Review Review

Dermato-Endocrinology 5:3, e2; September–December 2013; © 2013 Landes Bioscience

Vitamin D: Update 2013

From rickets prophylaxis to general preventive healthcare
Uwe Gröber1, Jörg Spitz2, Jörg Reichrath3, Klaus Kisters1,4, and Michael F Holick5
1
Academy for Micronutrient Medicine; Essen, Germany; 2Institute for Medical Information and Prevention; Wiesbaden, Germany; 3Universitätsklinikum des Saarlandes;
Homburg/Saar, Germany; 4St. Anna Hospital, Medical Clinic I; Herne, Germany; 5Boston University Medical Center; Boston, MA USA;

Keywords: vitamin D, 25-hydroxyvitamin D, vitamin D deficiency, osteoporosis, gene expression,

cardiovascular diseases, hypertension, diabetes mellitus, autoimmune diseases, degenerative brain disease,
respiratory tract infection, atopic dermatitis, cancer, drugs

have been found in over 35 target tissues that are not involved
Vitamin D has received a lot of attention recently as a result in bone metabolism. These include endothelial cells, islet cells
of a meteoric rise in the number of publications showing that of the pancreas, hematopoietic cells, cardiac and skeletal muscle
vitamin D plays a crucial role in a plethora of physiological func- cells, monocytes, neurons, placental cells and T-lymphocytes.
tions and associating vitamin D deficiency with many acute It is estimated that VDR activation may regulate directly and/
and chronic illnesses including disorders of calcium metabo- or indirectly a very large number of genes (0.5–5% of the total
lism, autoimmune diseases, some cancers, type 2 diabetes human genome i.e., 100–1250 genes).4 The fact that the vitamin
mellitus, infectious diseases and cardiovascular disease. The D receptor is expressed by many tissues results in the pronounced
recent data on vitamin D from experimental, ecological, case- pleiotropic effect of vitamin D hormone.1-5
control, retrospective and prospective observational studies,
as well as smaller intervention studies, are significant and con- From Sunshine Vitamin to Sunshine Hormone
firm the sunshine vitamin’s essential role in a variety of physio-
logical and preventative functions. The results of these studies
justify the recommendation to improve the general vitamin D Vitamin D—the sunshine vitamin—is formed in the skin
status in children and adults by means of a healthy approach from 7-dehydrocholesterol (7-DHC) via the intermediate previ-
to sunlight exposure, consumption of foods containing vita- tamin D3 and with the help of sunlight (UVB: 290–315 nm).
min D and supplementation with vitamin D preparations. In Previtamin D3 is converted by body heat to vitamin D3 [chole-
general, closer attention should therefore be paid to vitamin calciferol]. Excessive sunlight exposure degrades previtamin D3
D deficiency in medical and pharmaceutical practice than has and vitamin D3 to inactive photoproducts, thus preventing exces-
been the case hitherto. sive production of the sunshine vitamin in the skin. The liver
converts vitamin D3 via the enzyme 25-hydroxylase (25-OHase:
CYP27A1, CYP2R1) into 25-hydroxyvitamin D [25(OH)
Introduction D], also known as calcidiol. The mitochondrial CYP27A1 and
microsomal CYP2R1 are the two major enzymes involved in the
hydroxylation at C-25, although there are several CYP enzymes
Since the discovery of its antirachitic effect in the 1920s, that show 25-hydroxylase (25-OHase) activity but with higher
the sunshine vitamin was for many years only seen in relation K m and lower Vmax. Serum 25(OH)D (1 ng/mL = 2,5 nmol/L) is
to its function in calcium and bone metabolism. A variety of the barometer for the medical laboratory evaluation of the vita-
research results from recent years have shown that vitamin min D status.1-3
D in its hormonally active form, 1α,25-dihydroxyvitamin D 25(OH)D is then converted in the kidneys via the enzyme
[1α,25(OH) 2D; calcitriol] is not only a regulator of calcium and 25-hydroxyvitamin D-1-α-hydroxylase also known as cyto-
phosphate homeostasis, but has numerous extra-skeletal effects. chrome p450 27B1 (1-OHase: CYP27B1) into the metabolically
These include the significant impact of the vitamin D hormone active vitamin D hormone [1α,25(OH) 2D]. This enzyme is also
on the cardiovascular system, central nervous system, endocrine called renal 1-α-hydroxylase – since it occurs in the kidneys (→
system and immune system as well as on cell differentiation and endocrine effect). The renal synthesis of 1,25(OH) 2D is regulated
cell growth.1,2 by several factors including serum phosphorus, calcium, fibro-
1α,25(OH) 2D manifests its diverse biological effects (endo- blast growth factor 23 (FGF-23), parathyroid hormone (PTH)
crine, autocrine, paracrine) by binding to the vitamin D receptor and itself.3 Besides the kidneys, a multitude of tissues have a local
(VDR) found in most body cells (Fig. 1). Vitamin D receptors 1-α-hydroxylase (1-OHase) including bone, placenta, prostate,
keratinocytes, macrophages, T-lymphocytes, dendritic cells, sev-
eral cancer cells, and the parathyroid gland. Depending on the
*Correspondence to: Uwe Gröber; Email: [email protected] availability of 25(OH)D and the amounts required, these cells
Submitted: 07/15/2013; Revised: 10/07/2013; Accepted: 10/08/2013 can produce the biologically active vitamin D hormone with the
http://dx.doi.org/10.4161/derm.26738

