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Vitamin D is a group of fat-soluble
secosteroid 250px, The parent steroid skeleton. The B-ring of the parent steroid is broken between C9 and C10 to yield D vitamins. A secosteroid () is a type of steroid , hypothetical a steroid with 32 carbon atoms. Its core ring system (ABCD), composed o ...
s responsible for increasing intestinal absorption of
calcium Calcium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical elem ...

calcium
,
magnesium Magnesium is a chemical element upright=1.0, 500px, The chemical elements ordered by link=Periodic table In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science ...

magnesium
, and
phosphate In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo durin ...

phosphate
, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (also known as
cholecalciferol Cholecalciferol, also known as vitamin D3 and colecalciferol, is a type of vitamin D which is made by the skin when exposed to sunlight; it is also found in some foods and can be taken as a dietary supplement. Cholecalciferol is made in the sk ...

cholecalciferol
) and vitamin D2 (
ergocalciferol Ergocalciferol, also known as vitamin D2 and nonspecifically calciferol, is a type of vitamin D found in food and used as a dietary supplement. As a supplement it is used to prevent and treat vitamin D deficiency. This includes vitamin D deficie ...

ergocalciferol
). The major natural source of the vitamin is
synthesis Synthesis or synthesize may also refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors **Organic synthesis, the chemical synthesis of or ...
of cholecalciferol in the of the skin through a chemical reaction that is dependent on sun exposure (specifically
UVB radiation Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation is p ...

UVB radiation
). Cholecalciferol and ergocalciferol can be ingested from the diet and from 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 D. Dietary recommendations typically assume that all of a person's vitamin D is taken by mouth, as 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 Skin cancers are cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible Cancer s ...

skin cancer
risk. Vitamin D from the diet, or from skin synthesis, is biologically inactive. It is activated by two protein enzyme
hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemistry, chemical process that introduces a hydroxyl group (-OH) into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH ...
steps, the first in the liver and the second in the kidneys. As vitamin D can be synthesized in adequate amounts by most mammals if exposed to sufficient sunlight, it is not essential, so technically not a
vitamin A vitamin is an organic molecule , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, ...
. Instead it can be considered a
hormone A hormone (from the Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. Its population is approximately 10.7 m ...

hormone
, with activation of the vitamin D pro-hormone resulting in the active form,
calcitriol Calcitriol is the active form of vitamin D Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, t ...

calcitriol
, which then produces effects via a
nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing Steroid hormone, steroid and Thyroid hormone, thyroid hormones and certain other molecules. In response, these recep ...
in multiple locations. Cholecalciferol is converted in the liver to
calcifediol Calcifediol, also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D3 (abbreviated 25(OH)D3), is a form of vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of ca ...
(25-hydroxycholecalciferol);
ergocalciferol Ergocalciferol, also known as vitamin D2 and nonspecifically calciferol, is a type of vitamin D found in food and used as a dietary supplement. As a supplement it is used to prevent and treat vitamin D deficiency. This includes vitamin D deficie ...

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 Calcitriol is the active form of vitamin D Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, t ...

calcitriol
(also known as 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 Calcium is a chemical element In chemistry, an element is a pure Chemical substance, substance consisting only of atoms that all have the same numbers of protons in their atomic nucleus, nuclei. Unlike chemical compounds, chemical elem ...

calcium
and
phosphate In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo durin ...

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 Calcium metabolism is the movement and regulation of calcium ions (Ca2+) ''in'' (via the gastrointestinal tract, gut) and ''out'' (via the gut and kidneys) of the body, and ''between'' body compartments: the blood plasma, the extracellular fluid, ex ...
and metabolism. Its discovery was due to effort to find the dietary substance lacking in children with
rickets Rickets is a condition that results in weak or soft bones in children. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications may include bone fractures, muscle spasms, or an scoliosis, abnorm ...

rickets
(the childhood form of
osteomalacia Osteomalacia is a disease characterized by the softening of the bone A bone is a Stiffness, rigid tissue (anatomy), tissue that constitutes part of the vertebrate skeleton in animals. Bones protect the various organs of the body, produce red b ...
). 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, and another concluding no clear justification exists for recommending supplementation for preventing certain diseases, and that further research of similar design is not needed in these areas.


