Sponsored By
Robin Koon

January 31, 2011

12 Min Read
Understanding Vitamin D

Vitamin D (calcitriol) is structurally classified as a hormone, with several active metabolites or analogues. It is a fat-soluble vitamin compound that is miscible in oils and fats, soluble in ether hydrocarbons and chlorinated hydrocarbons, slightly soluble in alcohol and insoluble in water.

There are two main physiological sterol forms (considered to be pro-hormones) of vitamin D used in supplementation: D2 (ergocalciferol) from plants; and D3 (cholecalciferol) from animal sources (Figure 1). The two forms have traditionally been regarded as equivalent, but evidence suggests they are metabolized differently. Vitamin D3 is believed to be more than three times more effective than vitamin D2 in raising serum 25-hydroxyvitamin D [25(OH)D] concentrations and maintaining those levels for a longer time.



Vitamin D (D2 and D3) obtained from various sources (sun exposure, food and supplements) is a pro-hormone; as such, it is biologically inert and must undergo two separate conversions within the body before it can be utilized (Figure 2). The first conversion occurs in the liver where vitamin D is hydroxylated into 25(OH)D (known as calcidiol). The second conversion occurs primarily in the kidney by hydroxylation into two dihydroxylated metabolites: (1) the main physiologically active hormone form: 1,25-dihydroxycalciferol [1,25(OH)2D] (known as calcitriol) and (2) 24(R),25(OH)2D3 (24,25-dihydroxyvitamin D).



The conversion to the active metabolite form calcitriol is regulated by its own concentration, parathyroid hormone (PTH), and serum concentrations of calcium and phosphate. Following this conversion, the calcitriol is released into the blood circulation by binding to a carrier protein in the plasma [Vitamin D Binding Protein (VDBP)], and then it is then transported to various organs throughout the body. Vitamin D stored in the human body as calcidiol has a large volume of distribution and a half-life of about 15 to 20 days.

There are several sterol metabolite analogue forms (vitamers) known:

D1 - Ergocalciferol   calciferol (ergocalciferol with lumisterol, 1:1)

D2 - Ergocalciferol   ercalciol (from ergosterol)

D3 - Cholecalciferol  calciol (from 7-dehydrocholesterol)

D4 - 22,23-Dihydroercalciol

D5 - Sitocalciferol (from 7-dehydrocholesterol)

D6 - (22E)-(24R)-Ethyl-22,23-didehydrocalciol

Plus many others (e.g., alfacaleidol, calcidiol, tacalciol, dihydrotachysterol, etc.)

It is interesting to note that "vitamer" is a term that means one of two or more related chemical substances that fulfill the same specific vitamin function. These related chemical compounds are structurally related to a specific vitamin, and converted to the same overall active metabolites within the body. So they have the same kind of biological activity, although sometimes with lower potency. When there are several vitamers, the group of compounds exhibiting the biological activity of the specific vitamin is given a generic descriptor (e.g., vitamin A is the generic descriptor for retinol and its derivatives as well as several carotenoids). Chemically, these vitamer forms of vitamin D are known as secosteroids (i.e., steroids) in which one of the bonds in the steroid rings is broken.

Both vitamin D2 and D3 are used for human nutritional supplementation; the pharmaceutical analogue forms include calcitriol (1-alpha-25-dihydroxycholecalciferol, Rocaltrol® and various others), calcipotriene (Dovonex®), doxercalciferol (Hectorol®), paricalcitol (Zemplar®), dihydrotachysterol (Hytakerol®) and alcitonin (various).

Most people meet their vitamin D needs normally through exposure to sunlight. Ultraviolet (UV) light radiation with a wavelength of 270 to 315 nanometers penetrates skin and converts cutaneous 7-dehydrocholesterol into vitamin D3. Adequate amounts of vitamin D3 can be made in the skin after only 10 to 15 minutes of sun exposure at least two times per week without sunscreen. Factors that can affect outdoor UV vitamin D synthesis include seasons, geographic latitude, time of day, cloud cover, smog, skin melanin content and sunscreen.

Biological Functions

Vitamin D's main biological function is maintaining normal blood serum levels of calcium and phosphate; it is essential for the absorption and utilization of calcium and phosphate (aiding in the maintaining of normal bone mineralization and growth). It is the precursor for many hormones involved in the maintenance of calcium homeostasis and the regulation of cell proliferation and differentiation, where it has both endocrine and paracrine actions.

It is also vital for cell differentiation, proliferation and apoptosis; insulin secretion; blood pressure (renin secretion); reabsorption of calcium in the kidney tubules; parathyroid hormone secretion; thyroid hormone (calcitonin) secretion; energy metabolism; and preventing hypocalcemic tetany. Vitamin D has other roles in human health: muscle contraction, nerve conduction, general cellular function, modulation of immune function, antitumor activity, insulin production stimulation and  inflammation reduction.

Throughout the body are Vitamin D Receptors (VDR), a nuclear receptor on many cell types. Many genes that regulate cell proliferation, differentiation and apoptosis are modulated in part by vitamin D. The VDR is responsible for transcribing 913 genes and probably many more, directly (and/or indirectly) regulating 3 percent of the human genome.