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help of their local 1-OHase (→ autocrine and paracrine effect). This also explains why so many people, especially in the winter
1α,25(OH) 2D is like the sex hormones (e.g., estradiol) and cor- months, suffer from vitamin D deficiency [25(OH)D <20 ng/
ticosteroids (e.g., cortisone), which are all steroid hormones.2,4,5 mL or 50 nmol/L]. The UV index can also be used to estimate
Via a feedback mechanism, the 1α,25(OH) 2D level regulates the sun-dependent vitamin D formation in the skin. With a UV
synthesis of 1α,25(OH) 2D and reduces the synthesis and secre- index of less than 3, no vitamin D synthesis can take place in
tion of parathyroid hormone in the parathyroid glands (Fig. 1). the skin.2,3 An App for the iPhone dminder.info provides the
1α,25(OH) 2D induces its own destruction by activating the user anywhere on the planet information about how much vita-
25-hydroxyvitamin D-24-hydroxylase (24-OHase: CYP24A1), min D can be made in the skin during sun exposure. Vitamin
which leads to the multistep catabolism of both 25(OH)D and D intake in the diet plays only a minor role in the vitamin D
1α,25(OH) 2D into biologically inactive, water-soluble metabo- supply.1,2 Based on the results of recent studies, approximately 1
lites including calcitroic acid.1,3 billion people worldwide are affected by a vitamin D deficiency
[25-OH-D: <20 ng/mL] or a vitamin D insufficiency [25(OH)
The Barometer of Vitamin D Health: D: 21–29 ng/mL].3,14
25-hydroxyvitamin D
Health Risk: Vitamin D Deficiency
According to current scientific knowledge, the serum
25(OH)D level should be between 30 and 100 ng/mL to avoid According to recent studies, a vitamin D deficiency [serum
long-term negative health consequences. A 25(OH)D status 25(OH)D <20 ng/mL] is likely to be an important etiologi-
between 40 and 60 ng/mL or 100 to 150 nmol/L is ideal.3 A cal factor in the pathogenesis of many chronic diseases. These
pronounced vitamin D deficiency is present at 25(OH)D levels include autoimmune diseases (e.g., multiple sclerosis, type 1
below 20 ng/mL, with levels between 21–29 ng/mL designated diabetes) inflammatory bowel disease (e.g., Crohn disease),
as moderate vitamin D deficiency, also referred to as vitamin D infections (such as infections of the upper respiratory tract),
insufficiency. Vitamin D intoxication is only to be expected at immune deficiency, cardiovascular diseases (e.g., hypertension,
levels of 25(OH)D > 150 ng/mL.3,6 heart failure, sudden cardiac death), cancer (e.g., colon cancer,
Vitamin D deficiency is often accompanied with eleva- breast cancer, non-Hodgkin’s lymphoma) and neurocognitive
tion in serum parathyroid hormone (PTH) levels. Evidence is disorders (e.g., Alzheimer disease).5-11
increasing that PTH elevation may promote cardiovascular dis- The current results of the ESTHER study, a nationwide
ease through diminished cardiac contractility, enhanced coro- cohort study from the Saarland, involving about 10,000 women
nary risk, and cardiac valvular and vascular calcification. High and men aged 50 to 74 years in whom the 25(OH)D status was
PTH levels appear to be linked to the metabolic syndrome and ascertained, showed that a vitamin D deficiency significantly
are aligned with hyperlipidemia, decreased insulin sensitiv- increased general and cardiovascular mortality over a follow up
ity, and, perhaps, decreased insulin secretion. Increased PTH median of 9.5 years. The 25(OH)D levels and overall mortal-
also is associated with neuroendocrine activation, increased ity showed a pronounced nonlinear inverse association with
sympathetic activity, and endothelial stress. PTH values pro- increased risk beginning at 25(OH)D levels below 75 nmol/l
vide useful clinical diagnostic and prognostic information in (<30 ng/ml). A vitamin D deficiency was also associated with
monitoring many chronic ailments such as heart and renal fail- significantly increased cancer mortality and a higher mortality
ure and multiple sclerosis.13 25(OH)D values of ≥40 ng/mL or rate for respiratory diseases.11
100 nmol/L are necessary to avoid an increase of parathyroid
hormone (PTH) levels.1,3,4,6 However, in a recently published Bone, Muscle Metabolism, and Dental Health:
analysis of more than 312 962 paired PTH and 25(OH)D lev- Risk of Fractures, Falling and Caries
els, no threshold level of 25(OH)D-dependent parathyroid hor-
mone status was observed at which an increase of the 25(OH) Vitamin D plays an important role in the calcium and phos-
D value suppresses the PTH increase, even at 25(OH)D levels phorus metabolism and helps ensure adequate levels of these
>60 ng/mL. The high proportion of blood samples showing a minerals for metabolic functions and bone mineralization.
vitamin D deficiency and secondary hyperparathyroidism was 1α,25(OH) 2D increases the efficiency of intestinal calcium
remarkable in this analysis.1,11 Active 1,25(OH) 2D should not absorption from 10–15% to 30–40% by interacting with the
be measured to assess vitamin D status, since in the presence VDR-RXR and thereby promoting the expression of an epi-
of a vitamin D deficiency it is often normal or even shows a thelial calcium channel and a calcium-binding protein. Based
compensatory increase due to elevated parathyroid hormone on several animal experiments it has been estimated that
levels! 3,6 1α,25(OH) 2D also increases the intestinal phosphorus absorp-
North of the 35th parallel, the sun is not high enough in the tion from 50–60% to approximately 80%.1,3 Vitamin D defi-
sky from October to March to supply our skin with the neces- ciency is a widespread medical condition that plays a major role
sary 290 to 315 nm UVB radiation. The flat angle of incidence in human bone health. A severe vitamin D deficiency [25(OH)
of the sun is responsible for the low intensity of the sun’s rays. D <10 ng/mL] results in rickets in children and osteomalacia
Germany is located between 47th and 55th parallels, i.e., in in adults. The clinical symptoms of a severe vitamin D defi-
the northern hemisphere of the earth, at same level as Canada. ciency include, besides a mineralization disorder, a myopathy

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 Figure 1. Vitamin D in its hormonally active form, 1α,25-dihydroxyvitamin D is not only a regulator of calcium and phosphate homeostasis, but has
numerous nonskeletal functions effects. 1α,25(OH)2D manifests its diverse biological effects (endocrine, autocrine, paracrine) by binding to the vitamin
D receptor (VDR) found in most cells in the body. It is estimated that VDR activation may regulate directly and/or indirectly more than 200 genes, includ-
ing genes responsible for the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis.135,136

with proximal muscle weakness and muscle pain. The miner- hampers remodeling of the remaining mineralized bone tissue.
alization disorder osteomalacia can also cause bone pain and By spatially resolved synchrotron bone mineral density distribu-
fractures. The secondary hyperparathyroidism by vitamin D tion analyses and spectroscopic techniques, it was observed that
deficiency results in an increased osteoclastic activity which the bone tissue within the osteoid frame has a higher mineral
removes matrix and mineral causing bone mineral loss, this can content with mature collagen and mineral constituents, which
precipitate and exacerbate osteopenia and osteoporosis in adults. are characteristic of aged tissue. In situ fracture mechanics mea-
In older individuals vitamin D deficiency is associated with an surements and synchrotron radiation micro-CT of the crack path
increased risk of functional limitations, falling and fractures.14,15 have shown that a deficiency of vitamin D increases both the
Fracture susceptibility in the context of vitamin D deficiency initiation and propagation of cracks by 22–31%. These data shed
has been primarily associated with defective mineralization of a new light on the impact of vitamin D deficiency in bone health
collagenous matrix and osteoclastic destruction of the bone. and explains why a normal vitamin D status is essential to main-
Recent research has shown that bone’s fracture resistance is influ- tain bone’s structural integrity.16
enced by toughening mechanisms at various hierarchical levels In the most recent meta-analysis original data on 30 011 study
ranging from the nano to the microstructure. The characteristic participants from 11 double-blind and randomized studies were
increase in osteoid-covered surfaces in vitamin D-deficient bone pooled.17 The classic intent-to-treat analysis of 30,011 persons

