Image credit: Collin Grady — CC BY

Vitamin D

is a fat-soluble vitamin that is naturally present in
very few foods, added to others, and available as a dietary
supplement. It is also produced endogenously when ultraviolet rays
from sunlight strike the skin and trigger vitamin D synthesis.
Vitamin D obtained from sun exposure, food, and supplements is
biologically inert and must undergo two hydroxylations in the body
for activation. The first occurs in the liver and converts vitamin
D to 25-hydroxyvitamin D [25(OH)D], also known as calcidiol. The
second occurs primarily in the kidney and forms the
physiologically active 1,25-dihydroxyvitamin D [1,25(OH)₂D],also
known as calcitriol [1 ].

Vitamin D promotes calcium
absorption in the gut and maintains adequate serum calcium and
phosphate concentrations to enable normal mineralization of bone
and to prevent hypocalcemic tetany. It is also needed for bone
growth and bone remodeling by osteoblasts and osteoclasts [1,2]. Without sufficient
vitamin D, bones can become thin, brittle, or misshapen. Vitamin D
sufficiency prevents rickets in children and osteomalacia in
adults [1]. Together with calcium, vitamin D
also helps protect older adults from osteoporosis.

Vitamin D has other roles in the body, including modulation of
cell growth, neuromuscular and immune function, and reduction of
inflammation [1,3,4]. Many genes encoding proteins that regulate
cell proliferation, differentiation, and apoptosis are modulated
in part by vitamin D [1]. Many cells have
vitamin D receptors, and some convert 25(OH)D to 1,25(OH)₂D.

Serum concentration of 25(OH)D is the best indicator of vitamin D
status. It reflects vitamin D produced cutaneously and that
obtained from food and supplements [1] and has
a fairly long circulating half-life of 15 days [5].
25(OH)D functions as a biomarker of exposure, but it is not clear
to what extent 25(OH)D levels also serve as a biomarker of effect
(i.e., relating to health status or outcomes) [1].
Serum 25(OH)D levels do not indicate the amount of vitamin D
stored in body tissues.

In contrast to 25(OH)D, circulating 1,25(OH)₂D is
generally not a good indicator of vitamin D status because it has
a short half-life of 15 hours and serum concentrations are closely
regulated by parathyroid hormone, calcium, and phosphate [5]. Levels of 1,25(OH)₂D do not
typically decrease until vitamin D deficiency is severe [2,6].

There is considerable discussion of the serum concentrations of
25(OH)D associated with deficiency (e.g., rickets), adequacy for
bone health, and optimal overall health, and cut points have not
been developed by a scientific consensus process. Based on its
review of data of vitamin D needs, a committee of the Institute of
Medicine concluded that persons are at risk of vitamin D
deficiency at serum 25(OH)D concentrations <30 nmol/L (<12
ng/mL). Some are potentially at risk for inadequacy at levels
ranging from 30–50 nmol/L (12–20 ng/mL). Practically all people
are sufficient at levels ≥50 nmol/L (≥20 ng/mL); the committee
stated that 50 nmol/L is the serum 25(OH)D level that covers the
needs of 97.5% of the population. Serum concentrations >125
nmol/L (>50 ng/mL) are associated with potential adverse
effects [1] (Table 1).

* Serum concentrations of 25(OH)D are
reported in both nanomoles per liter (nmol/L) and nanograms per
milliliter (ng/mL).

** 1 nmol/L = 0.4 ng/mL

An additional complication in assessing vitamin D status is in
the actual measurement of serum 25(OH)D concentrations.
Considerable variability exists among the various assays available
(the two most common methods being antibody based and liquid
chromatography based) and among laboratories that conduct the
analyses [1,7,8].
This means that compared with the actual concentration of 25(OH)D
in a sample of blood serum, a falsely low or falsely high value
may be obtained depending on the assay or laboratory used [9]. A standard reference material for 25(OH)D
became available in July 2009 that permits standardization of
values across laboratories and may improve method-related
variability [1,10].

Reference Intakes

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 of The
National Academies (formerly National Academy of Sciences) [1]. DRI is the general term for a set of
reference values used to plan and assess nutrient intakes of
healthy people. These values, which vary by age and gender,
include:

• Recommended Dietary Allowance (RDA): average daily level of
  intake sufficient to meet the nutrient requirements of nearly
  all (97%–98%) healthy people.
• Adequate Intake (AI): established when evidence is
  insufficient to develop an RDA and is set at a level assumed to
  ensure nutritional adequacy.
• Tolerable Upper Intake Level (UL): maximum daily intake
  unlikely to cause adverse health effects [1].

