Vitamin D, the “sunshine vitamin,” is actually a hormone produced from sterols in the body by the action of ultraviolet light on the skin; individuals who receive modest exposures to sunlight are able to produce their own vitamin D. However, this is not the case for many people, such as those who live in northern latitudes, spend most of their days indoors, and/or have darker skin. Such individuals must obtain the nutrient from their diets; for them, vitamin D is a vitamin in the traditional sense. Vitamin D plays an important role, along with the essential minerals calcium, phosphorus, and magnesium, in the maintenance of healthy bones and teeth –an estimated 40–90% of adults worldwide are of insufficient vitamin D status. The prevalence of low vitamin D status has been estimated at 40% of adults in the United Kingdom. Rickets, the deforming and debilitating disease involving delayed or failed mineralization at the growth plates of the long bones, remains a problem in many countries, having been reported at prevalences as great as 10% among infants exclusively fed breast milk and children with little sun exposure.
Metabolic bone diseases target women, who are more susceptible to osteoporosis (i.e., the loss of bone leading to increased bone fragility) than are men. Starting during the fourth or fifth decade of life, both men and women lose bone mass at similar annual rates; however, after the onset of menopause, the rate of bone loss in women can increase as much as 10-fold owing to diminished production of estrogen, which is required along with vitamin D to maintain bone mineralization. Vitamin D status affects more than bone. The vitamin also functions in the regulation of cellular development and differentiation of most cells, in the regulation of the parathyroid gland and immune system function, in the skin, in cancer prevention, and in the metabolism of foreign compounds.
More than 2,000 analogs have been developed for use in treating disorders of vitamin D metabolism. The goal of such efforts has been to develop drugs active in the vitamin D-dependent functions in regulating cell proliferation and growth while also having low calcemic potential, thus avoiding the adverse effects of high levels of vitamin D in causing calcinosis. Vitamin D-active analogues include pro-drugs activated metabolically, typically by the same cytochrome P-450-based enzymes used to activate vitamin D.
Like other sterols, vitamin D is transported in the plasma largely in association with protein, vitamin D-binding protein (DBP). Being synthesized by the liver, BDP is depressed in patients with hepatic disease. Its synthesis is increased by trauma, during oestrogen therapy or pregnancy. Unlike the other fat-soluble vitamins, vitamin D is not stored by the liver. It reaches the liver within a few hours after being absorbed across the gut or synthesized in the skin, but from the liver it is distributed relatively evenly among the various tissues. Therefore, fatty tissues such as adipose cells show slightly greater concentrations. However, in that tissue the vitamin is found in the bulk lipid phase, from which it is only slowly mobilized.
Target tissues for vitamin D contain a specific nuclear receptor, the vitamin D receptor (VDR), to which the active metabolite binds. Vitamin D receptors have been identified in more than 30 different cell types; these include cells closely related to the maintenance of calcium homeostasis (bone, kidney, intestine), as well as immune, endocrine, hematopoietic, skin, and tumour cells. Such findings indicate a wide breadth of vitamin D genomic functions. Multiple polymorphic variations have been identified in the human VDR gene that are likely to affect mRNA expression stability and patterns, and thus VDR protein concentrations (1). Specific DNA promotor sequences acting as Vitamin D-Responsive Elements (VDREs) have been identified.
Some 50 genes have been identified as being regulated by vitamin D status. These include genes associated with many aspects of metabolism, including cell differentiation and proliferation, energy metabolism, hormonal signalling, mineral homeostasis, oncogenes, and chromosomal proteins, as well as vitamin D metabolism. The first gene product to be recognized as inducible by 1,25-(OH)2-D3 was for many years called calcium-binding protein (CaBP). Different forms of CaBP have subsequently been described; these are now called calbindins. It is thought that calbindins function in the absorption of calcium. Calbindins are not expressed in vitamin D deficiency, but are expressed in response to 1,25(OH)2-D3. VDR also downregulates the expression of some genes. These include genes encoding parathyroid hormone (PTH).
The most clearly elucidated and, apparently, most physiologically important function of vitamin D is in the homeostasis of Ca and phosphate (Pi). This is effected by a multi-hormonal system involving the controlled production of 1,25-(OH)2-D3 which functions with PTH and calcitonin (CT). Regulation of this system occurs at the points of intestinal absorption, bone accretion and mobilization, and renal excretion.