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showed a statistically non-significant reduction of hip fractures anti-inflammatory agent and stimulate the production of anti-
by 10%. However, an analysis of the effect in relation to the vita- microbial peptides.24,25
min D amount actually taken, showed a statistically significant
reduction of hip fractures by 30% among the subjects taking the Ecological Association Studies
highest dosage (792 to 2000 IU vitamin D/day; median: 800
IU vitamin D/day) compared with the control group. In persons Over the past 100 years there have been a variety of ecological
supplemented with less than 792 IU vitamin D per day, no sta- studies that have associated living at higher latitudes with many
tistically significant reduction of hip fractures was detectable. A acute and chronic illnesses. One of the first association studies
similar dose-effect dependence was detected for all non-vertebral was reported by Palm in 1889 when he realized that children liv-
fractures. The subgroup analysis showed a significant reduction ing in the inner cities of Great Britain were at extremely high risk
of fractures in all age groups, for elderly people living at home as for developing the devastating bone deforming disease rickets
well as those living in nursing homes with the highest vitamin while children living in India had little evidence for the disease.26
D dosage.17 The results of a bone biopsy study of 675 presumed He was one of the first to recommend sunbathing for promot-
healthy adults aged 20 to 90 years, who died in an accident indi- ing skeletal health and reducing risk for rickets. In 1921 Hess
cated a threshold level of 25(OH)D ≥75 nmol/L or ≥30 ng/mL and Unger reported that sun exposure was effective in treating
as a target value for healthy bone metabolism at which further no and preventing rickets.27 The relationship between sun exposure,
mineralization disorder (osteomalacia) was detected.22 rickets and vitamin D3 was finally appreciated in the early 1930s
In addition to a positive effect on bone mineral density, vita- when Windaus determined that vitamin D3 was produced in
min D has an immediate restorative effect on the muscles, which mammalian skin and was identified as the antirachtic factor by
can be explained in terms of a better influx of calcium into the many investigators.28
muscle cells as well as a receptor-mediated stimulation of muscle One of the first ecological studies relating latitude and can-
protein synthesis.18,19 It may be that this additional effect is a cer was reported by Hoffman in 1916.29 He observed that can-
crucial factor in the fracture reduction observed with vitamin D cer mortality between 1908 and 1912 was increased in people
supplementation, since falling represents the primary risk factor living at higher latitudes. Peller and Stephensen reported on the
for fractures. This is also supported by study results according incidence of cancer in navy personnel in the United States and
to which a significant reduction in the risk of falling is already noted that although navy personnel who were outside all the
observed after 2–3 mo of vitamin D supplementation, indicating time were 8 times more likely to develop skin cancer compared
that the musculature responds quite rapidly to vitamin D intake, with age-matched controls who work indoors they had a 60%
and fracture reduction is noticeable after only about 6 mo.20 In the reduced risk of dying of cancer than the civilian population.30
reanalysis of a meta-analysis of 8 double-blind and randomized This was followed by Apperly who in 1941 reported total cancer
studies, which had been published in 2009, with high-quality mortality in Americans and Canadians in the same population
detection of the factor falling, vitamin D demonstrated a benefit who were engaged in agriculture. He concluded that cancer mor-
in all studies (OR = 0.73 [.62, 0.87]; P = 0.0004). The relevance tality was highest in farmers living in the northeast compared
of vitamin D dosing with respect to reduction of falls could also with those living in the south.31 In the 1980s through the early
be confirmed: at the higher dose (700–1000 IU vitamin D/day), 2000s there were several reports of associations with increased
vitamin D reduced the risk of a fall by 34% (OR = 0.66 [0.53, risk for colon, ovarian, prostate cancer and many other cancers
0.82] P = 0.0002), while no reduction of falls was observed at the for people living at higher latitudes in the United States as well
lower dosage level (OR = 1.14 [0.69, 1.87]).21 as in Europe.32-37 Grant reported a dramatic inverse relationship
In addition to the crucial role of vitamin D for bone health between premature mortality due to cancer with UV exposure
several studies have shown an association between alveolar bone in both men and women.38 A meta-analysis of cancer incidence
density, osteoporosis and tooth loss. Low bone mass may be a rates for more than 100 countries including Australia, and China
risk factor for periodontal disease. A recent systematic review and among others confirm previous studies where it was concluded
meta-analysis of controlled clinical trials indicate that vitamin that there was an inverse relationship with solar UVB exposure
D is important for dental health and a promising factor in the for 15 types of cancers including endometrial, gastric, cervical,
prevention of caries. This could be due to the fact that vitamin bladder, pancreatic and colorectal cancer among others.39,39a Not
D has a direct effect on bone metabolism and can also act as an only the relative risk for developing deadly cancers was associ-
ated with less solar UVB exposure but also mortality from these
numerous malignancies was also related to less solar UVB expo-
sure.40 A study conducted in Canada reported that women who
Comment: Improvement in 25(OH)D status by supplementation with had the most sun exposure as teenagers and young adults had a
vitamin D2 or vitamin D3 is an important health strategy to promote bone more than 60% reduced risk of developing breast cancer com-
health at all age levels and to reduce the risk of fractures and falling in the
elderly. To maximize the osseous effect and intestinal calcium absorp-
pared with women living in the same locale who had minimum
tion, supplementation should achieve a 25(OH)D status of ≥75 nmol/l sun exposure during the same period of time.41 Luscombe et al.
or ≥30 ng/ml, this particularly applies in the pharmacotherapy of osteo- made a similar observation in men who worked outdoors; these
porosis with bisphosphonates as well as other medications. Apart from men had a 3 y hiatus before developing prostate cancer compared
bone health vitamin D seems to be an important factor for dental health. with indoor workers.42

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 The connection between increased sun exposure and living new candidate vitamin D response elements including TRIM27,
at lower latitudes with reduced risk for cancers with vitamin D CD83, COPB2, YRNA, and CETN3 which have been shown to
was first described by Garland and Garland.32 They first related be important for transcriptional regulation, immune function,
a strong significant negative correlation with colon cancer and response to stress and DNA repair were identified. The results
mortality with mean daily radiation in the United States. This of this study suggest that any improvement in vitamin D sta-
was followed by an 8 y prospective case-controlled study of adults tus will significantly affect the expression of genes, which have
living in Washington County where the risk of developing colon a wide variety of biological functions and are involved in more
cancer was reduced 3-fold in people who had a baseline 25(OH) than 80 metabolic pathways associated with the pathogenesis of
D >20 ng/mL.33 Giovannucci et al. conducted a prospective autoimmune diseases, cancers and cardiovascular diseases. This
study in men and found an inverse association with cancer inci- study reveals, for the first time, genetic fingerprints contributing
dence of GI related cancers and predictors of vitamin D status.43 significantly to an understanding of the non-skeletal effects of
These studies have been followed by a large number of publi- the sunshine vitamin on health at a molecular biochemical level.4
cations that have related increased sun exposure, living at lower
latitudes and increased vitamin D intake with reduced risk not Cardiovascular System: Hypertension
only for cancers but also autoimmune diseases including type and Cardiac Insufficiency
1 diabetes, rheumatoid arthritis, and multiple sclerosis, neuro-
logical disorders including depression and schizophrenia, infec- A deficiency of vitamin D [25(OH)D <20 ng/mL or 50
tious diseases including tuberculosis and lower blood pressure. nmol/L] significantly increases overall and cardiovascular mor-
Evidence suggests that living for the first 10 years of your life tality.25 The vitamin D receptor is present in endothelium, vascu-
below 35° north and above 35° south latitude reduces risk for lar smooth muscle, and cardiomyocytes and may protect against
developing multiple sclerosis by 50%.44,45 Being born and living atherosclerosis through the inhibition of macrophage cholesterol
near the equator reduces risk of type 1 diabetes by more than uptake and foam cell formation, reduced vascular smooth muscle
10-fold compared with living in the far northern and southern cell proliferation, and reduced expression of adhesion molecules
regions of the globe.90 Women living at higher latitudes in the US in endothelial cells and through inhibition of cytokine release
were at higher risk for developing rheumatoid arthritis.46 People from lymphocytes.51,52
in Scandinavia are more likely to develop schizophrenia com- In the Intermountain Heart Collaborative Study, a prospective
pared with people living near the equator and babies born at study with 41 504 participants, an inadequate vitamin D supply
the end of the winter are more likely to develop schizophrenia was determined in 63.6% [25(OH)D: < 30 ng/mL). A 25(OH)
even those born in Australia.47,48 Patients with TB were found to D level <15 ng/mL compared with a 25(OH)D levels >30 ng/mL
do better when exposed to sunlight and curiously it was known was associated with a highly significant increase in the prevalence
that living in the Alps above 5000 feet the incidence of TB was of type 2 diabetes, high blood pressure, dyslipoproteinaemia,
very low.49 Finally, it was demonstrated that the higher the lati- peripheral vascular diseases, coronary heart disease, myocardial
tude that you live in the northern hemisphere and the lower the infarction, cardiac insufficiency and stroke (P < 0.0001) as well
latitude that you live in the southern hemisphere, was associated as in the incidence of overall mortality, cardiac insufficiency, cor-
with a higher overall blood pressure.50 onary heart disease / myocardial infarction (P < 0.0001), stroke
Many of these ecologic observations which suggest a direct (P = 0.003), and their combination (P < 0.0001).53,54 The results
role of increased sun exposure and improved vitamin D status has of a meta-analysis covering the vitamin D status with the risk for
been supported by association and prospective and retrospective cerbrovascular events, including >1200 cases of stroke, revealed
studies relating vitamin D intake or vitamin D status with these that 25(OH)D levels ≤12.4 ng/ml compared with 25(OH)D lev-
chronic illnesses.112 els of >18.8 ng/ml was associated with an increase in the risk level
for strokes of 53%.55
Gene Expression: Link Between A systematic review and a meta-analysis conclude that vitamin
Vitamin D and Prevention D lowers systolic blood pressure by – 6.18 mmHg and reduces
diastolic blood pressure by – 3.1 mmHg in hypertensive patients.
In a recent randomized, placebo-controlled, double-blind No change in blood pressure was observed in normotensive per-
study, the influence of a daily supplementation of 400 IU or sons.56 Black US. Americans suffer significantly more frequently
2000 IU of vitamin D3 over a period of two months in winter on from high blood pressure than whites. Reduced blood levels of
the gene expression of white blood cells (leukocytes) in healthy 25(OH)D could be responsible for the higher risk of hyperten-
adults was investigated for the first time. The improvement of sion, since people with darker skin color generally produce less
25(OH)D status observed thereby was associated with a change vitamin D3 in the skin due to the higher content of melanin and
in gene expression of at least 1.5-fold in 291 genes. There was a thus have lower levels of 25(OH)D. In a recent 4-arm, double-
significant difference in the expression of 66 genes between sub- blind, placebo-controlled and randomized study of 283 blacks
jects at baseline with vitamin D deficiency [25(OH)D <20 ng/ (age: ± 51), the influence of 1000 IU, 2000 IU and 4000 IU
mL] and subjects with a 25(OH)D >20 ng/mL. After vitamin vitamin D3 per day or placebo on blood pressure was investigated
D3 supplementation gene expression of these 66 genes was simi- for a period of 3 months. Blood pressure and 25(OH)D levels
lar for both groups. Seventeen vitamin D-regulated genes with were determined at onset, after 3 months and after 6 months.

