Dietary supplements
In supplements and fortified foods, vitamin D is
available in two forms, D2 (ergocalciferol) and D3 (cholecalciferol).
Vitamin D2 is manufactured by the UV irradiation of ergosterol in
yeast, and vitamin D3 is manufactured by the irradiation of
7-dehydrocholesterol from lanolin and the chemical conversion of
cholesterol [11].
The two forms have traditionally been regarded as equivalent based on
their ability to cure rickets, but evidence has been offered that they
are metabolized differently. Vitamin D3 could be more than three times as effective as vitamin D2
in raising serum 25(OH)D concentrations and maintaining those levels
for a longer time, and its metabolites have superior affinity for
vitamin D-binding proteins in plasma [6,32,33].
Because metabolite receptor affinity is not a functional assessment, as
the earlier results for the healing of rickets were, further research
is needed on the comparative physiological effects of both forms. Many
supplements
are being reformulated to contain vitamin D3 instead of vitamin D2
[33]. Both forms (as well as vitamin D in foods and from cutaneous
synthesis) effectively raise serum 25(OH)D levels [6].
Vitamin D Intakes and Status

In
1988-1994, as part of the third National Health and Nutrition
Examination Survey (NHANES III), the frequency of use of some vitamin
D-containing foods and supplements was examined in 1,546 non-Hispanic
African American women and 1,426 non-Hispanic white women of
reproductive age (15-49 years) [34].
In both groups, 25(OH)D levels were higher in the fall (after a summer
of sun exposure) and when milk or fortified cereals were consumed more
than three times per week. The prevalence of serum concentrations of
25(OH)D ≤15 ng/mL (≤37.5 nmol/L) was 10 times greater for the African
American women (42.2%) than for the white women (4.2%).

The 2000-2004 NHANES provided the most recent data on the vitamin D nutritional status of the U.S. population [35].
Generally, younger people had higher serum 25(OH)D levels than older
people; males had higher levels than females; and non-Hispanic whites
had higher levels than Mexican Americans, who in turn had higher levels
than non-Hispanic blacks. Depending on the population group, 1-9% had
serum 25(OH)D levels <11 ng/mL (<27.5 nmol/L), 8-36% had levels
<20 ng/mL (<50 nmol/L), and the majority (50-78%) had levels
<30 ng/mL (<75 nmol/L). Among adults in the United Kingdom,
nationally representative data collected between 1992 and 2001 found
show that 5-20% in most age groups on average had serum 25(OH)D levels
<10 ng/ml (<25 nmol/L); the prevalence of deficiency was greater
(range 20-40%) for older people >65 years of age in residential care
homes and among women >85 years. Among all adults, 20-60% had levels
≤20 ng/ml (≤50 nmol/L) and 90% had levels ≤32 ng/ml (≤80 nmol/L) [36].
Vitamin D Deficiency

Nutrient
deficiencies are usually the result of dietary inadequacy, impaired
absorption and use, increased requirement, or increased excretion. A
vitamin D deficiency can occur when usual intake is lower than
recommended levels over time, exposure to sunlight is limited, the
kidneys cannot convert vitamin D to its active form, or absorption of
vitamin D from the digestive tract is inadequate. Vitamin D-deficient
diets are associated with milk allergy, lactose intolerance, and strict
vegetarianism [37].

Rickets
and osteomalacia are the classical vitamin D deficiency diseases. In
children, vitamin D deficiency causes rickets, a disease characterized
by a failure of bone tissue to properly mineralize, resulting in soft
bones and skeletal deformities [29]. Rickets was first described in the mid-17th century by British researchers [29,38].
In the late 19th and early 20th centuries, German physicians noted that
consuming 1-3 teaspoons of cod liver oil per day could reverse rickets [38].
In the 1920s and prior to identification of the structure of vitamin D
and its metabolites, biochemist Harry Steenbock patented a process to
impart antirachitic activity to foods [14].
The process involved the addition of what turned out to be precursor
forms of vitamin D followed by exposure to UV radiation. The
fortification of milk with vitamin D has made rickets a rare disease in
the United States. However, rickets is still reported periodically,
particularly
among African American infants and children [29,38]. A 2003 report from
Memphis, for example, described 21 cases of rickets among infants, 20
of whom were African American [38].