Absorption of dietary vitamin D takes place in the upper part of the small intestine with the aid of bile salts, if fat absorption is normal. It is incorporated into the chylomicron fraction and absorbed through the lymphatic system. Vitamin D is stored in adipose tissue. It has to be metabolized to become active. In blood serum plasma, Vitamin D Binding Protein (DBP) carries vitamin D and its metabolites to their various target organs; it also known as gc-globulin (group-specific component), a protein that in humans is encoded by the GCgene. Vitamin D is eliminated renally and by biliary excretion.

Vitamin D Deficiency

Some studies indicate between 50 percent and 70 percent of the population have low levels of vitamin D. Vitamin D deficiency (hypovitaminosis D) is primarily characterized by inadequate mineralization or by demineralization of the skeleton. Vitamin D deficiency can result from several conditions:

  • An inadequate intake or inadequate sunlight exposure (UV). Sunlight exposure, to avoid deficiency, carries other risks (e.g., skin cancer).

  • Reduced absorption (malabsorption) of vitamin D in the gastrointestinal (GI) tract due to disease state, surgical changes or medications.

  • Conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders.

  • Certain rare hereditary disorders.

  • Body characteristics such as darker skin color, obesity (body fat) and age (>50).

Deficiency can result in impaired bone mineralization. This can lead to bone loss, and to bone softening diseases, such as:

  • Rickets, a childhood disease characterized by impeded growth and deformity of the long bones. Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the 1930s, the United States started fortification of milk with 10 mcg (400 IU) of vitamin D per quart, which lead to a dramatic decline in the number of rickets cases.

  • Osteomalacia (only in adults), a bone-thinning disorder that is characterized by proximal muscle weakness, bone fragility, and chronic musculoskeletal pain. A number of reports indicate vitamin D deficiency may be related to other various types of pain as well.    

  • Osteoporosis, a condition of reduced bone mineral density (BMD) and increased bone fragility. Some studies have shown that as much as 50 percent of the elderly and women being treated for osteoporosis may be vitamin D deficient.

  • Hypocalcemia (low serum calcium), which stimulates production of parathyroid hormone (PTH), causing hyperparathyroidism. Hyperparathyroidism increases absorption, bone mobilization and renal conservation of calcium, but increases excretion of phosphateas a result, bone mineralization is impaired.

Infants are a group at more risk of vitamin D deficiency due to their high rate of skeletal growth. At birth, the infant's store of vitamin D is only sufficient for the first month or so of life. Infants who are breastfed are at higher risk too, since there is little vitamin D in human breast milk. Vitamin D deficiency in a pregnant woman causes deficiency in the fetus as well.

Deficiency can also lead to increased susceptibility or development of several chronic diseases or disease states such as cardiovascular disease (CVD), peripheral artery disease (PAD), high blood pressure, cancer (various), periodontal disease, multiple sclerosis (MS), chronic pain, Parkinson's disease, seasonal affective disorder, cognitive impairment (memory loss and foggy brain), tuberculosis, autoimmune diseases (e.g., diabetes) and weight loss.

Finally, in the absence of vitamin K or with drugs (particularly blood thinners) that interfere with vitamin K metabolism, vitamin D can promote soft tissue calcification.

Adequate Intake, Dosages

The Dietary Reference Intakes (DRI) recommendations for vitamin D were recently changed in Nov. 30, 2010. The new current daily DRI recommendations for Vitamin D are:  





Upper Limit (UL)

0-6 months

400 IU (10 mcg)



1,000 IU (25 mcg)

7-12 months

400 IU (10 mcg)



1,500 IU (38 mcg)

1-3 years

600 IU (15 mcg)



2,500 IU (63 mcg)

4-8 years

600 IU (15 mcg)



3,000 IU (75 mcg)

9-70 years

600 IU (15 mcg)

600 IU (15 mcg)

600 IU (15 mcg)

4,000 IU (100 mcg)

71+ years


800 IU (20 mcg)


4,000 IU (100 mcg)

Note: Intake reference values for vitamin D and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of The National Academies (formerly National Academy of Sciences). The adequate intakes (AIs) for vitamin D are based on the assumption that the vitamin is not synthesized by exposure to sunlight.

The biologic activity of vitamin D (mcg = µg):

            1 IU = 0.025 mcg

            40 IU = 1 mcg

The exact long-term safe dose of vitamin D is not known. Even what constitutes the optimal intake of vitamin D remains a matter of some disagreement. Some scientists/experts are calling for an upward revision; saying that optimal amounts for all adults should be to 800 to 1,000 IU/d (20 to 25 mcg). Others state the minimum should be as high as 2,000 IU/d.

Dosage of vitamin D analogs must be individualized with careful monitoring of serum calcium levels. Careful titration is necessary to avoid overdosage. Dietary and other sources of vitamin D must be considered. Calcium intake should be adequate. Periodic monitoring of serum calcium, phosphate, magnesium, alkaline phosphatase is recommended for patients taking prescriptive vitamin D analogs. There are two important populations to note:

Pregnancy: The safety of doses in excess of 10 mcg/d (400 IU) of vitamin D during pregnancy has not been established. Maternal hypercalcemia, possibly caused by excessive vitamin D intake during pregnancy, has been associated with hypercalcemia in neonates.