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The difference between the systolic blood pressure at baseline with sufficient vitamin D (RR = 3.5, 95% CI = 1.1–10.5, P =
and after 3 months in the placebo group was +1.7 mmHg in the 0.01). After adjusting for cardiovascular disease risk factors, VD
placebo group, −0.66 mg Hg in the group with 1000 IU vitamin insufficiency was independently associated with SCF. The linear
D3 per day, −3.44 mmHg in the group with 2000 IU vitamin regression analysis showed that VD insufficiency was correlated
D3 per day and – 4.0 mmHg in the group with 4000 IU vitamin independently with % flow-mediated dilatation (P  <  0.001) and
D3 per day (−1.4 mmHg for every 1000 I.U. of additional vita- carotid intima-media thickness (P < 0.001).61
min D3 intake, P = 0.04). For each increase of 25(OH)D levels
by 1 ng/ml, a significant reduction in systolic blood pressure of Comment: According to the data available to date from epidemiologi-
0.2 mmHg was detected (P = 0.02). However, no significant cal and prospective cohort studies as well as from smaller interventional
reduction in diastolic blood pressure was detected (P = 0.37).57 studies of vitamin D status in cardiovascular diseases such as hyperten-
In another 16-week randomized clinical trial with normotensive sion and cardiac insufficiency, 25(OH)D levels should always be checked
and be appropriately compensated by vitamin D2 or vitamin D3 supple-
black boys and girls the relation between 25(OH)D concentra-
mentation. Normalization of 25(OH)D status could also help reduce
tions and total body fat mass by dual-energy X-ray absorptiom- therapeutic requirements for antihypertensives and cardiac drugs (e.g.,
etry, and the arterial stiffness measured by pulse wave velocity diuretics, ACE inhibitors, calcium antagonists).
(PWV) in response to 2000 IU vitamin D supplementation was
analyzed. The results demonstrate that vitamin D supplementa-
tion may be effective in optimizing vitamin D status and coun- Diabetology
teracting the progression of aortic stiffness in black youth. Plasma
25(OH)D concentrations in response to the 2000 IU/d supple- Type 1 diabetes. The worldwide incidence rate of type 1 dia-
mentation were negatively influenced by adiposity.58 betes is increasing and accumulating data show that it is associ-
The suppression of parathyroid hormone (PTH) by vitamin ated with vitamin D deficiency. The chronic autoimmune disease
D, which has been known for some time, must now be seen in a type 1 diabetes usually results from a T cell mediated destruc-
new light, since PTH has been increasingly recognized in recent tion of insulin producing, pancreatic β-cells with a typical onset
years as a major risk factor for cardiovascular diseases such as in childhood or adolescence. There is evidence that vitamin D
high blood pressure or cardiac insufficiency. PTH can cause supplementation early in life is a protective factor against the
damage to the cardiovascular system at different levels, either development of type 1 diabetes. Furthermore, in animal mod-
directly or indirectly. Elevated PTH levels, as well as a hypercal- els, such as the NOD mice, the administration of 1α,25(OH) 2D
caemia, can promote the development of hypertension. In addi- or vitamin D analogs prevented or at least delayed the onset of
tion, hyperparathyroidism is associated with a high incidence diabetes.62-65
of hypercontractility of the heart muscle with consecutive left- In a Finnish cohort study involving 12 058 children, the influ-
ventricular hypertrophy and calcification of the myocardium. ence of supplementation of vitamin D in the first year of life on
Vitamin D counteracts these processes, in that it, among other incidence of diabetes was followed up over a period of 30 y. It was
things, promotes the synthesis of anti-inflammatory cytokines, found that newborn babies who receive 2000 IU of vitamin D3
such as interleukin 10, and of other substances that reduce vas- daily as rickets prophylaxis showed a 88% lower risk for type 1
cular calcification (e.g., matrix Gla protein). In addition, vitamin diabetes mellitus compared with those with lower-dosed supple-
D counteracts the adverse effects of the so-called “advanced gly- mentation. Children who suffered from rickets in the first year
cation endproducts” (AGEs) on the endothelium.59 In a recent of life had a 3-fold higher risk for type 1 diabetes compared with
placebo-controlled, double-blind study of 80 infants with cardiac healthy children.66 In a meta-analysis of 4 case-control studies,
insufficiency, daily supplementation of 1200 IU vitamin D3 for a the risk for type 1 diabetes in infants who received a vitamin
period of 12 weeks in the 42 children from the vitamin D group D supplement compared with those who received no vitamin D
compared with the 38 children in the placebo group resulted in was reduced by 29% (OR 0.71, 95% CI 0.60 to 0.84).67 The
a significant improvement in the performance of the heart mus- importance of maternal vitamin D status on subsequent develop-
cle (e.g., LVEF ↑) and the reduction of various cardiovascular ment of type 1 diabetes in newborns is described by a Norwegian
risk parameters (e.g., PTH, IL-6, TNFα levels ↓) (P < 0.001) in cohort study of 20 072 women. A low maternal 25(OH)D status
addition to a significant rise in 25(OH)D status (13.4 → 32,9 (≤54 nmol/L or 21.6 ng/mL) during pregnancy was associated
ng/ml).60 Another recent study evaluated the effect of vitamin with a more than 2-fold risk increase for the development of type
D insufficiency (< 30 ng/mL) on epicardial coronary flow rate, 1 diabetes later in life compared with a good maternal 25(OH)D
subclinical atherosclerosis, and endothelial function in 222 con- status (>89 nmol/L or 35.6 ng/mL).68
secutive patients who had undergone coronary angiography for Type 2 diabetes and metabolic syndrome. Vitamin D defi-
suspected ischemic heart disease and were found to have normal ciency has been implicated in decreased insulin secretion and
or near-normal coronary arteries. The mean level of 25(OH)D increased insulin resistance, hallmarks of type 2 diabetes mel-
was 31.8 ng/ml, and 47% (n = 106) of the patients had insuffi- litus. The results of a recent published prospective cohort study
cient 25(OH)D levels (<30 ng/ml). Baseline characteristics were and meta-analysis with 9841 participants of whom 810 developed
similar between vitamin D insufficient and vitamin D sufficient type 2 diabetes during a 29 years follow-up confirm once more
groups. The incidence of slow coronary flow (SCF) was signifi- an association of low 25(OH)D serum levels with an increased
cantly higher in the vitamin D insufficient group than in patients risk of type 2 diabetes. Lower 25(OH)D concentrations were