The FNB established an RDA for vitamin D representing a daily
intake that is sufficient to maintain bone health and normal
calcium metabolism in healthy people. RDAs for vitamin D are
listed in both International Units (IUs) and micrograms (mcg); the
biological activity of 40 IU is equal to 1 mcg (Table 2). Even
though sunlight may be a major source of vitamin D for some, the
vitamin D RDAs are set on the basis of minimal sun exposure [1].

* Adequate Intake (AI)

Sources of Vitamin D

Food

Very few foods in nature contain vitamin D. The flesh of fatty
fish (such as salmon, tuna, and mackerel) and fish liver oils are
among the best sources [1,11].
Small amounts of vitamin D are found in beef liver, cheese, and
egg yolks. Vitamin D in these foods is primarily in the form of
vitamin D₃ and its metabolite 25(OH)D₃ [12]. Some mushrooms provide vitamin D₂
in variable amounts [13,14].
Mushrooms with enhanced levels of vitamin D₂ from being
exposed to ultraviolet light under controlled conditions are also
available.

Fortified foods provide most of the vitamin D in the American
diet [1,14]. For example,
almost all of the U.S. milk supply is voluntarily fortified with
100 IU/cup [1]. (In Canada, milk is fortified
by law with 35–40 IU/100 mL, as is margarine at ≥530 IU/100 g.) In
the 1930s, a milk fortification program was implemented in the
United States to combat rickets, then a major public health
problem [1]. Other dairy products made from
milk, such as cheese and ice cream, are generally not fortified.
Ready-to-eat breakfast cereals often contain added vitamin D, as
do some brands of orange juice, yogurt, margarine and other food
products.

Both the United States and Canada mandate the fortification of
infant formula with vitamin D: 40–100 IU/100 kcal in the United
States and 40–80 IU/100 kcal in Canada [1].

Several food sources of vitamin D are listed in Table 3.

* IUs = International Units.

** DV = Daily Value. DVs were developed by the U.S. Food and Drug
Administration to help consumers compare the nutrient contents
among products within the context of a total daily diet. The DV
for vitamin D is currently set at 400 IU for adults and children
age 4 and older. Food labels, however, are not required to list
vitamin D content unless a food has been fortified with this
nutrient. Foods providing 20% or more of the DV are considered to
be high sources of a nutrient, but foods providing lower
percentages of the DV also contribute to a healthful diet.

The U.S. Department of Agriculture’s Nutrient Database Web site lists the
nutrient content of many foods. It also provides a comprehensive list of foods containing vitamin D.
A growing number of foods are being analyzed for vitamin D
content. Simpler and faster methods to measure vitamin D in foods
are needed, as are food standard reference materials with
certified values for vitamin D to ensure accurate measurements [15].

Sun exposure

Most people meet at least some of their vitamin D needs through
exposure to sunlight [1,2].
Ultraviolet (UV) B radiation with a wavelength of 290–320
nanometers penetrates uncovered skin and converts cutaneous
7-dehydrocholesterol to previtamin D₃, which in turn
becomes vitamin D₃ [1]. Season, time
of day, length of day, cloud cover, smog, skin melanin content,
and sunscreen are among the factors that affect UV radiation
exposure and vitamin D synthesis [1]. Perhaps
surprisingly, geographic latitude does not consistently predict
average serum 25(OH)D levels in a population. Ample opportunities
exist to form vitamin D (and store it in the liver and fat) from
exposure to sunlight during the spring, summer, and fall months
even in the far north latitudes [1].

Complete cloud cover reduces UV energy by 50%; shade (including
that produced by severe pollution) reduces it by 60% [16]. UVB radiation does not penetrate glass, so
exposure to sunshine indoors through a window does not produce
vitamin D [17]. Sunscreens with a sun
protection factor (SPF) of 8 or more appear to block vitamin
D-producing UV rays, although in practice people generally do not
apply sufficient amounts, cover all sun-exposed skin, or reapply
sunscreen regularly [1,18].
Therefore, skin likely synthesizes some vitamin D even when it is
protected by sunscreen as typically applied.