Prolonged
exclusive breastfeeding without the AAP-recommended vitamin D
supplementation is a significant cause of rickets, particularly in
dark-skinned infants breastfed by mothers who are not vitamin D replete
[6].
Additional causes of rickets include extensive use of sunscreens and
placement of children in daycare programs, where they often have less
outdoor activity and sun exposure [29,38].
Rickets is also more prevalent among immigrants from Asia, Africa, and
the Middle East, possibly because of genetic differences in vitamin D
metabolism and behavioral differences that lead to less sun exposure [29].

In adults, vitamin D deficiency can lead to osteomalacia, resulting in weak muscles and bones [7,8,15].
Symptoms of bone pain and muscle weakness can indicate inadequate
vitamin D levels, but such symptoms can be subtle and go undetected in
the initial stages.
Groups at Risk of Vitamin D Inadequacy

Obtaining
sufficient vitamin D from natural food sources alone can be difficult.
For many people, consuming vitamin D-fortified foods and being exposed
to sunlight are essential for maintaining a healthy vitamin D status.
In some groups, dietary supplements might be required to meet the daily
need for vitamin D.

Breastfed infants
Vitamin D requirements cannot be met by human milk alone [5,39], which provides only about 25 IU/L [17].
A recent review of reports of nutritional rickets found that a majority
of cases occurred among young, breastfed African Americans [40].
The sun is a potential source of vitamin D, but AAP advises keeping
infants out of direct sunlight and having them wear protective clothing
and sunscreen [41].
As noted earlier, AAP recommends that exclusively and partially
breastfed infants be supplemented with 400 IU of vitamin D per day [18].

Older adults
Americans aged 50 and older are at increased risk of developing vitamin D insufficiency [28].
As people age, skin cannot synthesize vitamin D as efficiently and the
kidney is less able to convert vitamin D to its active hormone form [5,42].
As many as half of older adults in the United States with hip fractures
could have serum 25(OH)D levels <12 ng/mL (<30 nmol/L) [6].

People with limited sun exposure
Homebound
individuals, people living in northern latitudes (such as New England
and Alaska), women who wear long robes and head coverings for religious
reasons, and people with occupations that prevent sun exposure are
unlikely to obtain adequate vitamin D from sunlight [43,44].

People with dark skin
Greater
amounts of the pigment melanin result in darker skin and reduce the
skin's ability to produce vitamin D from exposure to sunlight. Some
studies suggest that older adults, especially women, with darker skin
are at high risk of developing vitamin D insufficiency [34,45].
However, one group with dark skin, African Americans, generally has
lower levels of 25(OH)D yet develops fewer osteoporotic fractures than
Caucasians (see section below on osteoporosis).

People with fat malabsorption
As
a fat-soluble vitamin, vitamin D requires some dietary fat in the gut
for absorption. Individuals who have a reduced ability to absorb
dietary fat might require vitamin D supplements [46].
Fat malabsorption is associated with a variety of medical conditions
including pancreatic enzyme deficiency, Crohn's disease, cystic
fibrosis, celiac disease, surgical removal of part of the stomach or
intestines, and some forms of liver disease [15].