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associated with higher cumulative incidence of type 2 diabe-
tes (trend, P = 2 × 10(-7) and p = 4 × 10(−10)). Multivariable
adjusted hazard ratios of type 2 diabetes were 1.22 (95% CI
0.85–1.74) for 25(OH)D <5 vs ≥ 20 μg/L and 1.35 (1.09–1.66)
for lowest vs highest quartile. Also, the multivariable adjusted
hazard ratio of type 2 diabetes for a 50% lower concentration
of 25(OH)D was 1.12 (1.03–1.21); the corresponding hazard
ratio for those ≤58 years old was 1.26 (1.15–1.41). Finally, in a
meta-analysis of 16 studies, the odds ratio for type 2 diabetes was
1.50 (1.33–1.70) for the bottom vs top quartile of 25(OH)D.69
In a randomized, placebo-controlled study involving insulin-
resistant South Asian women (age: 23–68 years) with median
25(OH)D baseline levels of <10 ng/ml, daily supplementation of
4,000 IU vitamin D3 led to a significant improvement in insu-
lin sensitivity and reduction of insulin resistance (P = 0.003 and
P = 0.02) compared with placebo. Insulin resistance was particu- Figure 2. 25(OH)D levels are dose-dependently associated with a robust
larly reduced when the 25(OH)D levels rose to above 32 ng/mL reduction in all-cause mortality in subjects with the metabolic syn-
drome. Metabolic Syndrome and Kaplan-Meier plot for all-cause mortal-
(= 80 nmol/L). Optimum concentrations of 25(OH)D for the ity according to 25(OH)D groups in those with the metabolic syndrome.
improvement of insulin resistance ranged from 32 to 47.6 ng/mL Log-rank analysis indicated a significant difference between all 25(OH)D
( = 80–119 nmol/L).70 groups (p < 0.001). 35
Several studies showed an inverse correlation of 25(OH)D
concentration with metabolic syndrome risk or with the inci-
dence or severity of its components. Subjects with hypovitamino- D <20 ng/ml] seems to increase not only the progression of pre-
sis D are at higher risk of insulin resistance and the metabolic diabetes to manifest type 2 diabetes, but also influences mortal-
syndrome.71,72 The association of 25(OH)D level with the inci- ity in metabolic syndrome: In the LURIC study of 1801 patients
dence of metabolic syndrome was analyzed in 4,164 Australian with metabolic syndrome, a good vitamin D status [25(OH)D
adults (age ±50 years) in a recent prospective study. Waist mea- ≥30 ng/mL] was associated with a 66% reduction in cardiovas-
surement and the classic risk factors for metabolic syndrome were cular mortality and a 75% reduction in total mortality (Fig. 2)
recorded for all study participants. After 5 years of follow-up, compared with a severe vitamin D deficiency [25(OH)D <10 ng/
the scientists observed a significantly increased likelihood (OR ml]. Patients with a good vitamin D status [25(OH)D ≥30 ng/
1.41 and 1.74; CI 95%) of developing metabolic syndrome in mL] showed a mortality risk reduced by 85% and 76% due to
study participants with 25(OH)D levels <18 ng/mL and 18–23 sudden cardiac death or cardiac insufficiency respectively com-
ng/mL compared with those with a good vitamin D status of pared with those with a severe vitamin D deficiency. Even when
>34 ng/mL. They concluded that in Australian adults vitamin D patients with type 2 diabetes were eliminated from the analysis,
deficiency [25(OH)D <20 ng/mL] and vitamin D insufficiency those with an optimum vitiman D status showed a 64% reduc-
[25-OH-D: 21–29 ng/mL] were associated with a significantly tion in overall mortality compared with the subjects with severe
increased risk for metabolic syndrome (P < 0.01), insulin resis- vitamin D deficiency.75
tance (P < 0.01), high waist circumference (P < 0.001) and raised In a just-published interventional study of 100 patients (age:
glucose and triglyceride levels (P < 0.01).73 54.11 ± 11) with type 2 diabetes, oral supplementation of 50 000
The results of a further prospective study provide additional IU of vitamin D3 per week over a period of 8 weeks resulted in
meaningful results in support of the thesis that a vitamin D a significant improvement of the HOMA index (HOMA-IR:
deficiency accelerates the progression of pre-diabetes to mani- 3.57 ± 3.18 → 2.89 ± 3.28; P = 0.008), insulin resistance (insu-
fest type 2 diabetes. In this connection, the scientists studied lin: 10.76 ± 8.9 → 8.6 ± 8.25 μU/ml; P = 0.02) and the fasting
glucose tolerance and 25(OH)D levels in 980 women and 1398 glucose levels (FPG (mg/dl)): 138.48 ± 36.74 → 131.02 ± 39
men (age: 35–56 y old) with no type 2 diabetes prior to study 0.05; P = 0.05) in addition to an increase of 25(OH)D levels
onset. After 8–10 y of follow-up, the study participants with pre- (43.03 ± 19.28 → 60.12 ± 17.2; P = 0.02).76
diabetes or type 2 diabetes were compared with age-correlated
and sex-correlated controls with normal glucose tolerance. After Comment: According to current data concerning metabolic control,
elimination of potential confounding variables, the male study comorbidities and increased mortality, patients with diabetes mellitus,
participants from the highest quartile showed a 48% reduced risk insulin resistance and metabolic syndrome apparently benefit from vita-
min D supplementation.
for the progression of pre-diabetes to type 2 diabetes compared
with those in the lowest quartile of the 25-OH-D level (OR 0.52,
95% CI 0.30, 0.90). Men and women with pre-diabetes at base- Immune system. In addition to the endocrine effects, vita-
line showed a remarkable 25% reduction in type 2 diabetes inci- min D hormone [1,25(OH) 2D] has also autocrine and paracrine
dence per 4 ng/mL (=10 nmol/L) increase in 25(OH)D level.74 effects. Many body cells, including immunocompetent cells, such
According to the current data, a vitamin D deficiency [25(OH) as dendritic cells, macrophages and B and T lymphocytes, have

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 Figure 3. Vitamin D and immune system. 1α,25(OH)2D appears to influence susceptibility to and severity of infection via multiple mechanisms via the
innate and adaptive immune system.145

VDR and the enzymatic capability to synthesize 1,25(OH) 2D Vitamin D status correlated inversely with the rate of infection
from its precursor 25(OH)D. 1,25(OH) 2D is a potent modula- of the upper respiratory tract: Compared with subjects with nor-
tor of acquired immunity and the immune balance between Th1 mal 25(OH)D status ( ≥30 ng/mL), the subjects with insufficient
and Th2 cells (Fig. 3). Local or systemically produced vitamin D status (10–30 ng/mL) showed a 1.24-fold increase in infection
hormone inhibits the maturation of dendritic cells, among oth- rate, while the subjects with a pronounced vitamin D deficiency
ers, reduces Th1-mediated secretion of proinflammatory cyto- (<10 ng/mL) showed a 1.36-fold increase in infection rate (odds
kines such as TNFα, increases the differentiation of monocytes ratio [OR], 1.36; 95% CI, 1.01–1.84 at < 10 ng/mL and 1.24;
to macrophages and their rate of phagocytosis as well as the activ- 1.07–1.43 at 10–29 ng/ml). In patients with bronchial asthma
ity of lysosomal enzymes in macrophages.1-3 or chronic obstructive pulmonary disease (COPD), the infection
Respiratory tract diseases (RTI). A series of observational rate was even higher showing a 2.26-fold/5.67-fold increase (P =
and epidemiological studies, supported by interventional studies 0.007) (OR, 5.67 and 2.26). The average 25(OH)D level of all
and the ubiquitous evidence of vitamin D receptors in all major participants was 29 ng/mL.78
organ systems, show an association between 25(OH)D levels and In a recent randomized double-blinded trial with 247
a reduced incidence of infections of the upper respiratory system. Mongolian schoolchildren the effect of daily ingestion of vitamin
In a recent systematic review and meta-analysis of 11 randomized D unfortified or fortified milk (fortified with 300 IU vitamin D)
controlled trials with 5660 patients vitamin D showed a protec- was evaluated (control: n = 104; D-group: n = 143). At baseline,
tive effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). The the median serum 25(OH)D level was 7 ng/mL (interquartile
protective effect was larger in studies using once-daily dosing range: 5–10 ng/mL). At the end of the trial, follow-up was 99%
compared with bolus doses (OR = 0.51 vs OR = 0.86, P = 0.01).77 (n = 244), and the median 25(OH)D levels of children in the
In a US study of 18,883 persons (age >12 y) – a represen- control vs. vitamin D groups was significantly different (7 vs. 19
tative cross-section of the US population (3rd National Health ng/mL; P < 0.001). Compared with controls, children receiving
and Nutrition Examination Survey) – the relationship between vitamin D reported significantly fewer acute respiratory infec-
serum 25-OH-D levels and the susceptibility to infections of the tions (ARI) during the study period (mean: 0.80 vs. 0.45; P =
upper respiratory tract in relation to the season was examined. 0.047), with a rate ratio of 0.52 (95% CI: 0.31–0.89). Adjusting