Calcium is absorbed in the small intestine and 1,25-(OH)2-D3, stimulates the enteric absorption of calcium. The availability of calcium for both processes is affected by both exogenous (e.g., inhibition by food phytates or phosphate (Pi)) and endogenous (e.g., gastric acid secretion) factors. Vitamin D, as 1,25-(OH)2-D3, increases net Pi uptake. Vitamin D, as 1,25-(OH)2-D3, stimulates the resorption of both Pi and Ca in the renal tubule.
Calcium and Phosphate Homeostasis
Homeostatic control of Ca and P is dependent on functions of the parathyroid and thyroid glands. When Ca levels drop, the parathyroid loses VDR, reducing its sensitivity to 1,25-(OH)2-D3. It also secretes PTH into the circulation, which acts on target tissues to restore plasma Ca by stimulating renal tubular Ca reabsorption and renal 1-hydroxylation of 25-OH-D3. The resulting increase in circulating 1,25-(OH)2-D3 stimulates enteric Ca absorption and osteoclastic activity. Demineralization of bone serves to mobilize Ca and Pi from that reserve, thus maintaining the homeostasis of those minerals in the plasma. Increasing plasma Ca levels inhibits bone resorption and, at high doses, increases urinary Ca excretion. This system feeds back to regulate the synthesis of PTH through inhibition by 1,25-(OH)2-D3 binding a negative VDRE near the promoter of the PTH gene. A similar mechanism has been proposed for the downregulation of CT by 1,25-(OH)2-D3. The interplay of these hormones with Ca and 1,25-(OH)2-D3 produces fine control of circulating Ca levels.
Under hypercalcemic conditions, calcitonin (CT) is secreted by the thyroid. This hormone suppresses bone mobilization, and is also thought to increase the renal excretion of both Ca and Pi. In that situation, the 25-OH-vitamin D 1-hydroxylase may be feedback-inhibited by 1,25-(OH)2-D3, which may actually convert to the catalysis of the 24-hydroxylation of 25-OH-D3. Secondary hyperparathyroidism, characterized by elevated serum PTH concentrations, is common among elderly people. The condition can reflect some degree of renal insufficiency, with associated reduction in renal 25-OH-vitamin D3 1-hydroxylase activity. Accordingly, the PTH levels of people living in northern latitudes are highest during the winter for subjects not taking supplemental vitamin D.
Vitamin D function can be affected by several other mineral elements:
Zinc. Deprivation of zinc has been found to diminish the 1,25-(OH)2-D3 response to low calcium intake, and it has been suggested that zinc may indirectly affect renal 25-OH-D3 1-hydroxylase activity.
Iron. Iron deficiency has been shown to be associated with low serum concentrations of 24,25-(OH)2-D3 and reduced 25-OH-D3 responses to supplementation with vitamin D3. It has been suggested that iron deficiency, which is known to impair the enteric absorption of fat and vitamin A, may also impair the absorption of vitamin D.
Lead. Exposure to lead appears also to impair the 1-hydroxylation of 25-OH-D3. In children, blood levels of 1,25-(OH)2-D3 and calcium have been found to be inversely related to blood lead concentrations, suggesting that lead may inhibit the renal 1-hydroxylation of the vitamin, perhaps constituting an adaptation to protect against lead toxicity.
Boron. An interaction of vitamin D, magnesium, and calcium has been reported with boron.
Vitamin D Functions in Non-Calcified Tissues
That 1,25-(OH)2-D3 and nuclear VDRs occur in tissues not directly involved in Ca homeostasis (e.g., pancreatic β cells, specific brain cells, pituitary, muscle, mammary gland, and endocrine cells of the stomach suggests that the vitamin functions in the regulation and differentiation of many cells. These functions occur via VDR: at least 100 proteins (including several oncogenes) are known to be regulated by 1,25-(OH)2-D3. Responses to 1,25-(OH)2-D3 are observed at concentrations two to three orders of magnitude greater than circulating levels; hence it is possible that under normal circumstances they may be limited to specific sites of local production of the active metabolite.