The factors that affect UV radiation exposure and research to
date on the amount of sun exposure needed to maintain adequate
vitamin D levels make it difficult to provide general guidelines.
It has been suggested by some vitamin D researchers, for example,
that approximately 5–30 minutes of sun exposure between 10 AM and
3 PM at least twice a week to the face, arms, legs, or back
without sunscreen usually lead to sufficient vitamin D synthesis
and that the moderate use of commercial tanning beds that emit
2%–6% UVB radiation is also effective [6,19]. Individuals with limited sun exposure need
to include good sources of vitamin D in their diet or take a
supplement to achieve recommended levels of intake.

Despite the importance of the sun for vitamin D synthesis, it is
prudent to limit exposure of skin to sunlight [18]
and UV radiation from tanning beds [20]. UV
radiation is a carcinogen responsible for most of the estimated
1.5 million skin cancers and the 8,000 deaths due to metastatic
melanoma that occur annually in the United States [18].
Lifetime cumulative UV damage to skin is also largely responsible
for some age-associated dryness and other cosmetic changes. The
American Academy of Dermatology advises that photoprotective
measures be taken, including the use of sunscreen, whenever one is
exposed to the sun [21]. Assessment of vitamin
D requirements cannot address the level of sun exposure because of
these public health concerns about skin cancer, and there are no
studies to determine whether UVB-induced synthesis of vitamin D
can occur without increased risk of skin cancer [1].

Dietary supplements

In supplements and fortified foods, vitamin D is available in two
forms, D₂ (ergocalciferol) and D₃
(cholecalciferol) that differ chemically only in their side-chain
structure. 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 [6].
The two forms have traditionally been regarded as equivalent based
on their ability to cure rickets and, indeed, most steps involved
in the metabolism and actions of vitamin D₂ and vitamin
D₃ are identical. Both forms (as well as vitamin D in
foods and from cutaneous synthesis) effectively raise serum
25(OH)D levels [2]. Firm conclusions about any
different effects of these two forms of vitamin D cannot be drawn.
However, it appears that at nutritional doses vitamins D₂
and D₃ are equivalent, but at high doses vitamin D₂
is less potent.

The American Academy of Pediatrics (AAP) recommends that
exclusively and partially breastfed infants receive supplements of
400 IU/day of vitamin D shortly after birth and continue to
receive these supplements until they are weaned and consume ≥1,000
mL/day of vitamin D-fortified formula or whole milk [22]. Similarly, all non-breastfed infants
ingesting <1,000 mL/day of vitamin D-fortified formula or milk
should receive a vitamin D supplement of 400 IU/day [22]. AAP also recommends that older children
and adolescents who do not obtain 400 IU/day through vitamin
D-fortified milk and foods should take a 400 IU vitamin D
supplement daily. However, this latter recommendation (issued
November 2008) needs to be reevaluated in light of the Food and
Nutrition Board’s vitamin D RDA of 600 IU/day for children and
adolescents (issued November 2010 and which previously was an AI
of 200 IU/day).

Vitamin D Intakes and Status

The National Health and Nutrition Examination Survey (NHANES),
2005–2006, estimated vitamin D intakes from both food and dietary
supplements [4,23]. Average
intake levels for males from foods alone ranged from 204 to 288
IU/day depending on life stage group; for females the range was
144 to 276 IU/day. When use of dietary supplements was considered,
these mean values were substantially increased (37% of the U.S.
population used a dietary supplement containing vitamin D.) The
most marked increase was among older women. For women aged 51–70
years, mean intake of vitamin D from foods alone was 156 IU/day,
but 404 IU/day with supplements. For women >70 years, the
corresponding figures were 180 IU/day to 400 IU/day [1].

Comparing vitamin D intake estimates from foods and dietary
supplements to serum 25(OH)D concentrations is problematic. One
reason is that comparisons can only be made on group means rather
than on data linked to individuals. Another is the fact that sun
exposure affects vitamin D status; serum 25(OH)D levels are
generally higher than would be predicted on the basis of vitamin D
intakes alone [1]. The NHANES 2005–2006 survey
found mean 25(OH)D levels exceeding 56 nmol/L (22.4 ng/mL) for all
age-gender groups in the U.S. population. (The highest mean was
71.4 nmol/L [28.6 ng/mL] for girls aged 1–3 years, and the lowest
mean was 56.5 nmol/L [22.6 ng/mL] for women aged 71 and older.
Generally, younger people had higher levels than older people, and
males had slightly higher levels than females.) 25(OH)D levels of
approximately 50 nmol/L (20 ng/mL) are consistent with an intake
of vitamin D from foods and dietary supplements equivalent to the
RDA [1].