Types

Several forms (
vitamer Vitamins A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient which an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμ ...
s) 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 A chemical structure determination includes a chemist A chemist (from Greek ''chēm(ía)'' alchemy; replacing ''chymist'' from Medieval Latin ''alchemist'') is a scientist A scientist is a person who conducts Scientific method, scientific re ...
of vitamin D3 was defined and shown to result from the
ultraviolet irradiation Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation is p ...

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 Image:Trimethyl steroid-nomenclature.svg, 250px, The parent steroid skeleton. The B-ring of the parent steroid is broken between C9 and C10 to yield D vitamins. A secosteroid () is a type of steroid with a "broken" ring. The word ''secosteroid ''de ...
, that is,
steroid A steroid is a biologically active organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the prope ...

steroid
s 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 In organic chemistry Organic chemistry is a branch of chemistry that studies the structure, properties and reactions of organic compounds, which contain carbon in covalent bonding.Clayden, J.; Greeves, N. and Warren, S. (2012) ''Organic Chemis ...
, which contains a
double bond In chemistry, a double bond is a between two s involving four s as opposed to two in a . Double bonds occur most commonly between two carbon atoms, for example in s. Many double bonds exist between two different elements: for example, in a group ...

double bond
, between carbons 22 and 23, and a
methyl group A methyl group is an alkyl derived from methane, containing one carbon atom chemical bond, bonded to three hydrogen atoms — CH3. In chemical formula, formulas, the group is often skeletal formula#Pseudoelement symbols, abbreviated ...

methyl group
on carbon 24 in vitamin D2. Many
vitamin D analogues The active natural hormonal form of vitamin D Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, ...
have been synthesized.


Biology

The active vitamin D metabolite calcitriol mediates its biological effects by binding to the
vitamin D receptor The vitamin D receptor (VDR also known as the calcitriol receptor) is a member of the nuclear receptor of a heterodimer of the nuclear receptors PPAR-γ (green) and Retinoid X receptor alpha, RXR-α (cyan) bound to double stranded DNA (magenta) ...
(VDR), which is principally located in the
nuclei ''Nucleus'' (plural nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA ...

nuclei
of target cells. The binding of calcitriol to the VDR allows the VDR to act as a
transcription factor In molecular biology Molecular biology is the branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, m ...
that modulates the
gene expression Gene expression is the process by which information from a gene In biology, a gene (from ''genos'' "...Wilhelm Johannsen coined the word gene to describe the Mendelian_inheritance#History, Mendelian units of heredity..." (Greek language, ...

gene expression
of transport proteins (such as
TRPV6 TRPV6 is a membrane calcium channel, calcium (Ca2+) channel protein which is particularly involved in the first step in calcium metabolism#Effector organs, Ca2+absorption in the intestine. Classification Transient Receptor Potential Vanilloid su ...
and
calbindin Calbindins are three different calcium-binding proteins: calbindin, calretinin and S100G. They were originally described as vitamin D-dependent calcium-binding proteins in the intestine and kidney in the chick and mammals. They are now classifi ...
), which are involved in calcium absorption in the intestine. The vitamin D receptor belongs to the
nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing Steroid hormone, steroid and Thyroid hormone, thyroid hormones and certain other molecules. In response, these recep ...
superfamily of steroid/thyroid hormone receptors, and VDRs are expressed by cells in most
organs An organ is a group of tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's tissues can be broadly categorized as parenchyma Parenchyma () is the bulk of functional ...
, including the
brain A brain is an organ Organ may refer to: Biology * Organ (anatomy) An organ is a group of Tissue (biology), tissues with similar functions. Plant life and animal life rely on many organs that co-exist in organ systems. A given organ's tiss ...

brain
,
heart The heart is a cardiac muscle, muscular Organ (biology), organ in most animals, which pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste ...

heart
, skin,
gonads A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes A gamete ( /ˈɡæmiːt/; from Ancient Greek Ancient Greek includes the forms of the Greek language used in ancient Greece and the classical antiqu ...
,
prostate The prostate is both an accessory gland of the male reproductive system The male reproductive system consists of a number of sex organs that play a role in the process of human reproduction. These organs are located on the outside of the bod ...

prostate
, and
breast The breast is one of two prominences located on the upper ventral Standard anatomical terms of location deal unambiguously with the of s, including s. Terms used generally derive from or roots and used to describe something in its . Th ...