Healthful Vitamin D Status
The most informative indicator of vitamin D status is the concentration of 25-OH-D3 in serum/plasma. The recent report by the Institute of Medicine considered 50 nmol/l adequate for bone health in adults and children (2), although an expert consensus considered the level of 70–80 nmol/l as optimal (3). An analysis of multiple endpoints related to bone and dental health, lower extremity function, risks of falls, fractures, and cancer found the optimal serum 25-OH-D3 level to be 90–100 nmol/l. Such levels require regular daily vitamin D intakes of greater than 1000 IU (40 μg). The maintenance of such serum 25-OH-D3 levels requires the use of solar radiation, vitamin D supplements, and/or vitamin D-fortified foods.
Genetic polymorphisms have been found to affect circulating levels of 25-OH-D3, in some cases by as much as can deprivation of vitamin D (4). These include variants at three loci near genes encoding 7-dehydrocholesterol reductase, DBP, and a cytochrome P-450 isoform CYP2R1. Two of these are involved in the synthesis of the vitamin precursor and the transport of the dominant metabolite. The third, CYP2R1, has been suggested as having vitamin D3 25-hydroxylase activity. Serum 25-OH-D3 measurement may easily overestimate vitamin D intakes of individuals with such polymorphisms, who may also be more susceptible to adverse effects of vitamin D deprivation.
Serum 25-OH-D3 levels are more frequently low in pregnant women compared to non-pregnant women. A study in Boston found that 76% of new mothers (and 81% of their newborns) had serum 25-OH-D3 levels <20 ng/ml (5). Vitamin D status has been inversely associated with risks of pre-eclampsia, gestational diabetes, bacterial vaginosis, and primary caesarean section (perhaps related to pelvic deformities and/or weakened muscular function during labor). Circulating levels of 1,25-(OH)2-D3 increase by two- to three-fold in the first trimester of pregancy,. It has been suggested that 1,25-(OH)2-D3 functions in the placenta to suppress Th1-dependent immunity to facilitate immune tolerance to implantation and successful foetal maintenance. Serum 25-OH-D3 levels have also been found to be inversely associated with risks of acute respiratory infection and symptoms of asthma (6).
Vitamin D deficiency can result from inadequate irradiation of the skin, from insufficient intake from the diet or from impairments in the metabolic activation (hydroxylations) of the vitamin. Although sunlight can provide the means of biosynthesis of vitamin D3, it is a well-documented fact that many people, particularly those in extreme latitudes during the winter months, do not receive sufficient solar irradiation to support adequate vitamin D status. Even people in sunnier climates may not produce adequate vitamin D if their lifestyles or health status keep them indoors, or if such factors as air pollution or clothing reduce their exposure to UV light. Most people therefore show strong seasonal fluctuations in plasma 25-OH-D3 concentration; for some, this can be associated with considerable periods of suboptimal vitamin D status if not corrected by an adequate dietary source of the vitamin. Vitamin D deficiency can have privational and non-privational causes.
Privational causes involve inadequate vitamin D supply. They include: inadequate exposure to sunlight, and insufficient consumption of food sources of vitamin D. Non-privational causes relate to impairments in the absorption, metabolism or nuclear binding of the vitamin. They include: diseases of the gastrointestinal tract (e.g., small bowel disease, gastrectomy, pancreatitis), involving malabsorption of the vitamin from the diet; diseases of the liver (biliary cirrhosis, hepatitis), involving reduced activities of the 25-hydroxylase; diseases of the kidney (e.g., nephritis, renal failure), involving reduced activities of the 1-hydroxylase, the major source of 1,25-(OH)2-D3,145 or of 25-OH-D3 as in individuals with nephrotic syndrome, who lose 25-OH-D3 along with its globulin-binding protein into the urine; exposure to certain drugs (e.g., anticonvulsants) which induce the catabolism of 25-OH-D3 and 1,25-(OH)2-D3, reduce circulating levels of the former, and reduce elevated PTH levels; impaired parathyroid function resulting in hypoparathyroidism (reduced production of PTH), which impairs the ability to respond to hypocalcemia by increasing the conversion of 25-OH-D3 to 1,25-(OH)2-D3; genetic mutations resulting in impaired expression of the renal 25-(OH)-D3 1-hydroxylase in the condition referred to as vitamin D-dependent rickets type I; expression of a non-functional VDR and impairing the transcription of vitamin D-regulated genes involved in Ca and phosphorus homeostasis in the condition referred to as vitamin D-dependent rickets type II; resistance of PTH target cells, resulting in pseudohypoparathyroidism and involving hypocalcemia without compensating renal retention or bone mobilization of Ca despite normal PTH secretion; vitamin D-resistance involving impaired phosphate transport in the intestine and reabsorption in the proximal renal tubules, hypersensitivity to PTH, and impaired 1-hydroxylation of 25-OH-D3. It is also likely that genetic polymorphisms in DBP and other proteins involved in vitamin D metabolism/ function that result in suppressed circulating levels of 25-OH-D3 may render individuals at risk of vitamin D deprivation.
