Vitamin D Deficiency and Related Disorders 

Vitamin D deficiency in children can manifest as rickets (it is the most common cause of nutritional rickets), which presents as bowing of the legs. Vitamin D deficiency in adults results in osteomalacia, which presents as a poorly mineralized skeletal matrix. These adults can experience chronic muscle aches and pains.^[1] (See images below.)

Vitamin D is important for calcium homeostasis and for optimal skeletal health. The term vitamin D refers to either vitamin D2 or vitamin D3. Vitamin D3, also known as cholecalciferol, is either made in the skin or obtained in the diet from fatty fish. Vitamin D2, also known as ergocalciferol, is obtained from irradiated fungi, such as yeast. Vitamin D2 and vitamin D3 are used to supplement food products or are contained in multivitamins. Past studies suggested that vitamin D3 may be more effective than vitamin D2 in establishing normal vitamin D stores.^{[2, 3]} However, a study by Holick and colleagues demonstrated that vitamin D2 and vitamin D3 appear to be equipotent in raising 25(OH)D concentrations when given in daily doses of 1000 IU.^[4]

Vitamin D deficiency can result from a variety of causes, including inadequate exposure to sunlight, malabsorption problems, lack of vitamin D in breast milk, and the effects of certain medications. (See Causes.)

The production of vitamin D3 in the skin involves a series of reactions initiating with 7-dehydrocholesterol. Upon exposure to ultraviolet B (UVB) radiation between the wavelengths of 290-315 nm, 7-dehydrocholesterol is converted to previtamin D3, which is then converted to vitamin D3 after a thermally induced isomerization reaction in the skin. From the skin, newly formed vitamin D3 enters the circulation by binding to vitamin D binding protein (DBP). In order to become active, vitamin D requires 2 sequential hydroxylations to form 1,25-dihydroxyvitamin D (1,25[OH]₂ D).

Vitamin D is initially hydroxylated in the 25 position by the hepatic microsomal and/or mitochondrial enzyme vitamin D 25-hydroxylase. The second hydroxylation occurs in the kidney by the P450 enzyme 25-hydroxyvitamin D-1 alpha-hydroxylase. Upon entering the cell, the 1,25(OH)₂ D hormone binds to the vitamin D receptor (VDR). The bound vitamin D receptor then forms a heterodimer with the retinoic acid X receptor (RXR). This heterodimer then goes to the nucleus to bind deoxyribonucleic acid (DNA) and increases transcription of vitamin D–related genes.

The major function of vitamin D is to increase the efficiency of calcium absorption from the small intestine. Heaney and colleagues demonstrated that maximum calcium absorption occurs at levels of 25-hydroxyvitamin D (25[OH]D) greater than 32 ng/mL.^[5] Vitamin D also enhances the absorption of phosphorus from the distal small bowel. Adequate calcium and phosphorus absorption from the intestine is important for proper mineralization of the bone. The second major function of vitamin D is for the maturation of osteoclasts to resorb calcium from the bones.

Inadequate circulating 25(OH)D is associated with elevated parathyroid hormone (PTH); this condition is called secondary hyperparathyroidism. The rise in PTH may result in increased mobilization of calcium from the bone, which results in decreased mineralization of the bone.

Of note, prolonged exposure to the sun does not cause vitamin D toxicity. This is because after prolonged UVB radiation exposure, the vitamin D made in the skin is further degraded to the inactive vitamin D metabolites tachysterol and lumisterol.

Frequency

United States

Vitamin D insufficiency is highest among people who are elderly, institutionalized, or hospitalized. In the United States, 60% of nursing home residents^[6] and 57% of hospitalized patients^[7] were found to be vitamin D deficient.

However, vitamin D insufficiency is not restricted to the elderly and hospitalized population; several studies have found a high prevalence of vitamin D deficiency among healthy, young adults. A study from Boston determined that nearly two thirds of healthy, young adults in Boston were vitamin D insufficient at the end of winter.^[8]

Vitamin D status may fluctuate throughout the year, with the highest serum 25(OH)D occurring after the summer and the lowest serum 25(OH)D concentrations after winter. A study by Shoben at el demonstrated that mean serum 25(OH)D concentrations can vary as much as 9.5 ng/mL. Factors such as sex, greater latitude, and more physical activity are associated with greater differences in serum 25(OH)D concentrations from winter and summer.^[9]

International

Similar rates of vitamin D deficiency have been reported in Europe^[10] and Canada. A greater prevalence of vitamin D deficiency exists in Middle Eastern countries. A study of 316 young adults aged 30-50 from the Middle East showed that 72.8% had 25(OH)D values of less than 15 ng/dL (that is, severely deficient). This was significantly more common in women than in men (83.9% vs 48.5%). The difference between sexes probably reflects the cultural and religious practices leading to less skin exposure in women than in men.^{[11, 12, 13, 14]}