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 Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine. PTH influences bone rem ...
and
calcitonin Calcitonin is a 32 amino acid peptide hormonePeptide hormones or protein hormones are hormones whose molecules are peptides or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on ...

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 Bone resorption is resorption Resorption is the absorption into the circulatory system of cells or tissue, usually by osteoclast, osteoclasts. Types of resorption include: * Bone resorption * Herniated Disc Resorption * Tooth resorption * Fetal re ...
by increasing
osteoclast An osteoclast () is a type of bone cell An osteocyte, an oblate shaped type of bone A bone is a Stiffness, rigid tissue (anatomy), tissue that constitutes part of the skeleton in most vertebrate animals. Bones protect the various organs of the ...

osteoclast
number, maintaining calcium and phosphate levels for
bone formation 300 px, Bone is broken down by osteoclasts, and rebuilt by osteoblasts, both of which communicate through cytokine ( IGF) signalling.">Insulin-like_growth_factor.html" ;"title="TGF-β, Insulin-like growth factor">IGF) signalling. Ossification ( ...
, and allowing proper functioning of parathyroid hormone to maintain serum calcium levels.
Vitamin D deficiency Vitamin D deficiency, or hypovitaminosis D is defined as a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate sunlight exposure (in particular sunlight with adequate ultraviolet B rays (UVB)). Vita ...
can result in lower
bone mineral density A scanner used to measure bone density using dual energy X-ray absorptiometry Bone density, or bone mineral density (BMD), is the amount of bone mineral in bone tissue A bone is a Stiffness, rigid tissue (anatomy), tissue that constitutes pa ...
and an increased risk of reduced bone density (
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone massImage:Bone density scanner.jpg, A scanner used to measure bone density using dual energy X-ray absorptiometry Bone density, or bone mineral density (BMD), is the amount ...
) or
bone fracture A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of the bone. In more severe cases, the bone may be broken into several pieces. A bone fracture may be the r ...
because a lack of vitamin D alters mineral metabolism in the body. Thus, vitamin D is also critical for
bone remodeling Bone remodeling (or bone metabolism) is a lifelong process where mature bone tissue A bone is a rigid tissue Tissue may refer to: Biology * Tissue (biology), an ensemble of similar cells that together carry out a specific function * ''Trip ...
through its role as a potent stimulator of
bone resorption Bone resorption is resorption Resorption is the absorption into the circulatory system of cells or tissue, usually by osteoclast, osteoclasts. Types of resorption include: * Bone resorption * Herniated Disc Resorption * Tooth resorption * Fetal re ...
. The VDR regulates
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential growth, exponential increase in cell number and is therefore a rapid mechanism of tissue growth. C ...

cell proliferation
and
differentiation Differentiation may refer to: Business * Differentiation (economics), the process of making a product different from other similar products * Product differentiation, in marketing * Differentiated service, a service that varies with the identity o ...
. Vitamin D also affects the immune system, and VDRs are expressed in several
white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the cells of the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ...
s, including
monocyte Monocytes are a type of ''leukocyte'', or white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the cells of the immune system The immune system is a network of biological processes that protects an organi ...

monocyte
s and activated T and
B cell #REDIRECT B cell 3D rendering of a B cell B cells, also known as B lymphocytes, are a type of white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the cells of the immune system The immune system is a ne ...
s. In vitro, vitamin D increases expression of the
tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (c ...
gene in
adrenal The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex wh ...

adrenal
medulla Medulla or Medullary may refer to: Science * Medulla oblongata The medulla oblongata or simply medulla is a long stem-like structure which makes up the lower part of the brainstem. It is anterior and partially inferior to the cerebellum. It is ...
ry cells, and affects the synthesis of
neurotrophic factor Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and cell differentiation, differentiation of both developing and mature neurons. Most NT ...
s,
nitric oxide synthase Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide Nitric oxide ( nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitr ...
, and
glutathione Glutathione (GSH) is an antioxidant Antioxidants are that inhibit , a that can produce and s that may damage the of organisms. Antioxidants such as s or (vitamin C) may act to inhibit these reactions. To balance , plants and animals ma ...

glutathione
. Vitamin D receptor expression decreases with age and findings suggest that vitamin D is directly related to muscle strength, mass and function, all being important factors to an athlete's performance.