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 Vitamin D hormone [1,25(OH) 2D] has a pronounced mod-
ulating effect on the balance between the Th1 and Th-2 cells.
Th1:Th2 imbalances play a pathogenic role in atopic disease
in addition to autoimmune diseases such as multiple sclerosis.2
In two randomized, placebo-controlled, double-blind studies of
vitamin D supplementation only (1,600 IU / day, PO) and in
combination with vitamin E (600 IU/ day, PO) over a period of
60 d led to significant improvement of skin findings in patients
(age: 13–45 years of age) with mild, moderate, and severe
atopic dermatitis. To assess the extent and intensity of atopic
eczema, the SCORAD score (Scoring Atopic Dermatitis) was
used. In atopic dermatitis, the inflammatory processes in the
Figure 4. Respiratory tract infections and vitamin D: Relative risk reduc- skin are associated with an intensive infiltration of lymphocytes
tion by supplementation of 1,200 IU vitamin D3 compared to placebo and eosinophils, which release proinflammatory cytokines,
from December 2008 to March 2009 of influenza A and asthma attacks superoxide radicals, hydrogen peroxides and peroxynitrite.
in schoolchildren. 80 Remarkably, these studies demonstrated that not only vitamin
E, but also vitamin D reduces the oxidative load and inflamma-
for age, gender, and history of wheezing, vitamin D continued tory processes in the skin and significantly increases the activ-
to halve the risk of ARI (rate ratio: 0.50 [95% CI: 0.28–0.88]). ity level of the erythrocytic superoxide dismutase (SOD) (P =
Similar results were found among children either below or above 0.002) and catalase (CAT) (P = 0.004).83-851,25(OH) 2D and its
the median 25(OH)D level at baseline (rate ratio: 0.41 vs. 0.57; analogs have been shown to be effective when applied topically
p(interaction) = 0.27). Vitamin D supplementation significantly for the treatment of psoriasis.3
reduced the risk of ARIs in winter among Mongolian children Autoimmune disease: rheumatoid arthritis, IBD and mul-
with vitamin D deficiency.79 tiple sclerosis. In addition to infectious diseases Vitamin D
In a randomized, placebo-controlled, double-blind study of plays a contributory role in the pathophysiology of autoimmune
334 Japanese school children, the influence of vitamin D3 supple- diseases. This is further supported by various experimental
mentation on respiratory diseases such as influenza A and asthma findings showing vitamin D’s capability to regulate chemokine
was investigated. The children received a placebo or 1200 IU production, counteracting autoimmune inflammation and to
vitamin D3 daily during the intervention period from December induce differentiation of immune cells in a way that promotes
2008 to March 2009 (Fig. 4). The risk of influenza A was reduced self-tolerance. This involves the enhancement of the innate and
by the supplementation of vitamin D3 by 42% compared with the inhibition of the adaptive immune system by regulating the
placebo (RR: 0.58; 95% CI: 0.34, 0.99; P = 0.04). The protec- interactions between lymphocytes and antigen presenting cells.
tive effect was particularly pronounced in the children who took By increasing the quantity of Th2 lymphocytes and by induc-
no other vitamin D-containing supplements (RR: 0.36; 95% CI: ing proliferation of dendritic cells with tolerance properties,
0.17, 0.79; P = 0.006). The result in relation to the frequency of vitamin D exerts anti-inflammatory and immunoregulatory
asthma attacks is even more impressive: In the vitamin D group, effects.86
the frequency of asthma attacks decreased by 83% (RR: 0.17; The increased prevalence of auto-immune diseases at higher
95% CI: 0.04, 0.73; P = 0.006).80 Also in interventional studies latitudes has been shown for multiple sclerosis (MS),86,87 inflam-
with adults, the supplementation of vitamin D3 led to a signifi- matory bowel disease,88 rheumatoid arthritis89 and type 1 diabe-
cant reduction in seasonal flu-like infections.81 tes.86,87,90 The positive effect of supplementation and an adequate
25(OH)D blood level to prevent diabetes type 1 has already
Comment: With regard to the prevention of respiratory tract infections, been mentioned in the section about diabetology. Meanwhile
children and adults can benefit from a normalization of vitamin D status there exist almost as many studies about vitamin D and rheu-
based on the data from interventional studies. Further interventional matoid arthritis (RA) as with Diabetes type 1. Recent evidence
studies in the coming years must show whether patients with asthma indicates that vitamin D’s effects on the innate immune system
and COPD can benefit from a supplementation with vitamin D in con-
junction with enhancing the effectiveness of some medications (e.g.,
are predominantly through the toll-like receptors (TLR) and
corticoids). on the adaptive immune system through T cell differentiation,
particularly the Th17 response. As Th17 cells are critical in the
pathogenesis of RA, this has led to an interest in the effects of
Atopic dermatitis, psoriasis other dermatides. The abil- vitamin D deficiency in RA.91 Several studies have looked at the
ity of vitamin D to regulate local immune and inflammatory association of vitamin D deficiency with markers of disease activ-
responses offers exciting potential for understanding and treat- ity in RA with somewhat mixed results. In the Iowa womens
ing chronic inflammatory dermatitides. That is why vitamin health study of 29 368 women of ages 55–69 years without a his-
D and its analogs are playing an increasing role in the manage- tory of rheumatoid arthritis at study baseline showed that greater
ment of atopic dermatitis, psoriasis, vitiligo, acne and rosacea.82 intake (highest vs. lowest tertile) of vitamin D was inversely asso-
ciated with the risk of rheumatoid arthritis (RR 0.67; 95% CI:

