Vitamin D deficiency is now recognized as a pandemic. The major cause of vitamin D deficiency is the lack of appreciation that sun exposure in moderation is the major source of vitamin D for most humans. Very few foods naturally contain vitamin D, and foods that are fortified with vitamin D are often inadequate to satisfy either a child's or an adult's vitamin D requirement. Vitamin D deficiency causes rickets in children and will precipitate and exacerbate osteopenia, osteoporosis, and fractures in adults. Vitamin D deficiency has been associated with increased risk of common cancers, autoimmune diseases, hypertension, and infectious diseases. A circulating level of 25-hydroxyvitamin D of >75 nmol/L, or 30 ng/mL, is required to maximize vitamin D's beneficial effects for health. In the absence of adequate sun exposure, at least 800–1000 IU vitamin D3/d may be needed to achieve this in children and adults. Vitamin D2 may be equally effective for maintaining circulating concentrations of 25-hydroxyvitamin D when given in physiologic concentrations.
Some of the earliest phytoplankton life forms on earth that have existed unchanged in the Atlantic ocean for >750 y can make vitamin D when exposed to sunlight (1, 2). Most vertebrates, including amphibians, reptiles, birds, and lower primates, depend on sun exposure for their vitamin D requirement (2). The lack of sunlight and its association with the devastating bone-deforming disease rickets in children was first recognized by Sniadecki in 1822 (3). One hundred years would pass before it was observed that exposure to ultraviolet B radiation (UVB; 290–315 nm) from a mercury arc lamp or sunlight prevented and treated rickets (4). In the early 1930s, the US government set up an agency to provide recommendations to parents about the beneficial effect of sensible exposure to sunlight for the prevention of rickets (4-6).
The fortification of milk in the 1930s with 100 IU vitamin D2 per 8 ounces was effective in eradicating rickets in the United States and Europe. The unfortunate outbreak of hypercalcemia in the 1950s in Great Britain was blamed on the overfortification of milk with vitamin D, even though there was little evidence for this (7). Because milk was scarce at the end of the war, many local stores that sold milk would add vitamin D to it if it was not purchased by the expiration date. This was thought to extend the shelf-life of the vitamin D–fortified milk. This rise in the incidence of hypercalcemia in infants in the 1950s resulted in Europe forbidding the fortification of dairy products with vitamin D. Only recently have Finland and Sweden begun fortifying milk with vitamin D.
The major source of vitamin D for most humans is exposure to sunlight (1, 2, 4-6). As shown in Figure 1⇓, seasonal variation is found in the major circulating form of vitamin D, 25-hydroxyvitamin D [25(OH)D] (8). Few foods naturally contain vitamin D, including oily fish such as salmon, mackerel, and herring and oils from fish, including cod liver oil. We recently conducted a study and observed that wild-caught salmon had on average 500–1000 IU vitamin D in 100 g (3.5 ounces), whereas farmed salmon contained ≈100–250 IU vitamin D per 100-g serving (9). The most likely reason is that vitamin D is plentiful in the food chain but is not plentiful in the pelleted diet fed to farmed salmon. In the United States, milk, some juice products, some breads, yogurts, and cheeses are fortified with vitamin D. Multivitamins that contain 400 IU vitamin D and supplements containing vitamin D only are now available in various amounts including 400, 1000, 2000, 4000, 5000 and 50 000 IU vitamin D3. The pharmaceutical form of vitamin D in the United States is vitamin D2 and is available as 50 000 IU vitamin D2 in a capsule or 8000 IU vitamin D2/mL (4, 10). In Canada, Europe, Japan, and India, vitamin D3 is available as a pharmaceutical.
A: Relation between hours of sunshine and serum 25-hydroxyvitamin D [25(OH)D] concentrations. â?ª, hours of sunshine; •, 25(OH)D. B: Seasonal fluctuation in serum 25(OH)D according to frequency of sun exposure. â?ª, regular sun exposure; ♦, occasional sun exposure; •, avoiding direct sun exposure. Adapted from reference 8.
