The hormonally-active form of vitamin D,1,25-D plays an integral role in calcium homeostasis and in the maintenance of healthy bone.^2,3,5 1,25-D stimulates the absorption of calcium at the level of the intestine and may also serve to increase calcium and phosphate resorption at the kidney level.³ Vitamin D deficiency leads to the mobilization of calcium from bone.⁴ Individuals with more severe vitamin D deficiency can develop osteomalacia and/or osteoporosis.² Osteomalacia in children, also referred to as rickets, results in well described skeletal malformations since their bones are actively growing.² Recent clinical and epidemiological studies suggest that vitamin D deficiency may play a role in several conditions unrelated to bone including prostate cancer, breast cancer, colon cancer, heart disease, hypertension, multiple sclerosis, and type 1 diabetes.^2,4,5

A number of studies have shown that vitamin D deficiency is very common, especially in certain high-risk populations.² This situation has occurred, in part, because the foods in the typical American diet are very low in vitamin D. Fatty fish, such as mackeral and salmon and fish liver oils, are some of the few natural dietary sources of vitamin D.^2-5 Most people do not eat enough of these foods to maintain adequate vitamin D levels. In the United States, vitamin D is added to milk in order to prevent the occurrence of rickets in the pediatric population. Unfortunately, too many children do not drink enough milk to raise their vitamin D levels to the optimum range. Also, recent studies have shown that the level of vitamin D in fortified milk is frequently much lower than that recommended by the FDA.² Human milk contains very little vitamin D because many mothers are deficient, so children of mothers who choose to breast-feed are at risk of developing rickets if they are not given supplemental vitamin D. The American Academy of Pediatrics recommends that infants who are exclusively breast-feeding should be given a supplement of vitamin D.⁶

Several factors are associated with an increased risk of developing vitamin D deficiency. At risk populations include^2-4:

• Individuals with low dietary vitamin D levels: Infants fed only mother's milk and children who do not drink fortified milk are at risk.
• Individuals with malabsorption syndromes: Patients with pancreatic enzyme deficiency, Crohn's disease, cystic fibrosis, celiac disease, and surgical resection of stomach or intestines are at risk.
• Individuals with severe liver disease: Hepatic disease can reduce the conversion of vitamin D to 25-D and can lead to malabsorption of vitamin D.
• Individuals with kidney disease: Nephrotic syndrome can increase the urinary loss of vitamin D.
• Individuals taking certain drugs: Several medications, including phenytoin, phenobarbital, and rifampin accelerate the breakdown of vitamin D by the liver.
• Individuals who live at higher latitudes: Individuals who live in northern climates are at increased risk of deficiency, especially in winter months due to diminished exposure to UVB radiation.
• Individuals who spend little time outside: Individuals who are home-bound or simply choose to remain inside are at increased risk.
• Older adults: The skin becomes less efficient at producing vitamin D as one ages because of diminished levels of vitamin D precursors in the skin.
• Individuals with decreased sun exposure for cultural reasons: Women in some societies are required to cover themselves with heavy clothing, reducing exposure to the sun's rays.
• Races with high melanin levels: Increased skin pigmentation can reduce the efficiency of vitamin D conversion in the skin as much as 50-fold. Individuals with dark complexions living at higher latitudes are at increased risk.

Serum concentrations of 25-D are known to vary with age, sex, race, season, and geographic location.² This has led to establish seasonal expected ranges for the geographic location and local population. This approach provides a “reference interval,” but does not adequately determine health status with regard to vitamin D levels if a significant portion of the reference population is, in fact, deficient. A more useful parameter in clinical practice would be a nutritional threshold, below which an individual could be characterized as vitamin D deficient. Several investigators have approached this problem by assessing the correlation of plasma 25-D concentration with various biological markers.¹ For example, plasma 25-D levels have been shown to have an inverse relationship to serum parathyroid hormone levels.¹ Secondary hyperparathyroidism can be corrected when 25-D levels are increased to >32 ng/mL (80 nmol/L).¹ Serum concentrations <32 ng/mL have been shown to impair intestinal calcium absorption and subsequent skeletal density.¹ Further studies have shown that 25-D levels <32 ng/mL are associated with impaired insulin resistance and beta-cell function.¹ Together these data suggest that 32 ng/mL represents the appropriate threshold for identifying individuals with clinical vitamin D deficiency.¹