Vitamin D has 2 main forms:

• D2 (ergocalciferol)

• D3 (cholecalciferol): The naturally occurring form and the form used for low-dose supplementation

Vitamin D3 is synthesized in skin by exposure to direct sunlight (ultraviolet B radiation) and obtained in the diet chiefly in fish liver oils and salt water fish (see tableSources, Functions, and Effects of Vitamins). In some countries, milk and other foods are fortified withvitamin D. Human breast milk is low in). In some countries, milk and other foods are fortified with vitamin D. Human breast milk is low invitamin D, containing an average of only 10% of the amount in fortified cow’s milk.

Vitamin D levels may decrease with age because skin synthesis declines. Sunscreen use and dark skin pigmentation also reduce skin synthesis ofvitamin D.

Vitamin D is a prohormone with several active metabolites that act as hormones. It is metabolized by the liver to 25(OH)D (calcifediol, calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D), which is then converted by the kidneys to 1,25-dihydroxyvitamin D (1,25-dihydroxycholecalciferol,calcitriol, or activevitamin D hormone). 25(OH)D, the major circulating form, has some metabolic activity, but 1,25-dihydroxyvitamin D is the most metabolically active. The conversion to 1,25-dihydroxyvitamin D is regulated by its own concentration,parathyroid hormone (PTH), and serum concentrations of calcium and phosphate.

Vitamin D affects many organ systems (see tableActions ofVitamin D and Its MetabolitesActions of Vitamin D and Its Metabolites), but mainly it increases calcium and phosphate absorption from the intestine and promotes normal bone formation and mineralization.

Vitamin D and related analogs may be used to treatpsoriasis,hypoparathyroidism, andrenal osteodystrophy. Its usefulness in reducing all-cause mortality or in preventing leukemia and breast, prostate, colon, or other cancers has not been proved nor has its efficacy in treating various other nonskeletal disorders in adults (1–3).Vitamin D supplementation does not effectively treat or prevent depression or cardiovascular disease (4, 5) and has minimal effects on preventing acute respiratory infections (6). Taking the combined recommended dietary allowance of bothvitamin D and calcium may slightly reduce the risk of falls (). Taking the combined recommended dietary allowance of both vitamin D and calcium may slightly reduce the risk of falls (7) in patients who arevitamin D deficient, especially those who are institutionalized; however, large doses ofvitamin D may increase fracture risk (8, 9). Because the causes of falls are multifactorial, other studies have not found thatvitamin D supplements alone reduce falls and fractures in older adults (10, 11).

(See alsoOverview of Vitamins.)

Vitamin D deficiency may result from the following:

• Inadequate exposure to sunlight

• Inadequate intake ofvitamin D

• Reduced absorption ofvitamin D

• Abnormal metabolism ofvitamin D

• Resistance to the effects ofvitamin D

Vitamin D deficiency can cause muscle aches, muscle weakness, and bone pain at any age.

Vitamin D deficiency in a pregnant woman causes deficiency in the fetus. Occasionally, deficiency severe enough to cause maternal osteomalacia results in rickets with metaphyseal lesions in neonates.

In young infants, rickets causes softening of the entire skull (craniotabes). When palpated, the occiput and posterior parietal bones may indent easily.

In older infants with rickets, sitting and crawling are delayed, as is fontanelle closure; there is bossing of the skull and costochondral thickening. Costochondral thickening can look like beadlike prominences along the lateral chest wall (rachitic rosary).

In children 1 to 4 years, epiphyseal cartilage at the lower ends of the radius, ulna, tibia, and fibula enlarge; kyphoscoliosis develops, and walking is delayed.

In older children and adolescents, walking is painful; in extreme cases, deformities such asbowlegs andknock-knees develop. The pelvic bones may flatten, narrowing the birth canal in adolescent girls.

Tetany is caused byhypocalcemia and may accompany infantile or adultvitamin D deficiency. Tetany may cause paresthesias of the lips, tongue, and fingers; carpopedal and facial spasm; and, if very severe, seizures. Maternal deficiency can cause tetany in neonates.

Osteomalacia predisposes to fractures. In older adults, hip fractures may result from only minimal trauma.

• Levels of 25(OH)D (D2 + D3)

Vitamin D deficiency may be suspected based on any of the following:

• A history of inadequate sunlight exposure or dietary intake

• Symptoms and signs of rickets, osteomalacia, or neonatal tetany

• Characteristic bone changes seen on radiographs

Radiographs of the radius and ulna plus serum levels of calcium, phosphate, alkaline phosphatase,parathyroid hormone (PTH), and 25(OH)D are needed to differentiatevitamin D deficiency from other causes of bone demineralization.

Assessment ofvitamin D status and serologic tests for syphilis can be considered for infants with craniotabes based on the history and physical examination, but most cases of craniotabes resolve spontaneously. Rickets can be distinguished from chondrodystrophy because the latter is characterized by a large head, short extremities, thick bones, and normal serum calcium, phosphate, and alkaline phosphatase levels.

Tetany due to infantile rickets may be clinically indistinguishable from seizures due to other causes. Blood tests and clinical history may help distinguish them.