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 facilitates the clearance of translocated flora, and diverts CD4
T cell development away from inflammatory phenotypes.96 In a
small randomized double-blind placebo-controlled trial the ben-
efits of oral vitamin D3 treatment in 108 patients with Crohn’s
disease in remission was assessed. Supplementation of vitamin
D3 (1200 IU/day) increased significantly the 25(OH)D serum
level from mean 69 nmol/L to mean 96 nmol/L after 3 months
(P < 0.001). The relapse rate was lower among patients treated
with vitamin D3 (6/46 or 13%) than among patients treated
with placebo (14/48 or 29%), (P = 0.06).97 In a recently pub-
lished pilot study the influence of vitamin D3 supplementation
on Crohn’s disease activity index (CDAI) was tested in patients
with mild-to-moderate Crohn’s disease. Vitamin D3 oral therapy
was initiated at 1000 IU/d and after 2 weeks, the dose was esca-
lated incrementally until patients’ serum concentrations reached
Figure 5. Vitamin D and Crohn’s disease. Twenty-four weeks supplemen- 40 ng/ml 25(OH)D3 or they were taking 5000 IU/d. Vitamin D
tation with up to 5,000 IU/d vitamin D3 effectively raised serum 25(OH) supplementation significantly increased serum 25(OH)D3 levels
D3 and reduced CDAI scores in a small cohort of Crohn’s patients sug- from 16 ± 10 ng/ml to 45 ± 19 ng/ml (P < 0.0001) and reduced
gesting that restoration of normal vitamin D serum levels may be useful the unadjusted mean CDAI scores by 112 ± 81 points from 230 ±
in the management of patients with mild–moderate Crohn’s disease.144
74 to 118 ± 66 (P < 0.0001). Quality-of-life scores also improved
following vitamin D supplementation (P = 0.0004) (Fig. 5).144
0.44–1.00; p for trend = 0.05).92 In contrast in a larger cohort It is particularly notable that vitamin D receptor knockout and
of 186389 women followed in the Nurses Health Studies there vitamin D deficient mice have a surplus of effector T cells that
was no correlation between serum levels of Vitamin D and later have been implicated in the pathology of inflammatory bowel
development of RA.93 disease and multiple sclerosis (MS). 1α,25(OH) 2D directly and
On the other hand recently an evaluation of in vitro effects indirectly suppresses the function of these pathogenic T cells
of 1α,25(OH) 2D3 in primary cultures of peripheral blood while inducing several regulatory T cells that suppress the devel-
monocyte-derived macrophages of RA patients and healthy opment of IBD and MS. Nonetheless, current evidence suggests
subjects was reported. A significant dose-dependent decrease in that improving 25(OH)D status and/or using vitamin D recep-
TNFα and RANKL production by cultured RA macrophages tor agonists may be useful in the treatment of inflammatory
after 1α,25(OH) 2D3 treatment was observed, whereas a sig- bowel disease and multiple sclerosis.98
nificant reduction in normal cells was observed only at higher Even though the autoimmune origin of multiple sclerosis
concentrations. IL-1α, IL-1β and IL-6 levels were reduced by (MS) is increasingly discussed there is no doubt about the impor-
1α,25(OH) 2D3 at higher concentrations in all cell populations. tant role vitamin D plays in the development and progression of
TNFα immunostaining was less intense in treated cells compared MS.99,100 Epidemiologic evidence supports an association between
with untreated. 1α,25(OH) 2D3 significantly reduced NO levels vitamin D and susceptibility to and severity of autoimmune
regardless of the concentration used. Vitamin D downregulated disorders. In the specific case of MS, correlations of lower MS
pro-inflammatory mediators in monocyte-derived macrophages, prevalence, activity and mortality with high levels of vitamin D
and RA cells appeared more sensitive than normal cells. These nutrition have led to the hypothesis that high levels of vitamin D
effects further provide a rationale for the therapeutic value of could be beneficial for MS. Most convincingly, the risk of relapse
vitamin D supplementation in the treatment for RA.94 Another decreased by up to 12% for every 10-nmol/l (4 ng/mL) increase
just published clinical trial of 4,793 Japanese patients with RA in serum 25(OH)D in a prospective population-based cohort
shows a high prevalence of vitamin D deficiency (<20ng/mL) study.101 A study addressing vitamin D’s effect on multiple sclero-
and severe deficiency (<10 ng/mL) (71.8 and 11.5%, respec- sis showed the safety of high-dose vitamin D (~14 000 IU/day).
tively). In multivariate analysis, female gender, younger age, high It appeared to have immunomodulatory effects including a per-
Japanese version of health assessment questionnaire (HAQ) dis- sistent reduction in T-cell proliferation and resulted in a trend for
ability score, low serum total protein levels, low serum total cho- fewer relapse events.102 When examining the association between
lesterol levels, high serum alkaline phosphate (ALP) levels, and 25(OH)D-serum levels and the relapse rate in MS patients before
non-steroidal anti-inflammatory drug (NSAID) use were signifi- and after supplementation with ~3000 IU vitamin D per day, a
cantly associated with vitamin D deficiency (P < 0.01).95 significant strong inverse relationship between the relapse inci-
Inflammatory bowel disease (IBD) is associated with indus- dence rate and the 25(OH)D level (P < 0.0001) was found.103
trialization, and its incidence has increased markedly over time. However, there are unresolved clinical questions related to the
A review in 2013 described converging data sets that suggest effect of vitamin D supplementation and MS. In general the lit-
that local activation of vitamin D coordinates the activity of erature is often limited by small study sizes (ranging from 23 to
the innate and adaptive arms of immunity, and of the intesti- 68 patients), heterogeneity of dosing, form of vitamin D tested
nal epithelium, in a manner that promotes barrier integrity, (vitamin D3 in 4 trials and vitamin D2 in 1) and clinical outcome

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measures. The evidence for vitamin D as a treatment for MS is brain injury and reduce the effects of other therapies for TBI.112
inconclusive. Larger studies are warranted to assess the effect of Meanwhile, Vitamin D therapy in combination with progester-
vitamin D on clinical outcomes in patients with MS.104,105 one was evaluated in a clinical study with 60 patients and showed
improved results: The recovery rate in patients with severe
Comment: There is reason to believe that vitamin D could be an envi- brain trauma in the group receiving progesterone and vitamin
ronmental factor that plays a crucial role in the development of different D together was significantly higher than that of progesterone
autoimmune diseases. It seems to be reasonable to maintain a healthy group, which was in turn higher than that of placebo group.113
25(OH)D-status especially in patients with RA, IBD and MS, especially
during winter [25(OH)D target value: 40–60 ng/mL or 100–150 nmol/L].
Comment: 25(OH)D status should be monitored in all patients with
degenerative brain disease (e.g., Alzheimer, Parkinson disease) and be
treated by adequate vitamin D supplementation [25(OH)D target value:
Degenerative Brain Disease and Traumatic Injury 40–60 ng/mL or 100–150 nmol/L).

The links between vitamin D and brain function have

strengthened considerably in the past decade. The combination Cancers
of in vitro, ex vivo, and animal model data provide compelling
evidence that vitamin D has a crucial role in proliferation, differ- A large body of evidence indicates that solar UV-B (UVB)
entiation, neurotrophism, neuroprotection, neurotransmission, irradiance and vitamin D reduce the risk of incidence and death
and neuroplasticity. Vitamin D exerts its biological function not for many types of cancer. For men, the UVB index was sig-
only by influencing cellular processes directly, but also by influ- nificantly inversely correlated with 14 types of internal cancer-
encing gene expression through vitamin D response elements.106 bladder, breast, colon, gallbladder, kidney, laryngeal, liver, lung,
Occasionally, the evidence from these different research domains oral, pancreatic, pharyngeal, prostate, rectal and small intestine
converges.107 The strength of evidence varies for schizophrenia, cancer. For women, the same UVB index was inversely correlated
autism, Parkinson disease, amyotrophic lateral sclerosis and with bladder, breast and colon cancer. The results of many stud-
Alzheimer disease. ies provide support for the UVB-vitamin D-cancer hypothesis
In 2010 Knekt et al. looked at the Mini-Finland Health and suggest that the widespread fear of chronic solar UV (UV)
Survey, which was conducted from 1978 to 1980, with Parkinson irradiance may be misplaced.114,115
disease occurrence follow-up through the end of 2007 with 3,173 Vitamin D deficiency is common in cancer patients and cor-
men and women, aged 50 to 79 years and free of Parkinson dis- relates with disease progression. In observational studies, vita-
ease at baseline. Main Outcome Measure was Parkinson disease min D deficiency is associated with increased incidence of breast
incidence. Individuals with higher serum 25(OH)D concentra- and colon cancer as well as with an unfavorable course of non-
tions showed a reduced risk of Parkinson disease. The relative risk Hodgkin lymphoma.116-120 In a placebo-controlled, double-blind
between the highest and lowest quartiles was 0.33 (95% confi- study of 1179 postmenopausal women aged over 55 years, the
dence interval, 0.14–0.80) after adjustment for sex, age, mari- influence of 1400 mg of calcium daily, the combination of 1400
tal status, education, alcohol consumption, leisure-time physical mg of calcium and 1100 I.U. of vitamin D3 or placebo on the
activity, smoking, body mass index, and month of blood draw.108 cancer risk was studied over a period of 4 years. In the woman
114 patients with Parkinson disease were randomly assigned to who received the combination of calcium and vitamin D, the
receive vitamin D3 supplements (n = 56; 1200 IU/d) or a placebo 25(OH)D level rose from 28.7 ng/mL to 38.4 ng/mL. Vitamin
(n = 58) for 12 mo in a double-blind setting. Outcomes were D status remained unchanged in the two other groups. At the
clinical changes from baseline and the percentage of patients who end of the four-year period, the relative risk (RR) of developing
showed no worsening of the modified Hoehn and Yahr (HY) cancer was reduced by 60% in the calcium + vitamin D3 group
stage and Unified Parkinson Disease Rating Scale (UPDRS). as compared with the placebo group relative risk (RR) cancer
Compared with the placebo, vitamin D3 significantly pre- (RR: 0.402, CI: 0.20, 0.82; p = 0.013), while in the group with
vented the deterioration of the HY stage in patients (P = 0.005). calcium alone it was reduced by 47% (RR: 0.532, CI: 0.27, 1.03;
Compared with the placebo, vitamin D3 significantly prevented p = 0.063). A reevaluation using logistic regression to cancer-free
deterioration of the HY stage in patients with FokI TT (P = survival at 12 mo showed that the relative risk in the calcium +
0.009) and and FokI CT (P = 0.020) but not FokI CC.109 vitamin D3 group had been significantly reduced by 77% (RR
In addition to chronic brain diseases injuries arising from 0.232, CI: 0.09, 0.60, P < 0.005). The data in the calcium group
brain trauma (TBI) are among the causes of death and severe alone remained virtually unchanged (RR: 0.587, CI: 0.29, 1.21;
disabilities. Finding drugs which are effectively neuroprotective p = 0.147).121 Some studies indicate that the intake of vitamin D
is of special importance for prevention of secondary brain injury in the range of 1100 to 4000 IU/d and a 25(OH)D serum levels
after trauma. Similar to progesterone, 1α,25(OH) 2D is a neuros- between 60 and 80 ng/ml may be needed to reduce the cancer
teroid acting like progesterone in neuroprotective process, e.g., risk.122
1α,25(OH) 2D reduces the pro-inflammatory level of TH1 cyto- In a prospective cohort study, Canadian researchers from the
kines such as IL6, IL12, IL1B, and TNFα.110,111 Recent studies Mount Sinai Hospital in Toronto observed the course of dis-
have shown that vitamin D deficiency may intensify traumatic ease in 512 women with breast cancer for about 12 years from

