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Review Article

Vitamin D: Extra-skeletal effects

Vishal Gupta
Department of Endocrinology, Jaslok Hospital and Research Centre, Mumbai, India

A B S T R A C T

There is a growing concern of vitamin D deficiency and its relationship with several extra-skeletal pathological states, ranging from immune
disorders (systemic lupus erythematosus, type 1 diabetes mellitus, multiple sclerosis, inflammatory bowel diseases, and rheumatoid arthritis),
cardiovascular disorders (coronary artery disease, atherosclerosis, and hypertension), infections (viral and bacterial), endocrine disorders (growth
failure, infertility in males, metabolic syndrome, and type 2 diabetes mellitus), neuro-psychiatric, and neuro-degenerative disorders, renal disorders,
chronic lung disorders to cancer. Besides its positive effects on the musculo-skeletal system, vitamin D has shown to take an active part in
the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis. It has been shown to control approximately 3% of the
human genes directly or indirectly. Although there is a strong body of evidence toward implication of vitamin D deficiency with several
extra-skeletal disorders, it remains unclear if vitamin D supplementation may slow down, halt or even reverse the disease processes.This
review aims to discuss the potential associations of vitamin D with various extra-skeletal disorders.

Key words: Extra-skeletal effects, vitamin D, vitamin D deficiency

Introduction now recognized that the vitamin D receptor is ubiquitously

The growing concern of vitamin D deficiency and its
relationship with several pathological states has been the
recent buzz of the endocrine world, with a few skeptics
wondering whether we are overdoing the vitamin D saga.
Nevertheless what is obvious is that both the prevalence
and incidence of vitamin D deficiency are high and
steadily increasing especially in those with persistent
musculoskeletal complains (93%). The human being
seems to have eclipsed the sun (sunlight), which is the
natural source of vitamin D. Holick and colleagues have
shown that skin color and modern practices of cosmetic
dermatology (sun tan lotions and creams, etc.) have
significantly rendered the sun redundant.[1-4]
Conventionally the vitamin D endocrine system has been
thought to be responsible for musculoskeletal health. It is
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present in most tissue types (immune, endocrine
{parathormone, beta-cells of pancreas, rennin producing},
cardiovascular cells, pulmonary, neural, etc.) that respond
to active vitamin D (D3; 1,25-dihydroxy (OH)2 vitamin D)
exposure. Approximately 3% (more than 200 genes) of the
human genome is regulated, directly and/or indirectly, by
the vitamin D endocrine system. It also takes an active part
in the regulation of cellular proliferation, differentiation,
apoptosis, and angiogenesis.[5,6]
Vitamin D physiology
Source of vitamin D and metabolism [Figure 1]
Dietary: There are two forms of vitamin D, erogocalciferol
(D2; plant source), which is manufactured from the
ultraviolet irradiation of ergosterol (obtained from yeast
and mushrooms), and cholecalciferol (D3), which is
obtained from fatty fish, milk, and eggs. Unfortunately
in order to obtain the recommended daily requirements
of vitamin D, a very large quantity of food (approximately
40 eggs; 2.5 liters of milk or 10.5 ounces of fatty fish) needs
to be consumed which is both impractical and impossible
for most. Additionally one tablespoon of cod liver oil
contains 1360 IU, 3.5 oz salmon 360 IU, 3.5 oz mackerel
345 IU, 3.5 oz sardines 270 IU, 3.5 oz eel 200 IU, 1 egg
yolk 25 IU, 236 ml milk 100 IU of vitamin D.[1,3,5] One

Corresponding Author: Dr. Vishal Gupta, Department of Endocrinology, Jaslok Hospital and Research Centre, 15-Dr. Deshmukh Marg, Pedder
Road, Mumbai, India. E-mail: enquiry@drvishalgupta.com

Journal of Medical Nutrition and Nutraceuticals, Vol 1 / Issue1 / Jan-Jun 2012 17

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Gupta: Vitamin D – Extra-skeletal effects