Low circulating levels of 25-OH-D3 are frequently observed in patients with chronic renal disease and those with nephrotic syndrome and normal renal function. Some studies have found treatment with vitamin D analogues to reduce proteinuria in patients with chronic renal disease. A meta-analysis of 16 clinical trials concluded that such treatments are effective in increasing serum Ca and decreasing serum PTH, but ineffective in reducing either the need for dialysis or survival (7).
Excessive intakes of vitamin D are associated with increases in circulating levels of 25-OH-D3; this is especially true for vitamin D3, exposure to high levels of which produces higher serum levels of the 25-OH metabolite than do comparable intakes of vitamin D2. The 25-OH metabolite is believed to be the critical metabolite in vitamin D intoxication. At high levels it appears to compete successfully for VDR binding, thus bypassing the regulation of the 25-OH-D3 1-hydroxylase to induce transcriptional responses normally signalled only by 1,25-(OH)2-D3. Therefore, risk to hypervitaminosis D is increased under conditions such as chronic inflammation, in which the normal feedback regulation of the renal 25-OH-D3 1-hydroxylase is compromised. Hypervitaminosis D involves increased enteric absorption and bone resorption of calcium, producing hypercalcemia, with attendant decreases in serum PTH and glomerular filtration rate and, ultimately, loss of calcium homeostasis. The mobilization of bone also results in increased serum concentrations of zinc from that reserve. Vitamin D-intoxicated individuals show a variety of signs, including anorexia, vomiting, headache, drowsiness, diarrhoea, and polyuria. With chronically elevated serum calcium and phosphorus levels, the ultimate result is calcinosis – i.e., the deposition of calcium and phosphate in soft tissues, especially heart and kidney, but also the vascular and respiratory systems and practically all other tissues. It is not known whether calcinosis involves specific tissue lesions induced by high levels of vitamin D metabolites or whether it is simply a consequence of the induced hypercalcemia. Thus, the risk of hypervitaminosis D is dependent not only on exposure to vitamin D, but also on concomitant intakes of calcium and phosphorus. A systematic review of the clinical trial literature pointed out that no adverse effects have been reported for vitamin D3 doses as high as 10,000 IU/day, and that no consistent and reproducible effects, including hypercalcemia, have been reported for doses five times that amount. There are no documented cases of hypervitaminosis D due to excessive sunlight exposure. Vitamin D3 has been found safe for pregnant and lactating women and their children at oral doses of 100,000 IU/d.
SOURCES OF VITAMIN D
Vitamin D, as either ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3), is rather sparsely represented in nature; however, its provitamins are common in both plants and animals. Ergocalciferol and its precursor ergosterol are found in plants, fungi, moulds, and lichens. In fact, some microorganisms are quite rich in ergosterol. Ergosterol does not occur naturally in higher vertebrates. Cholecalciferol is widely distributed in animals, but has an extremely limited distribution in plants. In animals, tissue cholecalciferol concentrations are dependent on the vitamin D3 content of the diet and/or the exposure to sunlight. Few foods, however, are rich in the vitamin. Fish liver and oils are particularly rich sources of vitamin D3, which occurs in those materials in free form as well as esters of long-chain fatty acid esters. Oily fishes can provide significant amounts of vitamin D by virtue of their positions in the upper levels of food chains that consume lower level species, including ergosterol-containing plant eaters. However, farm-raised fish fed formulated diets may not contain significant amounts of vitamin D unless it has been added as a supplement to their rations. With a few notable exceptions, vitamin D3 is not found in plants. Most species appear not to discriminate between the vitamers D2 and D3. Studies in humans have demonstrated that each supports comparable plasma 25-OH-D responses, whether given individually or in mixtures (8).
Because most foods contain only very low amounts of vitamin D, it is the practice in many countries to fortify certain frequently consumed foods (e.g., baked goods, grain products, milk, yogurt, cheeses, margarines, orange juice, infant foods, and some breads). Both vitamers D2 and D3 are used in the fortification of foods. Vitamin D can also be obtained from nutritional supplements.