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 Rickets is a condition that results in weak or soft bones in children. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications may include bone fractures, muscle spasms, or an scoliosis, abnorm ...

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 Osteomalacia is a disease characterized by the softening of the bone A bone is a Stiffness, rigid tissue (anatomy), tissue that constitutes part of the vertebrate skeleton in animals. Bones protect the various organs of the body, produce red b ...
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 Rickets is a condition that results in weak or soft bones in children. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications may include bone fractures, muscle spasms, or an scoliosis, abnorm ...

Rickets
, a childhood disease, is characterized by impeded growth and soft, weak, deformed
long bones The long bones are those that are longer than they are wide. They are one of five types of bone A bone is a Stiffness, rigid tissue (anatomy), tissue that constitutes part of the vertebrate skeleton in animals. Bones protect the various organs ...
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; 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. Maternal
vitamin D deficiency Vitamin D deficiency, or hypovitaminosis D is defined as a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate sunlight exposure (in particular sunlight with adequate ultraviolet B rays (UVB)). Vita ...
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 , outbreaks have happened 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 A cereal is any grass Poaceae () or Gramineae () is a large and nearly ubiquitous family of monocotyledonous flowering plants known as grasses. It includes the cereal grasses, bamboo Bamboos are a diverse group of evergreen perenn ...

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 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 Denver () is a consolidated city and county, the capital Capital most commonly refers to: * Capital letter Letter case (or just case) is the distinction between the letters that are in larger uppercase or capitals (or more forma ...

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 Osteomalacia is a disease characterized by the softening of the bone A bone is a Stiffness, rigid tissue (anatomy), tissue that constitutes part of the vertebrate skeleton in animals. Bones protect the various organs of the body, produce red b ...
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 Standard anatomical terms of location deal unambiguously with the anatomy of animals, including humans. Terms used generally derive from Latin or Greek language, Greek roots and used to describe something in its standard anatomical position. This ...
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 The human musculoskeletal system (also known as the human locomotor system, and previously the activity system) is an organ system An organ system is a biological system A biological system is a complex biological network, network which conne ...
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain The International Association for the Study of Pain (IASP) is an international learned society A learned societ ...
, there is no persuasive evidence of lower vitamin D levels in chronic pain sufferers or that supplementation alleviates chronic nonspecific musculoskeletal pain.
Osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone massImage:Bone density scanner.jpg, A scanner used to measure bone density using dual energy X-ray absorptiometry Bone density, or bone mineral density (BMD), is the amount ...
is a condition of reduced
bone mineral density A scanner used to measure bone density using dual energy X-ray absorptiometry Bone density, or bone mineral density (BMD), is the amount of bone mineral in bone tissue A bone is a Stiffness, rigid tissue (anatomy), tissue that constitutes pa ...
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.


Use of supplements

Supplementation with vitamin D is a reliable method for preventing or treating
rickets Rickets is a condition that results in weak or soft bones in children. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications may include bone fractures, muscle spasms, or an scoliosis, abnorm ...

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 A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow Hemodynamics American and British English spelling differences#ae and oe, or haemodynamics are the Fluid dynamics, dynamics of blood flow. The circulatory sy ...

myocardial infarction
,
stroke A stroke is a medical condition A disease is a particular abnormal condition that negatively affects the structure or function (biology), function of all or part of an organism, and that is not due to any immediate external injury. Di ...

stroke
or
cerebrovascular disease Cerebrovascular disease includes a variety of Medicine, medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often Angiopathy, damaged or deformed in ...
, cancer,
bone fractures A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of the bone. In more severe cases, the bone may be broken into several pieces. A bone fracture may be the re ...
or knee
osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease An arthropathy is a disease of a joint. Signs and symptoms Arthralgia, Joint pain is a common but non-specific sign of joint disease. Signs will depend on the specific disease, and may ...