SKIN (UVB radiation) 7 –dehydrocholesterol (B ‐ ring

breaks to form pre‐d3 which converts to D3 or DIET
lumisterol/tachysterol (continued irradiation)

Vitamin D Bound to

binding protein & albumin

Liver ( 25 Hydroxylase forms 24 Hydroxylase

inactive 25 ‐ OH D)
24,25, Vitamin D
(substrate dependant)

Renal (1,25 Hydroxylase 24 Hydroxylase

forms active 1,25 OH2D) 1,24,25 Vitamin D

Vitamin D receptor
1) 3% genes
2) Bones
3) Calcium transport (intestine and Kidneys)
4) Hormone
- regulation (beta cells,
- renin, parathormone)
5) Cardiomyocytes
6) Endothelium
8) Immune system
9) Neural
10) Lulmonay
11) Renal
Figure 1: Metabolism of vitamin D

way of trying to meet the daily vitamin D requirements
is to fortify foods with vitamin D such as milk, breads,
cereals, and yogurts as occurs in the United States. In
Europe, food fortification got prohibited since 1950s in
most countries except Sweden and France, when there
were reported outbreaks of vitamin D intoxication in
infants.[7,8]
Skin: The principal source of vitamin D is however the
skin. For all practical purposes vitamin D will be referred
to both vitamin D2 and D3 unless specified. Ultraviolet
irradiation (280-310 nm) of the epidermis results in
photochemical isomerization of 7-dehydrocholesterol to
form previtamin D3, which is then transported to the liver
bound to the vitamin D binding protein or albumin. Excess
skin irradiation protects against formation of toxic levels
of D3 by converting 7-dehydrocholesterol to lumisterol
and tachysterol (both biologically inactive). Lumisterol
can reversibly be converted back to previtamin-D3 should
it be required. Factors that influence the degree of
vitamin D3 formation in the skin include time of day (9
am to 4 pm), season (summer, spring>>winter), latitude
(angle of the sun and degree of ozone density), sunscreen
use, clothing, and other barriers, skin pigmentation/type
and aging.[9-13]
1. Time of day: skin production of vitamin D3 starts
about 9 am and ceases after 4 pm even during the
summer. In countries such as Norway, vitamin D3
production may not start until 11 am even during
summer where sunlight is available for 24 hours.
2. Season: greater vitamin D3 is produced during
summer, spring, and fall because of greater availability