Over the past 20 years, mean serum 25(OH)D concentrations in the
United States have slightly declined among males but not females.
This decline is likely due to simultaneous increases in body
weight, reduced milk intake, and greater use of sun protection
when outside [24].

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 25(OH)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, ovo-vegetarianism, and veganism [1].

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 [16]. Rickets was first described in the
mid-17th century by British researchers [16,25]. In the late 19th and early 20th centuries,
German physicians noted that consuming 1–3 teaspoons/day of cod
liver oil could reverse rickets [25]. The
fortification of milk with vitamin D beginning in the 1930s has
made rickets a rare disease in the United States, although it is
still reported periodically, particularly among African American
infants and children [3,16,21].

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 [26]. 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 [16,25].
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.

In adults, vitamin D deficiency can lead to osteomalacia,
resulting in weak bones [1,5].
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 is
difficult. For many people, consuming vitamin D-fortified foods
and, arguably, being exposed to some 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 ordinarily be met by human milk
alone [1,27], which
provides <25 IU/L to 78 IU/L [22]. (The
vitamin D content of human milk is related to the mother’s vitamin
D status, so mothers who supplement with high doses of vitamin D
may have correspondingly high levels of this nutrient in their
milk [22].) A review of reports of nutritional
rickets found that a majority of cases occurred among young,
breastfed African Americans [28]. A survey of
Canadian pediatricians found the incidence of rickets in their
patients to be 2.9 per 100,000; almost all those with rickets had
been breast fed [29]. While the sun is a
potential source of vitamin D, the AAP advises keeping infants out
of direct sunlight and having them wear protective clothing and
sunscreen [30]. As noted earlier, the AAP
recommends that exclusively and partially breastfed infants be
supplemented with 400 IU of vitamin D per day [22],
the RDA for this nutrient during infancy.

Older adults

Older adults are at increased risk of developing vitamin D
insufficiency in part because, as they age, skin cannot synthesize
vitamin D as efficiently, they are likely to spend more time
indoors, and they may have inadequate intakes of the vitamin [1]. As many as half of older adults in the
United States with hip fractures could have serum 25(OH)D levels
<30 nmol/L (<12 ng/mL) [2].

People with limited sun exposure

Homebound individuals, women who wear long robes and head
coverings for religious reasons, and people with occupations that
limit sun exposure are unlikely to obtain adequate vitamin D from
sunlight [31,32]. Because
the extent and frequency of use of sunscreen are unknown, the
significance of the role that sunscreen may play in reducing
vitamin D synthesis is unclear [1]. Ingesting
RDA levels of vitamin D from foods and/or supplements will provide
these individuals with adequate amounts of this nutrient.

People with dark skin

Greater amounts of the pigment melanin in the epidermal layer
result in darker skin and reduce the skin’s ability to produce
vitamin D from sunlight [1]. Various reports
consistently show lower serum 25(OH)D levels in persons identified
as black compared with those identified as white. It is not clear
that lower levels of 25(OH)D for persons with dark skin have
significant health consequences. Those of African American
ancestry, for example, have reduced rates of fracture and
osteoporosis compared with Caucasians (see section below on
osteoporosis). Ingesting RDA levels of vitamin D from foods and/or
supplements will provide these individuals with adequate amounts
of this nutrient.

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 [33]. Fat malabsorption is associated with a
variety of medical conditions including some forms of liver
disease, cystic fibrosis, and Crohn’s disease [3].

People who are obese or who have undergone gastric bypass
surgery

A body mass index ≥30 is associated with lower serum 25(OH)D
levels compared with non-obese individuals; people who are obese
may need larger than usual intakes of vitamin D to achieve 25(OH)D
levels comparable to those of normal weight [1].
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. Obese
individuals who have undergone gastric bypass surgery may become
vitamin D deficient over time without a sufficient intake of this
nutrient from food or supplements, since part of the upper small
intestine where vitamin D is absorbed is bypassed and vitamin D
mobilized into the serum from fat stores may not compensate over
time [34,35].