CONSEQUENCES OF VITAMIN D DEFICIENCY ON THE MUSCULOSKELETAL SYSTEM
Much debate has taken place over the definition of vitamin D deficiency. Most agree that a 25(OH)D concentration <50 nmol/L, or 20 ng/mL, is an indication of vitamin D deficiency, whereas a 25(OH)D concentration of 51–74 nmol/L, or 21–29 ng/mL, is considered to indicate insufficiency; concentrations >30 ng/mL are considered to be sufficient (10-15; Figure 2⇓) This is based on the observation that intestinal calcium absorption is maximized above 80 nmol/L, or 32 ng/mL, in postmenopausal women (16) and that parathyroid hormone (PTH) concentrations in adults continue to decline and reach their nadir at ≈75–100 nmol/L, or 30–40 ng/mL (11, 14, 15). It has been assumed that children have the same requirement as adults; however, no comparable studies have been carried out on intestinal calcium transport or PTH levels in children. Vitamin D intoxication typically does not occur until 25(OH)D concentrations are >375 nmol/L, or 150 ng/mL (10, 16,17).
Schematic representation of the synthesis and metabolism of vitamin D for regulating calcium, phosphorus, and bone metabolism. During exposure to sunlight, 7-dehydrocholesterol (7-DHC) in the skin is converted to previtamin D3 (preD3) and then by a heat-dependent process to vitamin D3. Vitamin D (D represents D2 or D3) made in the skin or ingested in the diet is converted by the vitamin D-25-hydroxylase (25-OHase) to 25-hydroxyvitamin D [25(OH)D]. 25(OH)D is converted in the kidneys by the 25-hydroxyvitamin D-1α-hydroxylase (1-OHase) to its biologically active form 1,25-dihydroxyvitamin D [1,25(OH)2D]. 1,25(OH)2D increases the expression of the 25-hydroxyvitamin D-24-hydroxylase (24-OHase) to catabolize 1,25(OH)2D and 25(OH)D to the water-soluble biologically inactive calcitroic acid. 1,25(OH)2D enhances intestinal calcium absorption in the small intestine. 1,25(OH)2D is recognized by its receptor in osteoblasts, causing an increase in the expression of receptor activator of NFκB ligand (RANKL). CaBP, calcium binding protein; ECaC, epithelial channel calcium; FGF23, fibroblast growth factor 23; OJ, orange juice; Pi, inorganic phosphate; PTH, parathyroid hormone; UVB, ultraviolet B radiation.
Vitamin D deficiency in children will cause growth retardation (5, 18) and classic signs and symptoms of rickets (4-6, 18). In adults, vitamin D deficiency will precipitate and exacerbate both osteopenia and osteoporosis and increase the risk of fracture (10, 11, 19, 20).
Muscle weakness has long been associated with vitamin D deficiency. A vitamin D receptor is present in skeletal muscle (21), and vitamin D deficiency has been associated with proximal muscle weakness, increase in body sway, and an increased risk of falling (22-24).
Vitamin D deficiency in adults can also cause a skeletal mineralization defect. The unmineralized osteoid provides little structural support for the periosteal covering. As a result, patients with osteomalacia often complain of isolated or global bone discomfort along with aches and pains in their joints and muscles (25-27). These patients may be misdiagnosed with fibromyalgia, dysthymia, degenerative joint disease, arthritis, chronic fatigue syndrome, and other diseases (10, 25, 28).
The major source of vitamin D for humans is exposure to sunlight (4, 8, 10). Anything that diminishes the transmission of solar UVB radiation to the earth's surface or anything that interferes with the penetration of UVB radiation into the skin will affect the cutaneous synthesis of vitamin D3 (2, 9; Figure 3⇓) Melanin is extremely efficient in absorbing UVB radiation, and, thus, increased skin pigmentation markedly reduces vitamin D3 synthesis (29). Similarly, a sunscreen with a sun protection of 15 absorbs 99% of the incident UVB radiation, and, thus, when topically applied properly will decrease the synthesis of vitamin D3 in the skin by 99% (30). African Americans with very dark skin have an SPF of 15, and, thus, their ability to make vitamin D in their skin is reduced by as much as 99% (9,29). This along with decreased milk intake are the explanations for why most African Americans who live in a temperate climate are vitamin D deficient, whereas Africans living near the equator where vitamin D3 synthesis is more efficient because of the higher flux of UVB photons are not (31, 32).
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