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Gupta: Vitamin D – Extra-skeletal effects
of sunlight during these seasons. A cloudy environment
can reduce the degree of ultraviolet light by as much
as 99% compared to a clear day.
3. Latitude: ozone is thickest in the polar region.
It absorbs all ultraviolet B radiation before they
reach the earth’s surface. As the angle of the sun
(zenith angle) increases with increasing latitude, the
ultraviolet B photons have to travel a greater distance
making it less capable of inducing vitamin D3
production in the skin, e.g., Boston in the winter
(previtamin D3 synthesis begins in March and ends
in November).[13]
4. Sunscreen use: Use of sunscreen over 1/4th body
surface area in a dose of 2 mg/cm2 skin surface,
i.e., about 1 oz or 25% of a 4-oz bottle applied to all
sun exposed areas of the skin of a person wearing a
bathing suit with a sun protection factor (SPF) of 8,
reduces vitamin D3 production by more than 95%.
Use of SPF 15 reduced vitamin D3 production by
approximately 99%.[14,15]
5. Skin type: the skin type of Fitzpatrick is classified from
1 (lightest) to 6 (darkest), with the darkest skin type
(African origin) requiring 5 to 10 times the degree of
sunlight exposure to manufacture the same quantity
of vitamin D3 in the skin. Natural skin melanin acts
as a shield that absorbs the UVB photons. Therefore
darker the skin lesser is its capacity to generate
vitamin D. Despite all these differences once 1 MED
(minimal erythemal dose; minimum amount of UVB
that produces skin pinkness/redness 24 hours after
exposure) of sunlight exposure is attained, the degree
of vitamin D3 production seems to be similar across
all skin types.[16]
6. Clothing and other barriers: like transparent glass,
absorbs 100% of the UVB radiation and totally
prevents the formation of UVB photons and
vitamin D.
7. Aging: a 70-year-old person produces only 25% the
capacity of vitamin D3 compared to a 20 year old
In liver vitamin D is enzymatically hydroxylated at carbon
position 25 to form 25-hydroxy-D (25-OH-D) by a CYP-450
enzyme (CYP27A1; 25-hydroxylase). CYP27A1 is widely
distributed throughout different tissues with highest levels
in liver and muscle, but also in kidney, intestine, lung,
skin, and bone. 25-OHD is the major circulating form of
vitamin D that is biologically inert. Liver hydroxylation
of vitamin D is substrate dependent. It is converted to
its active form, 1,25-dihydroxyvitamin D (1,25-OH2D)
in the kidneys by enzyme 25OHD-1αhydroxylase
(CYP27B1) which is regulated by need and not substrate.
The principal regulators of CYP27B1 activity in the
Journal of Medical Nutrition and Nutraceuticals, Vol 1 / Issue1 / Jan-Jun 2012
kidney are parathyroid hormone (PTH), fibroblast
growth factor-23(FGF-23), calcium, phosphate, and 1,25-
OH2D. Extrarenal production of 1,25-OH2D tends to be
stimulated by cytokines such as interferon (INF)-gamma
and tumor necrosis factor (TNF)-alfa more effectively than
PTH and may be less inhibited by calcium, phosphate, and
1,25-OH2D. 1,25-OHD further binds to the vitamin D
receptor (VDR) in order to achieve its biological effects,
which will be discussed in detail.[17-19]
Catabolism and regulation of vitamin D
Excess vitamin D formation is prevented from accumulating
in the body by the following three processes:
1. On prolonged skin exposure toxic levels of previtamin
D3 are prevented because of conversion to lumisterol
and tachysterol, of which lumisterol can be reconverted
back to previtamin D3 should the need arise.
2. The 24-hydroxylase pathway [Figure 1] which breaks
down excess vitamin D2 and D3.
3. Negative feedback of 1,25-OH2D (renal) on the
production of 25-OHD in the liver.
Natural daily production of vitamin D
“Holick’s rule” states that sun exposure of 1/4th of an MED
over 1/4 of the body surface generated vitamin D equivalent
to approximately 1000 IU of orally consumed vitamin D.[20]
One MED exposure for as little 5–15 minutes between
the hours of 10 am and 3 pm in the spring, summer, and
fall at latitudes above and below 35° (and all year near the
