REVIEW
High Prevalence of Vitamin D Inadequacy and Implications for Health

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During the past decade, major advances have been made in vitamin D research that transcend the simple concept that vitamin D is important for the prevention of rickets in children and has little physiologic relevance for adults. Inadequate vitamin D, in addition to causing rickets, prevents children from attaining their genetically programmed peak bone mass, contributes to and exacerbates osteoporosis in adults, and causes the often painful bone disease osteomalacia. Adequate vitamin D is also important for proper muscle functioning, and controversial evidence suggests it may help prevent type 1 diabetes mellitus, hypertension, and many common cancers. Vitamin D inadequacy has been reported in approximately 36% of otherwise healthy young adults and up to 57% of general medicine inpatients in the United States and in even higher percentages in Europe. Recent epidemiological data document the high prevalence of vitamin D inadequacy among elderly patients and especially among patients with osteoporosis. Factors such as low sunlight exposure, age-related decreases in cutaneous synthesis, and diets low in vitamin D contribute to the high prevalence of vitamin D inadequacy. Vitamin D production from cutaneous synthesis or intake from the few vitamin D-rich or enriched foods typically occurs only intermittently. Supplemental doses of vitamin D and sensible sun exposure could prevent deficiency in most of the general population. The purposes of this article are to examine the prevalence of vitamin D inadequacy and to review the potential implications for skeletal and extraskeletal health.

Section snippets

SOURCES OF VITAMIN D

Solar UV-B (wavelengths of 290-315 nm) irradiation is the primary source of vitamin D (other than diet supplements) for most people.1, 3, 4 Dietary sources of vitamin D are limited. They include oily fish such as salmon (approximately 400 IU per 3.5 oz), mackerel, and sardines; some fish oils such as cod liver oil (400 IU/tsp); and egg yolks (approximately 20 IU). Some foods are fortified in the United States, including milk (100 IU per 8 oz) and some cereals (100 IU per serving), orange juice

VITAMIN D PHOTOBIOCHEMISTRY, METABOLISM, AND FUNCTIONS

UV-B irradiation of skin triggers photolysis of 7-dehydrocholesterol (provitamin D3) to previtamin D3 in the plasma membrane of human skin keratinocytes.18, 19, 20 Once formed in the skin, cell plasma membrane previtamin D3 is rapidly converted to vitamin D3 by the skin's temperature. Vitamin D3 from the skin and vitamin D from the diet undergo 2 sequential hydroxylations, first in the liver to 25(OH)D and then in the kidney to its biologically active form, 1,25-dihydroxyvitamin D (1,25[OH]2D) (

ASSESSMENT OF VITAMIN D STATUS

Serum 25(OH)D is the major circulating metabolite of vitamin D and reflects vitamin D inputs from cutaneous synthesis and dietary intake. The serum 25(OH)D level is the standard clinical measure of vitamin D status.1, 14 Although 1,25(OH)2D is the active form of vitamin D, it should not be measured to determine vitamin D status. It usually is normal or even elevated in patients with vitamin D deficiency.1, 3, 4 Testing of serum 25(OH)D is most useful in patients who are at risk of vitamin D

EPIDEMIOLOGY OF VITAMIN D INADEQUACY

Vitamin D inadequacy constitutes a largely unrecognized epidemic in many populations worldwide.39, 40, 41, 42, 43, 44, 45, 46, 47 It has been reported in healthy children,7, 8, 13, 15, 48 young adults,38, 39, 49 especially African Americans,7, 41, 42, 49, 50 and middle-aged and elderly adults.9, 10, 11, 12, 14, 36, 37, 40, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56 Typically, the prevalence of low 25(OH)D levels (<20 ng/mL [50 nmol/L]) is approximately 36% in otherwise healthy young

FACTORS THAT CONTRIBUTE TO VITAMIN D INADEQUACY

Physical factors that attenuate UV-B exposure, including clothing, sunscreens, and glass shielding, markedly reduce or completely eliminate the production of vitamin D3 in the skin.18 At latitudes above 37°N and below 37°S, sunlight is insufficient to induce cutaneous vitamin D3 synthesis during the winter months.16, 65, 66 Nevertheless, latitude is not the only determinant of 25(OH)D levels.1, 3, 8, 67, 68, 69 The high prevalence of osteomalacia in Saudi Arabian women, rickets in Saudi

SKELETAL CONSEQUENCES OF VITAMIN D INADEQUACY

Chronic severe vitamin D deficiency in infants and children causes bone deformation due to poor mineralization, commonly known as rickets.1, 4 In adults, proximal muscle weakness, bone pain, and osteomalacia may develop.55, 86, 87, 88, 89 Less severe vitamin D inadequacy prevents children and adolescents from attaining their optimal genetically programmed peak bone mass and in adults leads to secondary hyperparathyroidism, increased bone turnover, and progressive loss of bone, increasing the

NEUROMUSCULAR FUNCTION

The VDR has been identified in skeletal muscle tissue,167, 168, 169 and low serum 25(OH)D levels have been associated with reversible myopathy in patients with osteomalacia.89, 170 Patients with nonspecific muscle weakness, muscle aches and pains, and bone pain are sometimes discounted or diagnosed as having fibromyalgia or chronic fatigue syndrome despite strong scientific evidence that they have vitamin D inadequacy.41, 86, 89, 91 Several studies support the hypothesis that vitamin D