People who are obese
Individuals
with a body mass index (BMI) ≥30 typically have a low plasma
concentration of 25(OH)D [47]; this level decreases as obesity and body
fat increase [48].
Obesity does not affect skin's capacity to synthesize vitamin D, but
greater amounts of subcutaneous fat sequester more of the vitamin and
alter its release into the circulation. Even with orally administered
vitamin D, BMI is inversely correlated with peak serum concentrations,
probably because some vitamin D is sequestered in the larger pools of
body fat [47].
Vitamin D and Health

Optimal serum concentrations of 25(OH)D for bone and general health throughout life have not been established [6,11]
and are likely to vary at each stage of life, depending on the
physiological measures selected. The three-fold range of cut points
that have been proposed by various experts, from 16 to 48 ng/mL (40 to
120 nmol/L), reflect differences in the functional endpoints chosen
(e.g., serum concentrations of parathyroid hormone or bone fractures),
as well as differences in the analytical methods used. The numerous
assays for 25(OH)D provide differing results. One reason for these
issues of precision and variability is that no standard reference
preparations or calibrating materials are available commercially to
help reduce the variability of results between methods and
laboratories. Efforts are underway to standardize the quantification of
25(OH)D to measure vitamin D status.

In March 2007, a group of
vitamin D and nutrition researchers published a controversial and
provocative editorial contending that the desirable concentration of
25(OH)D is ≥30 ng/mL (≥75 nmol/L) [12].
They noted that supplemental intakes of 400 IU/day of vitamin D
increase 25(OH)D concentrations by only 2.8-4.8 ng/mL (7-12 nmol/L) and
that daily intakes of approximately 1,700 IU are needed to raise these
concentrations from 20 to 32 ng/mL (50 to 80 nmol/L).

Osteoporosis
More
than 25 million adults in the United States have or are at risk of
developing osteoporosis, a disease characterized by fragile bones that
significantly increases the risk of bone fractures [50].
Osteoporosis is most often associated with inadequate calcium intakes
(generally <1,000-1,200 mg/day), but insufficient vitamin D
contributes to osteoporosis by reducing calcium absorption [51].
Although rickets and osteomalacia are extreme examples of the effects
of vitamin D deficiency, osteoporosis is an example of a long-term
effect of calcium and vitamin D insufficiency [52].
Adequate storage levels of vitamin D maintain bone strength and might
help prevent osteoporosis in older adults, nonambulatory individuals
who have difficulty exercising, postmenopausal women, and individuals
on chronic steroid therapy [53].

Normal
bone is constantly being remodeled. During menopause, the balance
between these processes changes, resulting in more bone being resorbed
than rebuilt. Hormone therapy with estrogen and progesterone might be
able to delay the onset of osteoporosis. However, some medical groups
and professional societies recommend that postmenopausal women consider
using other agents to slow or stop bone resorption because of the
potential adverse health effects of hormone therapy [54-56].

Most
supplementation trials of the effects of vitamin D on bone health also
include calcium, so it is not possible to isolate the effects of each
nutrient. The authors of a recent evidence-based review of research
concluded that supplements of both vitamin D3 (at 700-800
IU/day) and calcium (500-1,200 mg/day) decreased the risk of falls,
fractures, and bone loss in elderly individuals aged 62-85 years [6].
The decreased risk of fractures occurred primarily in elderly women
aged 85 years, on average, and living in a nursing home. Women should
consult their healthcare providers about their needs for vitamin D (and
calcium) as part of an overall plan to prevent or treat osteoporosis.

African
Americans have lower levels of 25(OH)D than Caucasians, yet they
develop fewer osteoporotic fractures. This suggests that factors other
than vitamin D provide protection [57].
African Americans have an advantage in bone density from early
childhood, a function of their more efficient calcium economy, and have
a lower risk of fracture even when they have the same bone density as
Caucasians. They also have a higher prevalence of obesity, and the
resulting higher estrogen levels in obese women might protect them from
bone loss [57].
Further reducing the risk of osteoporosis in African Americans are
their lower levels of bone-turnover markers, shorter hip-axis length,
and superior renal calcium conservation. However, despite this
advantage in bone density, osteoporosis is a significant health problem
among African Americans as they age [57].