equator) to exposed parts of the body
a. Other than “body type of bathing suit” produces
between 3000 and 5000 IU of vitamin D.
b. Other than “bikini type bathing suit” produces
between 15,000 and 20,000 IU of vitamin D.
c. Involving “arms, legs and face” as occurs with shorts
and short-sleeved shirts (20–25%) produces 1000 IU
of vitamin D.
Ideal therapeutic levels
Based on the ability of vitamin D to promote bone
health and prevent secondary hyperparathyroidism and
osteoporosis, most experts including the Endocrine
Society of America and International Osteoporosis
Foundation believe that a cut-off of 30 ng/ml (multiply
by 2.49 for nmol/l) represents a safe lower limit of
vitamin D. These ranges are however only with respect
to bone health.[21,22] The questions that many healthcare
practitioners have is that, is the cut off of 30 ng/m
enough to achieve sufficient tissue concentration of
active vitamin D in order for it to achieve its extra-
skeletal effects? One such example is with regard to
cancer prevention, which many authors believe follows
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Gupta: Vitamin D – Extra-skeletal effects
a U-shaped curve with an increased incidence of cancer
with extreme serum concentration of vitamin D.
Prolonged vitamin D intake has been associated with
an increased risk of prostate cancer in Nordic males,
which is probably inherent to that population and cannot
be generalized.[23] This finding only adds confusion to
setting an optimal vitamin D target;[24] however despite
all these idiosyncracies most experts define vitamin D
sufficiency, insufficiency, and deficiency as follows:
Vitamin D insufficiency is defined as values between 21
and 29 ng/ml.
Vitamin D deficiency is defined as values 10–20 ng/ml.
Severe vitamin D deficiency is defined as <10 ng/ml.
Vitamin D replacement regimens
In order to raise the serum concentration of vitamin D
by approximately 1 ng/ml one must increase the daily
vitamin D intake by 100 IU for approximately 4–6
months, e.g., if patient serum vitamin D level is 15 ng/
ml and if one was to increase it to approximately 30
ng/ml, the average increase in vitamin D would have
to be 1500 IU approximately, in order to achieve the
target vitamin D level.[25] Vitamin D may be given as
either ergocalciferol or cholecalciferol (40 IU=1 µg).
Only cholecalciferol is available in India. Replacement
regimens are as follows:
1. Intermittent bolus “high-dose vitamin D: A total
of 300,000 IU every 6 months titrated to serum
vitamin D level >30 ng/ml.[26,27]
2. Intermittent bolus low-dose vitamin D: A total of
50,000 IU every week for six doses titrated to serum
vitamin D level >30 ng/ml, failing which a repeat of
the above can be done for vitamin D values persistently
<20 ng/ml and for values between 21 and 29 ng/ml,
50,000 IU may be instituted every 2–4 weeks for a
further six doses till desired result are achieved.
3. Daily vitamin D: Depending upon minimum
daily need as guided by the Endocrine Society and
serum vitamin D levels, the total daily dose can be
calculated based on the formula mentioned above,
-on an individual basis. For adults the upper limit
of vitamin D supplements is set at 10,000 IU/day
beyond which vitamin D toxicity may ensue.[1,3,4,21]
The recommended daily intake may be as follows
[Table 1]:
Parenteral replacement (intramuscular) should be avoided
as far as possible as they have consistently showed an
unpredictable and prolonged time required to attain the
desired serum vitamin D concentration coupled with a
lack of adequate suppression of serum parathormone,
compared to adequate oral replacement regimens.[27]
20 Journal of Medical Nutrition and Nutraceuticals, Vol 1 / Issue1 / Jan-Jun 2012
Table 1: Recommended daily vitamin D intake per day[1,3,4,21]
US institute Endocrine practice
of medicine guidelines
guidelines
Children <9 years 400 IU/day 400–1000 IU/day
(<1 year) (<1 year)
600 IU/day 600–1000 IU/day
Adults 600 IU/day 1500–2000 IU/day
Pregnant and lactating women 600 IU/day 1500–2000 IU/day
>18 years
Mechanism of action
