteoporosis can be a long-term effect of calcium and/or vitamin D insufficiency, at least in part. This may result from inadequate calcium intake, with insufficient vitamin D contributing by reducing calcium absorption.

Skin pigmentation

Dark-skinned people living in temperate climates have been shown to have low vitamin D levels but the significance of this is not certain. Dark-skinned people are less efficient at making vitamin D because melanin in the skin hinders vitamin D synthesis. Vitamin D deficiency is common in Hispanic and African-Americans in the United States, with levels dropping significantly in the winter. This is due to the levels of melanin in the skin, as it acts as a natural protectant from sun exposure.

Other

There is some evidence that pathogenesis of uterine fibroids may be associated with vitamin D levels.

Use of supplements

Supplementation with vitamin D is a reliable method for preventing or treating rickets. The effects of vitamin D supplementation on non-skeletal health are uncertain. A 2013 review did not find any effect from supplementation on the rates of non-skeletal disease, other than a tentative decrease in mortality in the elderly. Vitamin D supplements do not alter the outcomes for myocardial infarction, stroke or cerebrovascular disease, cancer, bone fractures or knee osteoarthritis. Low vitamin D levels may result from disease rather than cause disease.

A United States Institute of Medicine (IOM) report states: "Outcomes related to cancer, cardiovascular disease and hypertension, and 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." 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.

Mortality, all-causes

Vitamin D₃ supplementation has been tentatively found to lead to a reduced risk of death in the elderly, but the effect has not been deemed pronounced, or certain enough, to make taking supplements recommendable. Other forms (vitamin D₂, alfacalcidol, and calcitriol) do not appear to have any beneficial effects with regard to the risk of death. High blood levels appear to be associated with a lower risk of death, but it is unclear if supplementation can result in this benefit. Both an excess and a deficiency in vitamin D appear to cause abnormal functioning and premature aging. The relationship between serum calcifediol concentrations and all-cause mortality is "U-shaped": mortality is elevated at high and low calcifediol levels, relative to moderate levels. Harm from vitamin D appears to occur at a lower vitamin D level in the black population than in the white population.

Bone health

In general, no good evidence supports the commonly held belief that vitamin D supplements can help prevent osteoporosis. Its general use for prevention of this disease in those without vitamin D deficiency is thus likely not needed. For older people with osteoporosis, taking vitamin D with calcium may help prevent hip fractures, but it also slightly increases the risk of stomach and kidney problems. A study found that supplementation with 800 IU or more daily, in those older than 65 years was "somewhat favorable in the prevention of hip fracture and non-vertebral fracture". The effect is small or none for people living independently. Low serum vitamin D levels have been associated with falls, and low bone mineral density. Taking extra vitamin D, however, does not appear to change the risk.

Athletes who are vitamin D deficient are at an increased risk of stress fractures and/or major breaks, particularly those engaging in contact sports. The greatest benefit with supplementation is seen in athletes who are deficient (25(OH)D serum levels <30ng/mL), or severely deficient (25(OH)D serum levels <25ng/mL). Incremental decreases in risks are observed with rising serum 25(OH)D concentrations plateauing at 50ng/mL with no additional benefits seen in levels beyond this point.

A 2020 Cochrane systematic review has found limited evidence that vitamin D plus calcium, but not independently can improve healing in children with nutritional rickets, but the evidence was not conclusive for reducing fractures.

The US Food and Drug Administration (FDA) has required manufacturers to declare the amount of vitamin D on nutrition facts labels, as "nutrients of public health significance", since May 2016. By a proposed deadline extension, some manufacturers had until 1 July 2021, to comply.

Cancer

Potential associations have been found between low vitamin D levels and the risk of developing several types of cancer. Meta-analyses of observational studies have found reduced risk of cancer incidence related to vitamin D intake and 25(OH)D levels, particularly for colorectal cancer, although the strength of the associations was classified as weak. While randomized controlled trials have not confirmed that vitamin D supplements reduce the risk of cancer incidence, the relative risk of cancer deaths was lower by up to 16% in several meta-analyses.

Cardiovascular disease

Vitamin D supplementation is not associated with a reduced risk of stroke, cerebrovascular disease, myocardial infarction, or ischemic heart disease. Supplementation does not lower blood pressure in the general population.

Immune system

Infectious diseases

In general, vitamin D functions to activate the innate