Vitamin D is formed in animals by the action of ultraviolet light in the UVB range (290–310 nm) on 7-dehydrocholesterol in the skin. The activation reaction depends on the absorption of UV light (optimally, 295–300 nm) of the sterol nucleus, causing it to open and isomerize to form the energetically more stable s-trans, s-cis-previtamin D3. This physicochemical reaction appears to convert only 5–15% of the available 7-dehydrocholesterol to vitamin D3. That efficiency is affected by the physical properties of the skin and of the environment; thus, it differs between individuals and species, and shows great variation according to time of day, season, and latitude. The provitamin D, 7-dehydrocholesterol, is both a precursor to and a product of cholesterol (via different pathways); it is synthesized in the sebaceous glands of the skin and is secreted rather uniformly onto the surface, where it is reabsorbed into the various layers of the epidermis.
Vitamin D biosynthesis is therefore determined by environmental exposure to UV light, which also can increase risk to skin cancers in individuals experiencing episodes of severe burning. The amount of sunlight required to support adequate vitamin D status is substantially less than that which increases skin cancer risk. Vitamin D-producing UV irradiation varies with the zenith angle of the sun, being greatest at noon (60% occurs between 10 am and 2 pm), reaching an annual peak at midsummer, and declining with the distance from the Earth’s equator. In winter there is almost no UV light at latitudes 50°N/S, and above 40°N/S there is virtually no vitamin D biosynthesis in the skin. The vitamin D biosynthetic capacity of skin, while great, is diminished by factors that block UV penetration into the skin. Both the thickness and 7-dehydrocholesterol content of skin decline with age, such that the vitamin D biogenic response to solar irradiation is also diminished in older people (9). Accordingly, an age-related decline in plasma 25-OH-D3 concentration is typically seen in individuals without significant dietary intakes of the vitamin. The epidermal pigment melanin efficiently absorbs UVB, for which reason dark-skinned individuals require greater UV doses than light-skinned ones for comparable vitamin D biosynthesis. Compared to a person with light, type 1 skin (easily sunburned; never tan), an individual with dark, type 5 or 6 skin (seldom or never burn; always tan) can require 5–10 times as much solar exposure to produce the same amount of vitamin D3 (10).
Physical factors that reduce the exposure of the skin to UV light also reduce the biosynthesis of vitamin D3. These include factors associated with the lifestyle of humans (e.g., clothing, indoor living [glass and plexiglass absorb UV light], use of sun screens) (11). Properly applied topical suncreens with sun protection factors of 8 and greater have been shown to reduce cutaneous vitamin D3 production by >95% (11). That many people show seasonal changes in their serum 25-OH-D3 levels (greatest concentrations occurring in the autumn, i.e., after a summer of relatively great solar exposure) indicates that sunlight is generally more important than diet as a source of this critical nutrient. Under such conditions, vitamin D cannot be considered a vitamin at all; it is, instead, a pro-hormone produced in the skin.
Vitamin D in health and disease
Bone is the predominant target organ for vitamin D, accumulating more than one-quarter of a single dose of the vitamin within a few hours of its administration. That lesions in bone mineralization (rickets, osteomalacia) occur in vitamin D deficiency has long indicated its vital function in the metabolism of this organ. Vitamin D plays roles both in the formation (mineralization) and the mobilization of bone mineral (demineralization). In the absence of adequate levels of 1,25-(OH)2-D3, the failure of mineralization and/or net excess of osteoclastic demineralization have structural and functional consequences to bone, as bone density is a primary determinant of bone strength. Inadequate vitamin D status has also been associated with fracture risk, particularly in older individuals. A recent meta-analysis of 12 randomized controlled trials revealed that vitamin D doses of 700–800 IU/day reduced the relative risk of hip fracture by 26% and of any non-vertebral fracture by 23% (13). Risk reductions were not observed for trials that used a lower vitamin dose (400 IU/day) (14,15).
VDR genotype appears to contribute significantly to the variation observed in bone mineral density in populations, some 80% of which is thought to be due to genetic factors. Two VDR polymorphisms have been identified as independent risk factors for stress fracture (16).