Vitamin D is responsible for maintaining bone homeostasis
via regulating calcium and phosphorous metabolism.
It achieves this via a controlled and tightly regulated
vitamin D endocrine system, the active metabolite (1,25-
OH2D) of which is produced by the kidney. This then acts
on the vitamin D receptor to produce its biological effects.
At the level of the intestine it is responsible for calcium
and phosphorous absorption. The absence of vitamin D
results in not more than 10–15% of calcium absorption,
which is increased by approximately 40% for calcium and
80% for phosphorous once the vitamin D levels are in the
“sufficient” range. It achieves this by stimulating a calcium
channel (TrpV6) at the level of intestinal epithelial, cellular
calcium binding protein, and calmodulin and calcium-
ATPase at the basolateral membrane.[28,29] Bone is made
up of 30% organic substances and 70% inorganic mineral.
The inorganic tissue is made up of insoluble calcium and
phosphate salts that precipitate as hydroxyapatite on the
organic tissue.[30,31]
Extra-skeletal effects (possible mechanisms and evidence)
A. Muscular system: Vitamin D deficiency is associated
with a proximal myopathy and sarcopenia[32] of the
appendicular skeleton independent of obesity. It seems
to relate directly to the degree of vitamin D deficiency.
It is associated with muscle atrophy (type 2 muscle
fibers) and poor muscle strength/performance.[33] It
may affect muscle function via:
a. Reduced total body calcium levels and calcium-
related protein transcription in the muscle.
b. IGF-1 and IGF-BP3: IGF-1 is a 7.5 kDa polypeptide
that contains three isoforms (IGF-1Ea, IGF-
1Eb, and IGF-1Ec). This system seems to be
influenced/regulated by vitamin D3 and several
studies have shown a positive correlation between
IGF-1 and vitamin D3 levels during growth, of
children. IGF- 1Ea is the circulating form of IGF-1
expressed from the liver that stimulates terminal
differentiation of muscle cells into myotubes and
promotes stem-cell-mediated muscle regeneration.
IGF-1Ec, also called mechano-growth factor (MGF),
is the tissue isoform expressed from skeletal muscle
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Gupta: Vitamin D – Extra-skeletal effects
cells, believed to exert exclusively autocrine/
paracrine actions that responds to tissue damage,
controls local tissue repair, and causes muscle
hypertrophy. IGF-1 circulates in the serum 99%
bound to a carrier protein IGFBP-3. Vitamin D3
also seems to be one of the regulators of IGFBP-3
expression.[34-36] Vitamin D supplementation has
been shown to directly correlate with growth and
IGF-1 levels.
Adequate replacement of vitamin D has been
shown to increase muscle strength by as much as
24.8±8.0%.[37] Stabilization of the musculoskeletal
also results in falls prevention. A meta-analysis
showed that the minimum dose of vitamin D
supplementation required, to prevent falls was
700 IU/day. This resulted in a 19% reduction
in fall rate. Similarly the minimum serum
concentration of vitamin D required to do the
same was a value >=60 nmol/l (24.09 ng/dl). This
remains the only extra-skeletal indication that
has found place with regard to vitamin D testing
and monitoring, by the US Endocrine Society. It
becomes more importance due to the fact that one
in three elderly people (aged 65 years or older)
experiences at least one fall each year and of these
about 5–6% translates into a fracture.[38]
B. Endocrine
a. Obesity: The NHANES has shown that there is a
growing prevalence of vitamin D deficiency and
obesity. Numerous studies have shown an inverse
relationship between the two. A serum vitamin D
level of less of < 50.0 (20 ng/ml) nmol/l has shown
to be significantly associated with new-onset obesity
(defined as waist circumference of ≥88 cm for
women and ≥102 cm for men) in both in adults
and children/adolescents. In the latter the highest
incidence of obesity was found with a serum
vitamin D of <17 ng/ml.[39,40] One of the possible
mechanisms explaining the association is that a
larger fat mass promotes greater storage of vitamin D