Radiographs

Bone changes, seen on radiographs, precede clinical signs. In rickets, changes are most evident at the lower ends of the radius and ulna. The diaphyseal ends lose their sharp, clear outline; they are cup-shaped and show a spotty or fringy rarefaction. Later, because the ends of the radius and ulna have become noncalcified and radiolucent, the distance between them and the metacarpal bones appears increased. The bone matrix elsewhere also becomes more radiolucent. Characteristic deformities result from the bones bending at the cartilage-shaft junction because the shaft is weak. As healing begins, a thin white line of calcification appears at the epiphysis, becoming denser and thicker as calcification proceeds. Later, the bone matrix becomes calcified and opacified at the subperiosteal level.

Rickets

Image

Credit DU CANE MEDICAL IMAGING LTD / SCIENCE PHOTO LIBRARY

In adults, bone demineralization, particularly in the spine, pelvis, and lower extremities, can be seen on radiographs; the fibrous lamellae can also be seen, and incomplete ribbonlike areas of demineralization (pseudofractures, Looser lines, Milkman syndrome) appear in the cortex.

• Correction of calcium and phosphate deficiencies

• Supplementalvitamin DSupplemental vitamin D

Calcium deficiency (which is common) and phosphate deficiency should be corrected.

As long as calcium and phosphate intake is adequate, adults with osteomalacia and children with uncomplicated rickets can be cured by giving vitamin D3 40 mcg (1600 international units [IU]) orally once a day. Serum 25(OH)D and 1,25-dihydroxyvitamin D begin to increase within 1 or 2 days. Serum calcium and phosphate increase and serum alkaline phosphatase decreases within about 10 days. During the third week, enough calcium and phosphate are deposited in bones to be visible on radiographs. After about 1 month, the dose can usually be reduced gradually to the usual maintenance level of 15 mcg (600 IU) once/day.

If tetany is present,vitamin D should be supplemented with IV calcium salts for up to 1 week (seeHypocalcemia).

Some older adult patients need vitamin D3 25 to> 50 mcg (1000 to≥ 2000 IU) daily to maintain a 25(OH)D level> 20 ng/mL (> 50 nmol/L); this dose is higher than the recommended dietary allowance for people< 70 years (600 IU) or > 70 years (800 IU). The current upper limit forvitamin D is 4000 IU/day. Higher doses of vitamin D2 (eg, 25,000 to 50,000 IU every week or every month) are sometimes prescribed; however, because vitamin D3 is more potent than vitamin D2, it is now preferred.

Because rickets and osteomalacia due to defective production ofvitamin D metabolites arevitamin D–resistant, they do not respond to the doses usually effective for rickets due to inadequate intake. Endocrinologic evaluation is required because treatment depends on the specific defect. When 25(OH)D production is defective, vitamin D3 50 mcg (2000 IU) once a day increases serum levels and results in clinical improvement. Patients with kidney disorders often need 1,25-dihydroxyvitamin D (calcitriol) supplementation.–resistant, they do not respond to the doses usually effective for rickets due to inadequate intake. Endocrinologic evaluation is required because treatment depends on the specific defect. When 25(OH)D production is defective, vitamin D3 50 mcg (2000 IU) once a day increases serum levels and results in clinical improvement. Patients with kidney disorders often need 1,25-dihydroxyvitamin D (calcitriol) supplementation.

Type I hereditaryvitamin D–dependent rickets responds to 1,25-dihydroxyvitamin D 1 to 2 mcg orally once a day. Some patients with type II hereditaryvitamin D–dependent rickets respond to very high doses (eg, 10 to 24 mcg/day) of 1,25-dihydroxyvitamin D; others require long-term infusions of calcium.

Dietary counseling is particularly important for people in communities who are at risk ofvitamin D deficiency.

Fortifying unleavened chapati flour withvitamin D (125 mcg/kg) has been effective among Indian immigrants in Britain.Fortifying unleavened chapati flour with vitamin D (125 mcg/kg) has been effective among Indian immigrants in Britain.

The benefits of sunlight exposure forvitamin D status must be weighed against the increased skin damage and skin cancer risks.

All breastfed infants should be given supplementalvitamin D 10 mcg (400 IU) once a day from birth to 6 months; at 6 months, a more diversified diet is available. Any benefit of doses higher than the recommended dietary allowance is unproved.All breastfed infants should be given supplemental vitamin D 10 mcg (400 IU) once a day from birth to 6 months; at 6 months, a more diversified diet is available. Any benefit of doses higher than the recommended dietary allowance is unproved.

• Vitamin D deficiency is common and results from inadequate exposure to sunlight and inadequate dietary intake (usually occurring together) and/or from chronic kidney disease.

• The deficiency can cause muscle aches and weakness, bone pain, and osteomalacia.

• Suspectvitamin D deficiency in patients who have little exposure to sunlight and a low dietary intake, typical symptoms and signs (eg, rickets, muscle aches, bone pain), or bone demineralization seen on radiographs.

• To confirm the diagnosis, measure the level of 25(OH)D (D2 + D3).

• To treatvitamin D deficiency, correct deficiencies of calcium and phosphate and give supplementalvitamin D.deficiency, correct deficiencies of calcium and phosphate and give supplemental vitamin D.