Circulating concentrations of 25-OH-D3 have been found to be inversely correlated with the risk of periodontal disease in adults. This effect appears to be independent of those of bone mineral density. That it may involve the anti-inflammatory effects is supported by the finding that serum 25-OH-D3 levels were inversely related to susceptibility to gingival inflammation and tooth loss in the NHANES III survey.
RicketsRickets first appears in 6- to 24-month old children, but can manifest at any time until the closure of the bones’ growth plates. It is characterized by impaired mineralization of the growing bones with accompanying bone pain, muscular tenderness, and hypocalcemic tetany. Tooth eruption may be delayed, the fontanelle may close late, and knees and wrists may appear swollen. Affected children develop deformations of their softened, weight-bearing bones, particularly those of the rib cage, legs and arms; hence the characteristic leg signs, bow-leg, knock knee,which occur in nearly half of cases. Radiography reveals enlarged growth plates resulting from their failure to mineralize and continue growth. Rickets is most frequently associated with low dietary intakes of calcium, as in the lack of access to or avoidance of milk products.
Osteomalacia Osteomalacia occurs in older children and adults with formed bones whose epiphyseal closure has rendered that region of the bone unaffected by vitamin D deficiency. The signs and symptoms of osteomalacia are more generalized than those of rickets; e.g., muscular weakness and bone tenderness and pain, particularly in the spine, shoulder ribs or pelvis. Lesions involve the failure to mineralize bone matrix, which continues to be synthesized by functional osteoblasts; therefore, the condition is characterized by an increase in the ratio of non-mineralized bone to mineralized bone. Radiographic examination reveals abnormally low bone density (osteopenia) and the presence of pseudofractures, especially in the spine, femur, and humerus. Patients with osteomalacia are at increased risk of fractures of all types, but particularly those of the wrist and pelvis.
Osteoporosis Although it is sometimes confused with osteomalacia, osteoporosis is a very different disease, being characterized by decreased bone mass with retention of normal histological appearance. Its etiology (loss of trabecular bone with retention of bone structure) is not fully understood; it is considered a multifactorial disease associated with aging and involving impaired vitamin D metabolism and/or function associated with low or decreasing estrogen levels. The disease is the most common bone disease of postmenopausal women, and also occurs in older men (e.g., non-ambulatory geriatrics, postmenopausal women) and in people receiving chronic steroid therapy, which groups show high incidences of fractures, especially of the vertebrae, hip, distal radius, and proximal femur.
In women, osteoporosis is characterized by rapid loss of bone (e.g., 0.5–1.5%/year) in the first five to seven years after menopause. The increased skeletal fragility observed in osteoporosis appears not to be due solely to reductions in bone mass, but also involves changes in skeletal architecture and bone remodeling (e.g., losses of trabecular connectivity, as well as inefficient and incomplete microdamage repair). Affected individuals show abnormally low circulating levels of 1,25-(OH)2-D3, suggesting that estrogen loss may impair the renal 1-hydroxylation step – i.e., that the disease may involve a bihormonal deficiency. Studies of the use of various vitamers D in the treatment of osteoporotic patients, most of which have involved low numbers of subjects, have produced inconsistent results. Results of the Nurses’ Health Study showed that adequate vitamin D intake (>12.5 μg/day) was associated with a 37% reduction in risk of osteoporotic hip fracture (17); a meta-analysis of randomized intervention trials showed that 1,25-(OH)2-D3 treatment at doses of 0.5–1 μg/day decreased vertebral and at least some non-vertebral (e.g., forearm) fractures in postmenopausal women (18).
Musculoskeletal Pain Deep pain is common among rickets and osteoporosis patients. Some reports have indicated persistent, non-specific musculoskeletal pain among asymptomatic adults with low circulating levels of 25-OH-D3; however, a systematic review of published data found no convincing evidence of either low vitamin D status or latitude being associated with chronic pain prevalence in non-cases (19). Similarly, well controlled intervention trials have largely been negative.
VDRs have been identified in most immune cells, including most antigen-presenting cells (e.g., macrophages, dendritic cells) and CD4, CD8 T lymphocytes. These cells can also express the 25-OH-D3 1- and -24-hydroxylases; they are thus capable of producing and catabolizing 1,25-(OH)2-D3. Some (dendritic cells) can also express the vitamin D3-25-hydoxylase. Vitamin D treatment in vitro has been found to enhance T cell activation, and divert immature dendritic cells from development as effector T cells toward development as regulatory (CD4, CD25) T cells. In addition, 1,25-(OH)2-D3 has been found to enhance macrophage and monocyte phagocytosis, bacterial killing, and heat shock protein production. Vitamin D deficiency has been associated with inflammation; studies have shown the circulating marker of inflammation, C-reactive protein, to be inversely correlated with serum concentrations of 25-OH-D3, and decreased in response to vitamin D treatment.