effectively reducing bioavailable vitamin D.[41]
b. Metabolic syndrome and diabetes mellitus: Obesity
is associated with insulin resistance and metabolic
syndrome.[42-44] Whether the insulin resistance
is due to vitamin D deficiency and secondary
hyperparathyroidism[45] needs to be clarified.
Vitamin D has shown to stimulate insulin secretion
via regulating intracellular calcium, modulating
beta-cell depolarization-stimulated insulin release,
and preventing apoptosis.[46-48] This was particularly
seen in patients with type 1 diabetes mellitus
(T1DM) where significantly low vitamin D levels
Journal of Medical Nutrition and Nutraceuticals, Vol 1 / Issue1 / Jan-Jun 2012
(<10 ng/ml) were associated with higher insulin
requirements suggesting an insulin secretory action
of vitamin D.[49] Although debatable,[50] a few
pilot studies have demonstrated that vitamin D
supplementation may help improve insulin
sensitivity and markers of metabolic syndrome.[51]
c. Growth: As outlined above it is clear that vitamin D
influences growth linearly in a manner related
directly to serum concentrations of IGF-1. IGFBP-3
binds to IGF-I, which augments the half-life and
biological actions of IGF on target cells. IGFBP-3
seems to be regulated by specific growth promoters
and inhibitors, one of which is vitamin D. A
vitamin D receptor-responsive element has been
found to be located between 3296 and 3282
upstream of the human IGFBP-3 gene.[52]
d. Fertility: The metabolizing hormones (25 and
1,25 hydroxylase) of vitamin D and their receptor
have been seen in round elongated spermatids,
mature spermatozoa, epididymis, glandular
epithelium of cauda epididymis, testicular tissue,
and prostate. Spermatogonia express CYP27B1 (1,
25 hydroxylase; activating hormone) and CYP24A1
(24 hydroxylase; inactivating hormone) without
any 25-hydroxylase. Vitamin D augments the
synthesis of calcium transporters, calcium pump,
calbindin, and calmodulin, all required for sperm
function.[53] In a study that assessed the degree of
sperm function with serum levels of vitamin D,
the authors found that up to 44% of patients with
vitamin D deficiency had impaired sperm motility
that correlated positively and inversely with serum
parathormone levels. Vitamin D supplementation-
induced sperm motility and acrosomal reaction
indicating that it has an important role in
maintaining fertility in males.[54]
C. Cardiovascular system
a. Ischemic heart disease: A number of epidemiological
studies have evaluated the risk of developing
cardiovascular disease with calcium and vitamin D
deficiency. The results are very inconsistent and
most experts are unable to form a consensus with
regard to the same. Positive studies favoring calcium
and vitamin D intake include those conducted by
Bostick et al.[55] (higher intake of calcium, but not
of vitamin D was associated with reduced ischemic
heart disease mortality in postmenopausal women),
Kims et al.[56] (NHANES; vitamin D <20 ng/mL
was associated with increased prevalence of self-
reported coronary heart disease, heart failure, and
peripheral vascular disease), Giovannucci et al.
[57]
(US Health Professionals Follow-up Study;
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Gupta: Vitamin D – Extra-skeletal effects
vitamin D <15 ng/ml was associated with twofold
increased rate of myocardial infarction), Wang
et al.[58] (Framingham Offspring Study; vitamin D
<10 ng/ ml was associated with a 1.80-fold increase
rate of developing the first cardiovascular event
compared with subjects with levels >15 ng/ml),
and Pilz et al. [59] (vitamin D levels <10 ng/ml was
associated with three to five times risk of sudden
cardiac death or heart failure during a 7-year
follow-up period). Vitamin D deficiency has been
shown to directly relate to coronary calcification
even in patients with type 1 diabetes mellitus. [60,61]
To dampen the enthusiasm on the above studies
a meta-analysis of calcium intake showed no
significant benefits of calcium supplement use
in reducing the risk of coronary artery disease
or stroke [62] while on the other hand only a