VITAMIN D AND EXTRASKELETAL HEALTH

The small intestine, kidneys, and bones are the primary organs and tissues responsive to vitamin D that are involved in mineral metabolism that affects skeletal health. However, the effects of vitamin D are not limited to mineral homeostasis and the maintenance of skeletal health. The presence of the VDR in other tissues and organs suggests that vitamin D may also be important in nonskeletal biological processes.176, 177, 178 Additionally, the enzyme responsible for conversion of 25(OH)D to the

VITAMIN D AND CANCER

Vitamin D is one of the most potent hormones for regulating cell growth; 1,25(OH)2D inhibits proliferation and induces differentiation into normally functioning cells.1, 4, 176, 177, 197 Some evidence suggests that 1,25(OH)2D helps to regulate cell growth and prevent cancer progression1, 176, 177, 198 by reducing angiogenesis,153 increasing cell differentiation and apoptosis of cancer cells, and reducing cell proliferation156, 157, 158 and metastases.1, 4, 126, 151, 156, 176, 177, 179, 181 The

VITAMIN D AND CARDIOVASCULAR DISEASE

Adding to the evidence of the effect of vitamin D on extraskeletal tissues are data that suggest that inadequate vitamin D and calcium and living at higher latitudes may be independent contributing factors in the pathogenesis and progression of hypertension and cardiovascular disease.1, 2, 201, 214 1,25(OH)2D is involved in controlling the production of renin, one of the most important hormones for regulating blood pressure.215 Ecological evidence also exists that African Americans, who have

VITAMIN D AND PSORIASIS

One of the great successes of vitamin D therapy for treating an extraskeletal disorder is in the treatment of psoriasis.193, 196 Smith et al27 showed that 1,25(OH)2D3 inhibited the proliferation of human keratinocytes that express the VDR in vitro and accelerated their differentiation. This suggested that hyperproliferative skin disorders such as psoriasis might be responsive to treatment with 1,25(OH)2 D3.222 Initial treatments with topical 1,25(OH)2D3 showed great improvements in reducing the

VITAMIN D AND MULTIPLE SCLEROSIS

As with previous epidemiological data reporting a latitudinal risk gradient for cancer and cardiovascular disease,2, 161, 163, 166, 204, 209, 215 a similar risk gradient exists for developing multiple sclerosis.205, 224, 225, 226 Subjects who were born and/or lived below 35°N latitude for the first decade of life had decreased overall lifetime risks of developing multiple sclerosis.205, 225 However, as with other ecological studies, the observed differences could be related to any number of

VITAMIN D AND TYPE I DIABETES MELLITUS

1,25(OH)2D acts as an immunomodulator, reducing cytokine production and lymphocyte proliferation, which have been implicated in the destruction of insulin-secreting β cells in the pancreas and the development of type 1 diabetes mellitus.142 In addition, β-islet cells express the VDR and respond to 1,25(OH)2D by increasing insulin production.1, 142, 230, 231

In animals, the administration of 1,25(OH)2D prevents the development of experimentally induced type 1 diabetes mellitus.142, 144 Zella and

VITAMIN D IN OTHER DISEASES

A possible role of vitamin D has also been implicated in several other diseases, including rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, osteoarthritis, and periodontal disease. Many of these studies are epidemiological studies and animal models, and the effect in humans is unknown. Recent findings suggest that vitamin D intake is inversely associated with rheumatoid arthritis208 and that 1,25(OH)2D3 supplementation can inhibit disease progression in mouse

VITAMIN D DOSING, SUPPLEMENTATION, AND UV IRRADIATION AND/OR SENSIBLE SUN EXPOSURE

Supplementation with vitamin D has been estimated to prevent vitamin D deficiency in approximately 98% of the general population.1, 16, 236 Vitamin D supplementation and exposure to sunlight or simulated sunlight have been shown to increase serum 25(OH)D levels in elderly patients 11, 84, 87, 89, 90, 92, 94, 97, 102, 107, 237, 238, 239, 240 (Figure 3).

The Institute of Medicine's adequate intake for the United States and Canada is 200 IU/d for all children and adults younger than 51 years, 400

TREATMENT OF SEVERE VITAMIN D DEFICIENCY

Although severe vitamin D deficiency (25[OH] levels <10 ng/mL [25 nmol/L]) is much less common than inadequacy, it does occur, especially in elderly house-bound people. The best method for treating vitamin D deficiency is an oral dose of 50,000 IU/wk of vitamin D2 for 8 weeks, then checking 25(OH)D levels.1, 11 In some cases, another once-weekly 8-week course of 50,000 IU of vitamin D2 may be necessary to boost 25(OH)D levels into the desired range of more than 30 to 50 ng/mL (75-125 nmol/L).

CONCLUSION

Vitamin D is important for calcium and phosphorus homeostasis and musculoskeletal health. In children, severe vitamin D deficiency (25[OH]D, <10 ng/mL [24.9 nmol/L]) manifests as rickets, and vitamin D inadequacy (25[OH]D, 10-29 ng/mL [24.9-72.4 nmol/L]) can impair or retard attainment of peak bone mass. In adults, inadequate vitamin D can result in secondary hyperparathyroidism, decreased BMD, osteoporosis, osteomalacia, and increased risk of fragility fractures.250, 251, 252

Vitamin D

Acknowledgments

I thank Dr Joseph West and Christine McCrary Sisk of Merck and Catherine St. Clair for assistance with preparation of the submitted manuscript.

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    This work was supported in part by National Institutes of Health grants MOIRR00533 and AR369637 and the UV Foundation.

    *

    Dr Holick is an Academic Associate for Nichols Institute Diagnostics.

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