osteoarthritis
. Low vitamin D levels may result from disease rather than cause disease. A United States
Institute of Medicine The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit A nonprofit organization (NPO), also known as a non-business entity, not-for-profit organization, or nonprofit inst ...
(IOM) report states: "Outcomes related to
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumor A benign tumor is a mass of cells Cell most often refers to: * Cell (biolo ...

cancer
,
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart The heart is a cardiac muscle, muscular Organ (biology), organ in most animals, which pumps blood through the blood vessels of the circulatory system. The pumped ...
and
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Long-Term Capital Management L.P. (LTCM) was a hedge fund''A financial History of the United States Volume II: 1970–2001'', Jerry W. Markham, Chapter 5: "Bank ...

hypertension
, and
diabetes Diabetes mellitus, commonly known as just diabetes, is a group of metabolic disorders characterized by a hyperglycemia, high blood sugar level over a prolonged period of time. Symptoms often include frequent urination, Polydipsia, increased th ...

diabetes
and metabolic syndrome, falls and physical performance, immune functioning and
autoimmune disorder An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. There are at least 80 types of autoimmune diseases. Nearly any body part can be involved. Common symptoms include low grade fever and fatigue ...
s, infections, neuropsychological functioning, and
preeclampsia Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term Disease, medical condition in which the blood pressure in the arter ...
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 Osteoporosis is a systemic skeletal disorder characterized by low bone massImage:Bone density scanner.jpg, A scanner used to measure bone density using dual energy X-ray absorptiometry Bone density, or bone mineral density (BMD), is the amount ...
. 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 A scanner used to measure bone density using dual energy X-ray absorptiometry Bone density, or bone mineral density (BMD), is the amount of bone mineral in bone tissue A bone is a Stiffness, rigid tissue (anatomy), tissue that constitutes pa ...
. 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 fracture A stress fracture is a fatigue-induced bone fracture caused by repeated stress over time. Instead of resulting from a single severe impact, stress fractures are the result of accumulated injury from repeated submaximal loading, such as running or ...
s 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. Because it found mounting evidence for a benefit to bone health, though it had not found good evidence of other benefits, the US
Food and Drug Administration The United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, st ...
(FDA) has required manufacturers to declare the amount of vitamin D on
nutrition facts label The nutrition facts label (also known as the nutrition information panel, and other slight variations) is a label required on most packaged food in many countries, showing what nutrients (to limit and get enough of) are in the food. Labels are usua ...
s, as "nutrients of public health significance", since May 2016. By a proposed deadline extension, some manufacturers had until July 1, 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 In fields such as epidemiology Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants In mathematics, the determinant is a Scalar (mathematics), scalar value that is a function (mathematics ...
have found reduced risk of cancer incidence related to vitamin D intake and 25(OH)D levels, particularly for
colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer Cancer is a group of diseases A disease is a particular abnormal condition that negatively affects the structure o ...
, although the strength of the associations was classified as weak. While
randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical tec ...
s have not confirmed that vitamin D supplements reduce the risk of cancer incidence, the relative risk of cancer deaths has been found to be reduced by up to 16% in several meta-analyses.


Cardiovascular disease

Taking vitamin D supplements does not meaningfully reduce the risk of
stroke A stroke is a medical condition A disease is a particular abnormal condition that negatively affects the structure or function (biology), function of all or part of an organism, and that is not due to any immediate external injury. Di ...

stroke
,
cerebrovascular disease Cerebrovascular disease includes a variety of Medicine, medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often Angiopathy, damaged or deformed in ...
,
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow Hemodynamics American and British English spelling differences#ae and oe, or haemodynamics are the Fluid dynamics, dynamics of blood flow. The circulatory sy ...

myocardial infarction
, or
ischemic heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), Ischemia, ischemic heart disease (IHD), or simply heart disease, involves the reduction of blood flow to the myocardium, heart muscle due to build-up of plaque (atherosclero ...
. Supplementation may have no effect on
blood pressure Blood pressure (BP) is the pressure Pressure (symbol: ''p'' or ''P'') is the force In physics Physics is the natural science that studies matter, its Elementary particle, fundamental constituents, its Motion (physics), motio ...

blood pressure
.


Immune system


Infectious diseases

In general, vitamin D functions to activate the
innate {{Short pages monitor