slight but statistically nonsignificant reduction
in cardiovascular risk was seen in another meta-
analysis in patients on moderate to high doses
vitamin D supplementation (approximately 1000
IU/day).[63]
The primary mechanisms proposed for the
cardiovascular benefit are
1. Renin and angiotensin dowregulation: Vitamin D
has shown to regulate the rennin–angiotensin
system (RAS) and vitamin D receptor null mice
have shown to exhibit high-blood pressure,
cardiac hypertrophy, and polyuria. Human studies
have shown that vitamin D acts as an endocrine
inhibitor of the RAS. Vitamin D insufficiency
(15.0–29.9 ng/ml) and deficiency (<15.0 ng/ml)
having higher circulating angiotensin II levels
and a significantly blunted renal plasma flow
response to infused angiotensin II suggesting that
low plasma vitamin D may upregulate RAS and
induce hypertension contributing to coronary
heart disease.[64-66]
2. Cardiomyocyte: Vitamin D may directly affect
myocardial contractility by reducing intramyocardial
calcium.[67]
b. Hypertension: Vitamin D supplementation
has shown down regulate the RAS and reduce
systemic blood pressure. An upregulated RAS
has been implicated in the development of
beta-cell dysfunction[68] and insulin resistance all
contributing the development of hypertension.[69]
Short-term vitamin D supplementation (800 IU)
was shown to decrease systolic blood pressure by
approximately 9%[70] confirming the possible role
of vitamin D in cardiovascular protection.
D. Immune system: Vitamin D has shown to inhibit the
following:
22 Journal of Medical Nutrition and Nutraceuticals, Vol 1 / Issue1 / Jan-Jun 2012
1. T cell proliferation, in particular the TH1 (T-helper
cell 1) response (cytotoxic) by reducing gamma-
interferon and interleukin 2.
2. Costimulatory molecules CD40, CD80, CD86 on
dendritic cells which leads to reduced secretion of
IL-12 (critical for Th1 development).
3. Differentiation of B cell precursors into plasma cells
thereby reducing immunoglobulin production.
4. TH17 response: They are a subset of T helper cells
that produce interleukin 17 (IL-17) considered
developmentally distinct thought to play a key role
in autoimmune disease.
5. Antigen presenting dendritic and macrophage cells.
Vitamin D deficiency impairs macrophage ability
to mature, produce macrophage-specific surface
antigens, lysosomal enzyme acid phosphatase, and
to secrete hydrogen peroxide, which is essential to
their antimicrobial function.
It has shown to up-regulate the following:
1. Protective TH2 (T-helper cell 2) response by increasing
IL-4,5 and 10.
2. T-cell regulatory cells (Treg): Regulatory T cells
actively suppress activation of the immune system and
prevent pathological self-reactivity, i.e., autoimmune
disease. [71,72]
a. Autoimmune disorders: Vitamin D deficiency
has been implicated in pathogenesis of systemic
lupus erythematosus, type 1 diabetes mellitus,
multiple sclerosis, inflammatory bowel diseases,
and rheumatoid arthritis. [73,74] Up to 77% of
patients with multiple sclerosis and >60% with
rheumatoid arthritis have vitamin D levels <55
nmol/l. A Finnish study showed that the risk for
developing type 1 diabetes mellitus in infants who
received daily vitamin D supplementation (50 mg/
day) over a 30-year follow-up study was markedly
low (relative risk 0.12).[75,76]
b. Infections
Bacterial:
Tuberculosis: In a survey conducted in London
approximately 56% had undetectable levels of
vitamin D, and an additional 20% had levels below
9 ng/ml. Vitamin D has shown to inhibit the
growth of Mycobacterium tuberculosis via activation
of the Toll-like receptor (TLR2/1) which reduces
its viability within macrophages and monocytes.
[77]
Skin infections (staphylococcus aureu,s pseudomonas
auroginosa): Keratinocytes treated with vitamin D
have been shown to have substantially more killing
abilities toward epidermal bacteria mediated by
enhanced cathelicidiin expression in human
epidermal keratinocytes. Following epidermal
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Gupta: Vitamin D – Extra-skeletal effects