Cancer
Laboratory
and animal evidence as well as epidemiologic data suggest that vitamin
D status could affect cancer risk. Strong biological and mechanistic
bases indicate that vitamin D plays a role in the prevention of colon,
prostate, and breast cancers. Emerging epidemiologic data suggest that
vitamin D has a protective effect against colon cancer, but the data
are not as strong for a protective effect against prostate and breast
cancer, and are variable for cancers at other sites [58-59].
Studies do not consistently show a protective effect or no effect,
however. One study of Finnish smokers, for example, found that subjects
in the highest quintile of baseline vitamin D status have a three-fold
higher risk of developing pancreatic cancer [60].

Vitamin
D emerged as a protective factor in a prospective, cross-sectional
study of 3,121 adults aged ≥50 years (96% men) who underwent a
colonoscopy. The study found that 10% had at least one advanced
cancerous lesion. Those with the highest vitamin D intakes (>645
IU/day) had a significantly lower risk of these lesions [61].
However, the Women's Health Initiative, in which 36,282 postmenopausal
women of various races and ethnicities were randomly assigned to
receive 400 IU vitamin D plus 1,000 mg calcium daily or a placebo,
found no significant differences between the groups in the incidence of
colorectal cancers over 7 years [62].
More recently, a clinical trial focused on bone health in 1,179
postmenopausal women residing in rural Nebraska found that subjects
supplemented
daily with calcium (1,400-1,500 mg) and vitamin D3 (1,100 IU) had a
significantly lower incidence of cancer over 4 years compared to women
taking a placebo [63].
The small number of cancers reported (50) precludes generalizing about
a protective effect from either or both nutrients or for cancers at
different sites. This caution is supported by an analysis of 16,618
participants in NHANES III, where total cancer mortality was found to
be unrelated to baseline vitamin D status [64].
However, colorectal cancer mortality was inversely related to serum
25(OH)D concentrations; levels >80 nmol/L were associated with a 72%
risk reduction than those <50 nmol/L.

Further research is
needed to determine whether vitamin D inadequacy in particular
increases cancer risk, whether greater exposure to the nutrient is
protective, and whether some individuals could be at increased risk of
cancer because of vitamin D exposure [58].

Other conditions
A
growing body of research suggests that vitamin D might play some role
in the prevention and treatment of type 1 [65] and type 2 diabetes
[66], hypertension [67], glucose intolerance [68], multiple sclerosis
[69], and other medical conditions [70-71].
However, most evidence for these roles comes from in vitro, animal, and
epidemiological studies, not the randomized clinical trials considered
to be more definitive. Until such trials are conducted, the
implications of the available evidence for public health and patient
care will be debated.

A recent meta-analysis found that use of
vitamin D supplements was associated with a reduction in overall
mortality from any cause by a statistically significant 7% [72-73].
The subjects in these trials were primarily healthy, middle aged or
elderly, and at high risk of fractures; they took 300-2,000 IU/day of
vitamin D supplements.
Health Risks from Excessive Vitamin D

Vitamin
D toxicity can cause nonspecific symptoms such as nausea, vomiting,
poor appetite, constipation, weakness, and weight loss [74].
More seriously, it can also raise blood levels of calcium, causing
mental status changes such as confusion and heart rhythm abnormalities [8].
The use of supplements of both calcium (1,000 mg/day) and vitamin D
(400 IU/day) by postmenopausal women was associated with a 17% increase
in the risk of kidney stones over 7 years in the Women's Health
Initiative
[75]. Deposition of calcium and phosphate in the kidneys and other soft
tissues can also be caused by excessive vitamin D levels [5]. A serum
25(OH)D concentration consistently >200 ng/mL (>500 nmol/L) is
considered to be potentially toxic [15]. In an animal model,
concentrations ≤400 ng/mL (≤1,000 nmol/L) were not associated with harm
[16].