Vitamin D and Health

Optimal serum concentrations of 25(OH)D for bone and general
health have not been established; they are likely to vary at each
stage of life, depending on the physiological measures selected [1,2,6].
Also, as stated earlier, while serum 25(OH)D functions as a
biomarker of exposure to vitamin D (from sun, food, and dietary
supplements), the extent to which such levels serve as a biomarker
of effect (i.e., health outcomes) is not clearly established [1].

Furthermore, while serum 25(OH)D levels increase in response to
increased vitamin D intake, the relationship is non-linear for
reasons that are not entirely clear [1]. The
increase varies, for example, by baseline serum levels and
duration of supplementation. Increasing serum 25(OH)D to >50
nmol/L requires more vitamin D than increasing levels from a
baseline <50 nmol/L. There is a steeper rise in serum 25(OH)D
when the dose of vitamin D is <1,000 IU/day; a lower, more
flattened response is seen at higher daily doses. When the dose is
≥1,000 IU/day, the rise in serum 25(OH)D is approximately 1 nmol/L
for each 40 IU of intake. In studies with a dose ≤600 IU/day, the
rise is serum 25(OH)D was approximately 2.3 nmol/L for each 40 IU
of vitamin D consumed [1].

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 was ≥75 nmol/L (≥30
ng/ml) [36]. They noted that approximately
1,700 IU/day of vitamin D are needed to raise serum 25(OH)D
concentrations from 50 to 80 nmol/L (20–32 ng/mL).

However, the FNB committee that established DRIs for vitamin D
extensively reviewed a long list of potential health relationships
on which recommendations for vitamin D intake might be based [1]. These health relationships included
resistance to chronic diseases (such as cancer and cardiovascular
diseases), physiological parameters (such as immune response or
levels of parathyroid hormone), and functional measures (such as
skeletal health and physical performance and falls). With the
exception of measures related to bone health, the health
relationships examined were either not supported by adequate
evidence to establish cause and effect, or the conflicting nature
of the available evidence could not be used to link health
benefits to particular levels of intake of vitamin D or serum
measures of 25(OH)D with any level of confidence.

Osteoporosis

More than 40 million adults in the United States have or are at
risk of developing osteoporosis, a disease characterized by low
bone mass and structural deterioration of bone tissue that
increases bone fragility and significantly increases the risk of
bone fractures [37]. Osteoporosis is most
often associated with inadequate calcium intakes, but insufficient
vitamin D contributes to osteoporosis by reducing calcium
absorption [38]. 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. Adequate storage levels of
vitamin D maintain bone strength and might help prevent
osteoporosis in older adults, non-ambulatory individuals who have
difficulty exercising, postmenopausal women, and individuals on
chronic steroid therapy [39].

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 [40,41,42].

Most supplementation trials of the effects of vitamin D on bone
health also include calcium, so it is difficult to isolate the
effects of each nutrient. Among postmenopausal women and older
men, supplements of both vitamin D and calcium result in small
increases in bone mineral density throughout the skeleton. They
also help to reduce fractures in institutionalized older
populations, although the benefit is inconsistent in
community-dwelling individuals [1,2,43]. Vitamin D
supplementation alone appears to have no effect on risk reduction
for fractures nor does it appear to reduce falls among the elderly
[1,2,43];
one widely-cited meta-analysis suggesting a protective benefit of
supplemental vitamin D against falls [44] has
been severely critiqued [1]. However, a large
study of women aged ≥69 years followed for an average of 4.5 years
found both lower (<50 nmol/L [<20 ng/mL]) and higher(≥75
nmol/L [≥30 ng/mL]) 25(OH)D levels at baseline to be associated
with a greater risk of frailty [45]. 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.

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 may have 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 [1,46,47]. Studies do not
consistently show a protective or no effect, however. One study of
Finnish smokers, for example, found that subjects in the highest
quintile of baseline vitamin D status had a threefold higher risk
of developing pancreatic cancer [48]. A recent
review found an increased risk of pancreatic cancer associated
with high levels of serum 25(OH)D (≥100 nmol/L or ≥40 ng/mL) [49].

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 [50]. 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 [51]. 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 with women taking a placebo [52].
The small number of cancers (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 (1988–1994), in which total
cancer mortality was found to be unrelated to baseline vitamin D
status [53]. However, colorectal cancer
mortality was inversely related to serum 25(OH)D concentrations. A
large observational study with participants from 10 western
European countries also found a strong inverse association between
prediagnostic 25(OH)D concentrations and risk of colorectal cancer
[54].