Vitamin D has a paracrine function in the skin. Keratinocytes express 25-(OH)2-D3 1-hydroxylase; therefore, they can not only produce vitamin D3 with solar exposure, but also metabolize it to 1,25-(OH)2-D3. VDRs are also expressed throughout the epidermis as well as in hair follicles. Among the gene products induced by VDR activation in the skin is cathelicidin antimicrobial peptide (CAMP), which functions both in the direct killing of pathogens as well as a host response involving cytokine release, inflammation, and cellular immune response. Mutations of VDR occur in patients with hereditary vitamin D-resistant rickets. They show alopecia, the basis of which is unclear as the condition is not caused by vitamin D deficiency per se or by loss of 25-OH-D3 1-hydroxylase activity.
The finding that 1,25-(OH)2-D3 can inhibit proliferation and induce terminal differentiation of cultured keratinocytes stimulated the study of its potential value in the treatment of proliferative skin disorders. Clinical studies have shown that both oral and topical applications of appropriate doses of 1,25-(OH)2-D3 can be safe and effective in the management of psoriasis (20). Decreased levels of cathelicidin have been observed in atropic dermatitis, and abnormal processing of the cathelicidin peptide has been found to be involved in the inflammatory and vascular responses in rosacea. Because the use of 1,25-(OH)2-D3 carries risks of hypercalcemia and hypercalciuria, there is interest in developing treatment regimens for such diseases involving the application of high doses of the vitamin in a safe and effective manner.
A role of vitamin D in brain development and function was first indicated by the finding of 25-OH-D3 in cerebrospinal fluid, and of VDR and 25-OH-D3 1-hydroxylase activity in brain tissue. It has been suggested that vitamin D may act as a neurosteroid with direct effects on brain development, including reduction of risk of neuropsychiatric disorders (21).
Rheumatoid Arthritis (RA)
VDR is expressed by articular chondrocytes in osteoarthritic cartilage, which also express matrix metalloproteinases (MMPs) not found in normal cartilage. Such observations suggest a role of the vitamin in this immune-mediated disease characterized by articular inflammation leading to disability. One study noted an inverse relationship of vitamin D intake, particularly from supplements, and risk of developing RA.(22)
It has been long recognized that multiple sclerosis (MS), an autoimmune disease characterized by immune attacks on the myelin sheaths of nerves, is more prevalent in northern, temperate parts of the world than in the tropics. In fact, the prevalence has been found to be strongly inversely related to the numbers of hours of annual or winter sunlight. Two studies have found the use of vitamin D supplements to reduce the risk of developing MS by as much as 40% (23).
Insulin-Dependent Diabetes (Type 1 Diabetes, T1D)
It has been suggested that vitamin D may play a role in reducing the risk of T1D, which results from the T-cell dependent destruction of insulin-producing pancreatic β cells by cytokines and free radicals from inflammatory infiltrates. Epidemiological studies have found the incidence of T1D to be positively associated with latitude and negatively associated with hours of sunlight. Two prospective trials have been conducted to evaluate the efficacy of vitamin D in preventing T1D: one found positive effects of vitamin D doses of 50 μg/day (24); the other detected no benefits using lower doses (<10 μg/d) (25). A large, multi-centre case–control study (26) and a cohort study (27) have found vitamin D supplementation in infancy reduced T1D risk in later life.
Non-Insulin-Dependent Diabetes (Type 2 Diabetes, T2D)
Protection against T2D by vitamin D may involve the vitamin protecting pancreatic β cells from inflammatory damage. Subclinical, low-intensity, chronic inflammation has been associated with insulin resistance, which has been found to be inversely related to serum 25-OH-D3 concentrations over a wide range (28). The results of the Third National Health and Nutrition Examination Survey (NHANES III) showed serum level of 25-OH-D3 to be inversely associated with diabetes risk in a multi-ethnic sample of over 6,000 adults (29). Swedish researchers have found T2D incidence to be highest during the winter months, when circulating 25-OH-D3 levels are lowest (30). A 20-year follow-up of the Nurses’ Health Study cohort found T2D risk to be one-third less for women reporting the use of vitamin D and Ca supplements (31). While T2D risk was inversely associated with both vitamin D and Ca intakes, most of these effects were attributed to the use of supplements of these nutrients. The hypothesis that improving vitamin D status could improve glycaemic control was recently tested in a randomized clinical conducted in Iran, a country with high reported prevalences of low vitamin D status, metabolic syndrome, and T2D. This showed that vitamin D supplementation improved glycaemic control in T2D patients, as indicated by reductions in fasting glucose level and insulin resistance.