volume, reduced differentiation, and diminished

injury 1,25-hydroxylase activity in the skin increases
expression of neutropic factors. This may occur as a
suggesting the contributory role of vitamin D in
result of genomic and nongenomic mechanisms, some
maintaining structural skin integrity by fighting
of which involve nitric oxide synthase, cyco-oxygenase
infection. Leprosy:[78] vitamin D has also been
2, nerve growth factor, L-type calcium channels, and
shown to have an effect on leprosy either directly
prostaglandins. Vitamin D replacement has shown to
through the vitamin D receptors or via other
positively influence mood and cognitive performance
indirect means.
in elderly patients with neurodegenerative brain
Viral: Vitamin D sufficiency is an independent
disorders. The question remains as to whether
predictor of sustained virological response
vitamin D treatment can halt or even reverse the
following antiviral therapy given for chronic hepatitis
pathology remains to be seen.[85-87]
C infection. [79] An increased associated with the
G. Pulmonary system: Vitamin D deficiency has been
common cold and flu[80] has also been seen with low
linked to chronic lung conditions such as childhood
vitamin D levels with severe infections requiring
asthma in patients with maternal vitamin D deficiency,
intensive care associated with the lowest range of
infections such as influenza A and mycobacterial
vitamin D levels (<20 ng/ml).
tuberculosis, cyctic fibrosis, interstitial lung disease,
E. Cancer Prevention: Vitamin D has shown to
and chronic obstructive pulmonary disease.[88] There
reduce the incidence of cancer via inhibiting tumor
is a suggestion that there may be a role of vitamin D
angiogenesis, stimulating cell adherence by enhancing
supplementation in patients with acute exacerbation
intercellular communication gap junctions, inhibiting
of severe chronic obstructive pulmonary disease in
cell proliferation, and inducing tumor cell apoptosis.
patients with a baseline vitamin D of <10 ng/ml).[89]
Vitamin D receptor has several genotypes with “bb”
Vitamin D deficiency has been also directly related
showing the strongest relationship with development
to prolonged requirements of oxygen therapy, worse
of cancer (twice for colon and prostate cancer in
quality of life scores, tendency to have lower percent
men; and twice the risk for breast cancer in women)
predicted forced expiratory volume in 1 seconds (FEV1)
compared to the “BB” phenotype.[81] A high incidence
during pulmonary rehabilitation.[90]
of vitamin D deficiency has been seen in patients with
H. Renal: Vitamin D has shown to have protective effects
head and neck,[82] breast, colon, ovarian, and prostate
on the kidneys via its blood pressure lowering ability
cancer. Severe vitamin D deficiency can be seen in up to
and also has shown to reduce the albumin excretion
45% of head and neck cancers. Although the evidence
rate which is an independent marker of future kidney
with regard to an increased incidence of vitamin D
function.[91] It has also shown to reduce cardiovascular
deficiency exists in populations at an increased risk of
mortality in patients with stage 3/4 chronic kidney
cancer, it is not clear whether vitamin D or calcium
disease (21% in the vitamin D group versus 44% in
supplementation can reduce the risk of cancer. In the
the control group over a 27-month follow-up, at an
Cancer Prevention Study II Nutrition Cohort (United
average vitamin D dose of 1650 IU/day).[92] Possible
States), calcium supplementation (but not vitamin D)
mechanisms proposed have been antihypertensive
was associated with a marginal decrease in the risk of
effect, renin–angiotensin down-regulation and hence
colon cancer;[83] however a meta-analysis[84] did not
preventing ventricular remodeling and improvement
show any benefit of vitamin D supplementation with
in parathormone-related adverse events. Most of
regard to cancer prevention. To further confuse the
the cardiovascular protective data published so far
issue it has been shown that higher than normal levels
have shown mixed results, probably because of low-
can be associated with an increased risk of cancer and
vitamin D doses used in the past, not enough to reach
that the risk of cancer follows a U-shaped curve with
sufficient tissue concentrations. The average dose used
regard to serum vitamin D levels.[23]
in the above study (1650 IU/day) was much higher
F. Neurodegeneration (Alzheimers disease): There
than previously reported, leaving room for argument
is a high prevalence of vitamin D in patients with
that current practices may not have got it entirely
Alzheimers disease, Parkinson disease, depression,
correct with regards adequate daily vitamin D doses
and schizophrenia. The vitamin D receptor has been
meant to be used per day.
implicated as a candidate gene in the etiopathogenesis
of Parkinsons disease and other developmental brain
disorders. Preclinical studies have shown that total
Conclusion
gestational deprivation of vitamin D causes mild
The saga of vitamin D seems to be unfolding with every
distortion of the brain, increased lateral ventricular

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Gupta: Vitamin D – Extra-skeletal effects
passing year. Its deficiency is clearly being implicated in
virtually every disease state ranging from cardiovascular
disease to autoimmune disorders. Although a clear
association exists between several pathology states and
vitamin D deficiency it remains to be seen if vitamin D
supplementation can slow down, halt or even reverse the
disease processes with which they are associated.
Besides the musculo-skeletal effects of vitamin D, most
other extra-skeletal effects are a matter of conjecture at
this time and robust studies are need to firmly establish
justifying vitamin D testing and supplementation other
than for muscle or bone-related problems.
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How to cite this article: Gupta V. Vitamin D: Extra-skeletal effects. J
Med Nutr Nutraceut 2012;1:17-26.
Source of Support: Nil. Conflict of Interest: None declared.

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