Renal patients: Patients with chronic renal disease may have low levels of D, since many of these patients cannot convert calcifediol to calcitriol. Because alfacalcidol, calcitriol and dihydrotachysterol (D analogs) do not require renal hydroxylation, they are useful in patients with renal failure.

Toxicity can occur with vitamin D, although it primarily results from ingesting an excessive amount, such as when taking a prescription drug version or overuse of a vitamin supplement. The main symptoms of excessive vitamin D are: hypercalcemia, anorexia, constipation, nausea and vomiting, high blood pressure, polyuria, polydipsia, weakness, nervousness, pruritus, kidney stones, and renal damage or failure.

In infants, ingestion of 1,000 mcg/d (40,000 IU) of vitamin D produces toxicity within one to four months. In adults, taking 1,250 mcg/d (50,000 IU) for a period of several months can produce toxicity. Other medical sources indicate the threshold for vitamin D toxicity in humans is 500 to 600 mcg/d per kilogram of body weight.

Note that exposure to sunlight for extended periods of time does not normally cause vitamin D toxicity. This is because the concentration of vitamin D precursors produced in the skin reaches an equilibrium point, so further vitamin D production slows or ceases. Maximum endogenous production with full body exposure to sunlight, is estimated to be approximately 250 mcg/d (10,000 IU).

There are certain classes of drugs that may interact with vitamin D absorption and bioavailability. These include:

Antacids (magnesium-containing): Hypermagnesemia may develop when these agents are used concurrently with vitamin D, particularly in patients with chronic renal failure.

Anticonvulsants (Phenytoin and Phenobarbital): Decreased vitamin D effects may occur when certain anticonvulsants are administered, as they may induce hepatic microsomal enzymes and accelerate the conversion of vitamin D to inactive metabolites.

Cholesterol-lowering resin drugs: bile acid sequestrant cholestyramine (brand names Questran®, LoCholest® and Prevalite®) and colestipol (Cholestid®). Intestinal absorption of vitamin D may be impaired. Patients on cholestyramine or colestipol should be advised to allow as much time as possible between the ingestion of these drugs and vitamin D.

Fat-blocking weight-loss drugs: orlistat (brand names Xenical® and alli) and mineral oil. Intestinal absorption of vitamin D may be impaired.

Digoxin: vitamin D should be used with caution in patients on digoxin as hypercalcemia (which may result with vitamin D use) may cause cardiac arrhythmias.

Thiazide Diuretics: concurrent administration of thiazide diuretics and vitamin D to hypoparathyroid patients may cause hypercalcemia, which may be transient or may require discontinuation of vitamin D.

Sources of Vitamin D

The average U.S. diet only provides 100 IU/d. Vitamin D-deficient diets are also associated with those who have milk allergy, lactose intolerance or are strict vegetarians.

Natural food sources of vitamin D include:

  • Fish liver oils, such as cod liver oil

  • Fatty fish species, such as:

  • Herring, 3 ounces (1,383 IU)

  • Catfish, 3 ounces (425 IU)

  • Salmon, cooked, 3.5 ounces (360 IU)

  •  Mackerel, cooked, 3.5 ounces (345 IU)

  • Sardines, canned in oil, drained, 1.75 ounces (250 IU)

  • Tuna, canned in oil, 3 ounces (200 IU)

  •  Eel, cooked, 100 g (3.5 oz), 200 IU

  • A whole egg (20 IU)

  • Milk, 1 cup (98 IU)

  • Swiss cheese, 1 ounce, (12 IU)

  • Beef liver, cooked, 3.5 ounces (15 IU)

For use in supplements and fortified foods, vitamin D is available in two forms, D2 and D3. Vitamin D2 is manufactured by the UV irradiation of ergosterol in yeast, while vitamin D3 is manufactured synthetically by the irradiation of 7-dehydrocholesterol from lanolin (from ruminant lamb's wool grease) and the chemical conversion of cholesterol.

Vitamin D testing can help determine whether bone weakness, bone malformation, disease or abnormal metabolism of calcium (reflected by atypical levels of calcium, phosphorus, PTH) is occurring as a result of a deficiency or excess amount of vitamin D.

In clinical practice, there are two serum tests performed to determine vitamin D blood levels: 25(OH)D and 1,25(OH)D. The 25(OH)D is the generally preferred test, since it represents a summation of the total cutaneous production of vitamin D and the oral ingestion of either vitamin D2 or vitamin D3.

Robin Koon is senior vice president at Best Formulations , has more than 25 years of pharmaceutical experience in clinical pharmacy and as a drug chain executive overseeing operations, managed-care and in retail mass market.

About the Author(s)

Robin Koon

Robin Koon is executive vice president at Best Formulations , and has more than 35 years of pharmaceutical experience in clinical pharmacy, as a retail drug chain executive, in managed-care and in manufacturing.


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