The efficacy of vitamin D in preventing T2D may depend on an individual’s adiposity. Studies have shown that serum 25-OH-D3 levels are inversely correlated with body mass index, body fat mass, and insulin resistance, and directly associated with weight loss resultant of caloric restriction (32). The relationship of vitamin D status and T2D risk appears to be greatest among overweight/obese individuals (33). It has been suggested that the exacerbation of the T2D risk of low vitamin D status by adiposity may be due to the sequestration of vitamin by partitioning into bulk lipid depots in adipose tissue. According to this hypothesis, adipocytes would be involved in two opposing ways: responding to 1,25-(OH)2-D3 in the regulation of cytokine production, and sequestering 25-OH-D3. It has been proposed that vitamin D deficiency may also cause obesity (34). According to this hypothesis, the circulating 25-OH-D3 level evolved to serve as a UVB-sensitive photoreceptor. In species with low dietary vitamin D intakes, 25-OH-D3 levels decline with shortening of day-length during winter, to stimulate accumulation of fat and induce a winter metabolism – i.e., the metabolic syndrome. This would imply that vitamin D supplements may be effective in preventing obesity. This is supported by findings that 1,25-(OH)2-D3 can induce apoptosis in adipocytes. In addition, 1,25-(OH)2-D3 has been shown to suppress adipose fat deposition by stimulating the expression of the steroid-metabolizing enzyme 11β-hydroxysteroid hydroxylase, thus promoting glucocorticoid production.
That vitamin D plays an important role in muscle is evidenced by the muscle weakness that is typical of vitamin D-deficient subjects, the presence of VDR in myocytes, and the lack of muscle development observed in VDR-knockout mice. Vitamin D, 1,25-(OH)2-D3, has been shown to be essential for the homeostatic control of intracellular Ca, thus affecting both contractility and myogenesis.
Risk of Falling
It has been suggested that insufficient vitamin D status may increase the risk to bone fracture by affecting strength, balance, and gait. Falls have been shown to be the most frequent causes of fractures (causing >90% of hip fractures) and are known to increase with age, particularly after 70 years. Their prevalence has also been shown to vary with both season (being greater in the winter months) and latitude (being greater at northern latitudes). Several observational studies with older adults have found significant positive associations of plasma levels of 25-OH-D3 and/or 1,25-(OH)2-D3 and factors related to risk of falling: postural balance and strength (measured by such parameters as leg extension power, quadriceps strength, arm muscle strength, handgrip strength, ability to climb stairs, and physical activity) (35). Two meta-analyses of the eight published randomized controlled trials showed that supplementation with 700–1000 IU/day reduced by 14% and 19% the risk of falling by older subjects, although individual studies have reported reductions by nearly 50% (36). The greatest benefits were observed when vitamin D was given with supplemental Ca.
Epidemiological studies have shown that low circulating 25-OH-D3 levels, as well as factors known to affect vitamin D status (latitude, altitude, season), are associated with the prevalence of coronary risk factors and cardiovascular disease (CVD) mortality. Vitamin D is known to suppress several mechanisms of CVD pathogenesis: proliferation of vascular smooth muscle, vascular calcification, production of pro-inflammatory cytokines, and regulation of the renin–angiotensin system. Therefore, it has been suggested that low vitamin D status may be a risk factor for CVD. Two intervention trials have been conducted to test this hypothesis; they found small (<10%) reductions in systolic and/or diastolic blood pressure in hypertensive patients treated with vitamin D. A large, prospective, general population study found no effects.
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Keywords:-vitamin D, rickets, osteomalacia, osteoporosis, musculoskeletal pain, bone health, immunity, skin, psoriasis, muscle weakness, rheumatoid artritis, type I diabetes, type II diabetes, obesity, falls, cardiovascular disease