Mortality/Morbidity

• The treatment of vitamin D insufficiency can decrease the risk of hip and nonvertebral fractures.^{[15, 16]} A meta-analysis by Boonen et al of postmenopausal women and of men aged 50 years or older reporting a risk of hip fracture found that oral vitamin D supplementation reduced the risk of hip fractures by 18% when vitamin D and calcium were taken together.^[17] Most of the trials that demonstrated the antifracture efficacy of vitamin D used approximately 800 IU of vitamin D3. The minimum 25(OH)D level at which antifracture efficacy was observed was 30 ng/ml (74 nmol/L), suggesting a threshold for optimal levels of 25(OH)D for fracture protection.
• Bischoff-Ferrari et al, in another meta-analysis, evaluated the efficacy of oral vitamin D supplementation in the prevention of hip and other nonvertebral bone fractures.^[18] The analysis, of individuals aged 65 years or older, took into account 12 double-blind, randomized, controlled trials (RCTs) for nonvertebral fractures (n = 42,279) and 8 RCTs for hip fractures (n = 40,886), comparing the results obtained from the use of oral vitamin D (with or without calcium) with those derived from the administration of calcium alone and from placebo use.
• The results indicated that vitamin D offers dose-dependent protection against fractures. In this study, doses of more than 400 IU per day were found to reduce fractures by at least 20% in individuals aged 65 years or older. In contrast to the Boonen study, the investigators maintained that these effects were independent of calcium supplementation.
• Vitamin D insufficiency contributes to osteoporosis by decreasing intestinal calcium absorption.^{[5, 19]} Treatment of vitamin D deficiency has been shown to improve bone mineral density.^{[20, 21]} An analysis of the Third National Health and Nutrition Examination Survey (NHANES III) demonstrated a positive correlation between circulating 25(OH)D levels and bone mineral density.^[22]
• Vitamin D supplementation has been associated with a reduction in falls and improved muscle strength in the elderly A meta-analysis demonstrated that vitamin D supplementation resulted in a reduction in falls of about 22% in ambulatory and institutionalized elderly subjects, as compared with controls.^{[23, 24]} Another meta-analysis examining muscle strength associated with vitamin D supplementation found significant improvement in reduced postural sway, timed up-and-go test results, and lower extremity strength in a pooled analysis of 13 studies.^[25]
• Epidemiologic data suggest that vitamin D deficiency places adults at risk for developing cancer;^{[26, 27, 28, 29, 30]} these apparently include breast, colon, and prostate cancer.^{[31, 32]} Several studies using cultured cancer cells in mice models have also supported the notion that vitamin D prevents the growth of cancers.^[33] Larger, randomized clinical trials are underway in humans to establish the role of vitamin D in the prevention of cancers.
• Vitamin D insufficiency may increase the risk for type I and type II diabetes mellitus.^{[34, 35]} In NHANES III, lower vitamin D status was associated with higher fasting glucose and 2-hour glucose after an oral glucose tolerance test.^[36] Furthermore, vitamin D supplementation in adults has been associated with improved insulin sensitivity in several small, case-control studies.^[34] Joergensen et al determined that vitamin D deficiency in type 1 diabetes may predict all causes of mortality but not development of microvascular complications.^[37] The contribution of vitamin D deficiency to mortality must be mediated by nonvascular mechanisms.
• A meta-analysis evaluated the effect of vitamin D supplementation (using a mean supplementation dosage of about 500 IU daily) on all-cause mortality in 18 randomized controlled trials and found a 7% relative risk reduction for death.^[38]
• A recent Cochrane Review studied 50 randomized controlled trials that included more than 94,000 individuals, who were primarily elderly women. The review found that vitamin D3 supplementation decreased mortality. Other forms of vitamin D, including vitamin D2, calcitriol, and alpha-calcidiol, did not reduce mortality.^[39]

Race

Darker skin interferes with the cutaneous synthesis of vitamin D. A study from by Holick and coauthors demonstrated that non-Hispanic black subjects require 6 times the amount of UV radiation necessary to produce the similar serum vitamin D concentration seen in non-Hispanic white subjects.^[40] The explanation for the increased radiation necessary to increase vitamin D levels is that melanin absorbs ultraviolet radiation.

A higher prevalence of vitamin D insufficiency exists among non-Hispanic black persons. Dawson-Hughes and colleagues demonstrated that in Boston, 73% of elderly black subjects were vitamin D insufficient, compared with 35% of elderly non-Hispanic whites.^[41] In a large survey of 1500 healthy black women younger than 50 years, 40% were vitamin D deficient (25[OH]D < 16 ng/mL), as compared with 4% of 1400 white women in that study.^[42] The decreased efficacy of vitamin D production by darker-pigmented skin explains the higher prevalence of vitamin D insufficiency among darker-skinned adults.

Age

Vitamin D production in the skin declines with advancing age, making elderly populations more dependent on dietary vitamin D. For the average older person, higher dietary intake of vitamin D may be required to achieve optimal serum levels of 25(OH)D.^[35]