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 [46,55]. Taken together, however, studies to date
do not support a role for vitamin D, with or without calcium, in
reducing the risk of cancer [1].

Other conditions

A growing body of research suggests that vitamin D might play some
role in the prevention and treatment of type 1 [56]
and type 2 diabetes [57], hypertension [58], glucose intolerance [59],

multiple sclerosis [60], and other medical
conditions [61,62].
However, most evidence for these roles comes from in vitro,
animal, and epidemiological studies, not the randomized clinical
trials considered to be more definitive [1].
Until such trials are conducted, the implications of the available
evidence for public health and patient care will be debated. One
meta-analysis found use of vitamin D supplements to be associated
with a statistically significant reduction in overall mortality
from any cause [63,64],
but a reanalysis of the data found no association [43].
A systematic review of these and other health outcomes related to
vitamin D and calcium intakes, both alone and in combination, was
published in August 2009 [43].

Warning!

Health Risks from Excessive Vitamin D

Vitamin D toxicity can cause non-specific symptoms such as
anorexia, weight loss, polyuria, and heart arrhythmias. More
seriously, it can also raise blood levels of calcium which leads
to vascular and tissue calcification, with subsequent damage to
the heart, blood vessels, and kidneys [1]. The
use of supplements of both calcium (1,000 mg/day) and vitamin D
(400 IU) by postmenopausal women was associated with a 17%
increase in the risk of kidney stones over 7 years in the Women’s
Health Initiative [65]. A serum 25(OH)D
concentration consistently >500 nmol/L (>200 ng/mL) is
considered to be potentially toxic [5].

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
[6]. In addition, thermal activation of
previtamin D₃ in the skin gives rise to various
non-vitamin D forms that limit formation of vitamin D₃
itself. Some vitamin D₃ is also converted to nonactive
forms [1]. Intakes of vitamin D from food that
are high enough to cause toxicity are very unlikely. Toxicity is
much more likely to occur from high intakes of dietary supplements
containing vitamin D.

Long-term intakes above the UL increase the risk of adverse
health effects [1] (Table 4). Most reports
suggest a toxicity threshold for vitamin D of 10,000 to 40,000
IU/day and serum 25(OH)D levels of 500–600 nmol/L (200–240 ng/mL).
While symptoms of toxicity are unlikely at daily intakes below
10,000 IU/day, the FNB pointed to emerging science from national
survey data, observational studies, and clinical trials suggesting
that even lower vitamin D intakes and serum 25(OH)D levels might
have adverse health effects over time. The FNB concluded that
serum 25(OH)D levels above approximately 125–150 nmol/L (50–60
ng/mL) should be avoided, as even lower serum levels
(approximately 75–120 nmol/L or 30–48 ng/mL) are associated with
increases in all-cause mortality, greater risk of cancer at some
sites like the pancreas, greater risk of cardiovascular events,
and more falls and fractures among the elderly. The FNB committee
cited research which found that vitamin D intakes of 5,000 IU/day
achieved serum 25(OH)D concentrations between 100–150 nmol/L
(40–60 ng/mL), but no greater. Applying an uncertainty factor of
20% to this intake value gave a UL of 4,000 IU which the FNB
applied to children aged 9 and older, with corresponding lower
amounts for younger children.

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 [66,67,68]
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 [67,68].

Other medications

Both the weight-loss drug orlistat (brand names Xenical® and
alli^TM) and the cholesterol-lowering drug
cholestyramine (brand names Questran®, LoCholest®, and
Prevalite®) can reduce the absorption of vitamin D and other
fat-soluble vitamins [69,70].
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 [71].

Vitamin D and Healthful Diets

The federal government’s 2010 Dietary Guidelines for
Americans notes that “nutrients should come primarily from
foods. Foods in nutrient-dense, mostly intact forms contain not
only the essential vitamins and minerals that are often contained
in nutrient supplements, but also dietary fiber and other
naturally occurring substances that may have positive health
effects. …Dietary supplements…may be advantageous in specific
situations to increase intake of a specific vitamin or mineral.”

For more information about building a healthful diet, refer to
the Dietary Guidelines for Americans and
the U.S. Department of Agriculture’s food guidance system, MyPlate.

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 some brands of yogurt and orange juice. Cheese
  naturally contains small amounts of vitamin D.

• Includes lean meats, poultry, fish, beans, eggs, and nuts.

  Fatty 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.