Excessive
sun exposure does not result in vitamin D toxicity because the
sustained heat on the skin is thought to photodegrade previtamin D3 and vitamin D3 as it is formed [11,30].
High intakes of dietary vitamin D are very unlikely to result in
toxicity unless large amounts of cod liver oil are consumed; toxicity
is more likely to occur from high intakes of supplements.

Long-term intakes above the UL increase the risk of adverse health effects [5]
(Table 4). Substantially larger doses administered for a short time or
periodically (e.g., 50,000 IU/week for 8 weeks) do not cause toxicity.
Rather, the excess is stored and used as needed to maintain normal
serum 25(OH)D concentrations when vitamin D intakes or sun exposure are
limited [15,76].

Table 4: Tolerable Upper Intake Levels (ULs) for Vitamin D [5]AgeChildrenMenWomenPregnancyLactation
Birth to 12 months 25 mcg
(1,000 IU)
1-13 years 50 mcg
(2,000 IU)
14+ years 50 mcg
(2,000 IU) 50 mcg
(2,000 IU) 50 mcg
(2,000 IU) 50 mcg
(2,000 IU)

Several nutrition scientists recently challenged these ULs, first published in 1997 [76].
They pointed to newer clinical trials conducted in healthy adults that
found no evidence of vitamin D toxicity at doses ≥10,000 IU/day.
Although vitamin D supplements above recommended levels given in
clinical trials have not shown harm, most trials were not adequately
designed to assess harm [6].
Evidence is not sufficient to determine the potential risks of excess
vitamin D in infants, children, and women of reproductive age.
Interactions with Medications

Vitamin
D supplements have the potential to interact with several types of
medications. A few examples are provided below. Individuals taking
these medications on a regular basis should discuss vitamin D intakes
with their healthcare providers.

Steroids
Corticosteroid medications such as prednisone, often prescribed to reduce inflammation, can reduce calcium absorption [77-79]
and impair vitamin D metabolism. These effects can further contribute
to the loss of bone and the development of osteoporosis associated with
their long-term use [78-79].

Other medications
Both
the weight-loss drug orlistat (brand names Xenical® and alli™) and the
cholesterol-lowering drug cholestyramine (brand names Questran®,
LoCholest®, and Prevalite®) can reduce the absorption of vitamin D and
other fat-soluble vitamins [80-81]. Both phenobarbital and phenytoin
(brand name Dilantin®),
used to prevent and control epileptic seizures, increase the hepatic
metabolism of vitamin D to inactive compounds and reduce calcium
absorption [82].
Vitamin D and Healthful Diets

According to the 2005 Dietary Guidelines for Americans,
"nutrient needs should be met primarily through consuming foods. Foods
provide an array of nutrients and other compounds that may have
beneficial effects on health. In certain cases, fortified foods and
dietary supplements may be useful sources of one or more nutrients that
otherwise might be consumed in less than recommended amounts. However,
dietary supplements, while recommended in some cases, cannot replace a
healthful diet."

The Dietary Guidelines for Americans describes a healthy diet as one that

* Emphasizes a variety of fruits, vegetables, whole grains, and fat-free or low-fat milk and milk products.
Milk
is fortified with vitamin D, as are many ready-to-eat cereals and a few
brands of yogurt and orange juice. Cheese naturally contains small
amounts of vitamin D.
* Includes lean meats, poultry, fish, beans, eggs, and nuts.
Fish
such as salmon, tuna, and mackerel are very good sources of vitamin D.
Small amounts of vitamin D are also found in beef liver and egg yolks.
* Is low in saturated fats, trans fats, cholesterol, salt (sodium), and added sugars.
Vitamin D is added to some margarines.
* Stays within your daily calorie needs.

For
more information about building a healthful diet, refer to the Dietary
Guidelines for Americans
(http://www.health.gov/dietaryguidelines/dga2005/document/default.htm)
and the U.S. Department of Agriculture's food guidance system, My
Pyramid (http://www.mypyramid.gov).

http://dietary-supplements.info.nih.gov/factsheets/vitamind.asp