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Table 1. Prescription and over the counter drugs that can activate the pregnane X receptor (PXR) (selection)
PXR ligands Examples
Androgen receptor antagonists Cyproterone acetate
Antiepileptics Phenytoin, carbamazepine
Antiestrogens Tamoxifen
Antihypertensives Nifedipine, spironolactone
Antimycotics Clotrimazole
Antiretroviral drugs (NNRTI/protease inhibitors) Efavirenz, nevirapine / ritononavir, saquinavir
Antituberculosis drugs Rifampicin
Glucocorticoids Dexamethasone
Phytopharmaceuticals Kava-kava, St. John’s wort (hyperforin)
Cytostatics Cyclophosphamide, paclitaxel

1997 to 2008. The average age of the women was 50.4 years that the pathophysiologic mechanism(s) underpinning osteone-
at diagnosis. 37.5 percent of the breast cancer patients had a crosis of the jaw may involve the interaction between bisphos-
vitamin D deficiency [25(OH)D <20 ng/mL or <50 nmol/L] phonates and compromised vitamin D functions in the realm
when diagnosed. Only 24 percent of the affected women had an of skeletal homeostasis and innate immunity.138 In a recently
almost normal vitamin D status [25(OH)D > 29 ng/mL or 72 published case-control study with 43 patients, 77% of patients
nmol/L]. Vitamin D deficiency was associated with the occur- with BRONJ were osteomalacic compared with 5% of patients
rence of more aggressive forms of breast cancer. After 12 y, the without BRONJ, according to histomorphometry (P < 0.001).
risk of a metastasis in women with a vitamin D deficiency was Osteomalacia represents a new and previously unreported risk
increased by 94 percent compared with those with normal vita- factor for the development of bisphosphonate-related osteone-
min D status (hazard ratio [HR] = 1.94; 95% CI, 1.16 to 3.25). crosis of the jaw (BRONJ).146 In vitamin D deficiency (until it is
The probability of premature death due to the disease rose in the corrected) oral bisphosphonates should not be used.139,140
presence of a vitamin D deficiency by 73 percent (HR = 1.73;
95% CI, 1.05 to 2.86).123
Comment: Vitamin D status should be monitored in all cancer patients
In breast cancer patients under polychemotherapy with and treated by adequate vitamin D supplementation [25(OH)D target
anthracycline and taxane, a significant drop in 25(OH)D lev- value: 40–60 ng/mL or 100–150 nmol/L). This applies in particular to
els was observed.124 Some cytostatics (e.g., cyclophosphamide, cancer patients with poor nutritional status, treatment with aromatase
paclitaxel) are ligands of the pregnane X receptor and can inhibitors, bisphosphonates, and CTX containing anthracycline taxane
therefore increase the enzymatic degradation of 25(OH)D and as well as in cases of muscular or mucocutaneous disorders, fatigue and
tumor cachexia.
1α,25(OH) 2D via the induction of 24-hydroxylase in the course
of chemotherapy.112,132 Docetaxel is a known trigger for cutane-
ous adverse reactions and taste disorders. A vitamin D deficiency
can lead to the occurrence of chemotherapy-induced mucositis Medical Drugs and Vitamin D
and dysgeusia. There have been case reports of mucocutaneous
side effects (e.g., stomatitis) and taste disorders occurring in can- Drug-induced vitamin D imbalances must be reconsidered in
cer patients under polychemotherapy with TCH (T: docetaxel, the light of the high prophylactic potential of the sunshine vita-
C: carboplatin, H: trastuzumab) or FOLFOX6, which could min. It is known that many drugs can interfere with vitamin D
be treated successfully with supplementation of vitamin D3.126 metabolism. Already in 1967 the association between osteomala-
Also, arthralgias and fatigue during treatment with aromatase cia and antiepileptic drug therapy was reported. Since then there
inhibitors such as letrozole were significantly reduced by supple- have been many reports of abnormalities in calcium, vitamin D,
mentation of vitamin D3 (e.g., 50 000 IU vitamin D3 /week for and bone metabolism in subjects chronically treated not only
12 weeks, PO) in breast cancer patients with vitamin D defi- with antiepileptic drugs but also with corticoids, rifampicin, and
ciency.127,128 Similar results are on record for use of bisphospho- antiretroviral drugs.130,131 A drug-induced vitamin D deficiency
nates. The osseous effectiveness of bisphosphonates is improved [25(OH)D <20 ng/mL] may manifest as secondary hyperpara-
by an adequate vitamin D status [25(OH)D ≥33 ng/ml]. This thyroidism, bone mineralization disorders including the develop-
could be related to the fact that a cessation of the parathyroid ment of osteoporosis, and osteomalacia.
hormone increase is not achieved until a 25(OH)D level ≥40 One possible mechanism discussed by various authors that
ng/ml is reached.2,5,129 Necrotic bone exposure in the oral cavity explains the abnormalities in bone metabolism under medica-
has recently been reported in patients treated with nitrogen-con- tion is the activation of pregnane X rececptor (PXR) by some
taining bisphosphonates as part of their therapeutic regimen for drugs (Table 1), that may be responsible for the acceleration
multiple myeloma or metastatic cancers to bone. It is suggested of vitamin D catabolism through the upregulation of CYP3A4

e2-342 Dermato-Endocrinology Volume 5 Issue 3

and CYP24A1, leading to vitamin D deficiency and, eventu- with how much vitamin D they are producing but also tells them
ally, to osteopenia or osteomalacia. Human PXR (hPXR) is when to stop being exposed to sunlight without sun protection
also named steroid and xenobiotic receptor (SXR). CYP24 is a to prevent sunburn.
multifunctional 24-hydroxylase and the major vitamin D cata- Oral vitamin D (vitamin D2 or D3) can be taken on an
bolic enzyme that directs the side-chain oxidation and cleavage empty stomach or with a meal. Both vitamin D2 and vitamin
of 1α,25(OH) 2D and 25(OH)D to catabolic carboxylic acid D3 at physiologic doses are effective in raising the blood level of
end products. This could mean: drugs that can stimulate the 25(OH)D.141 The meal does not need to contain fat in order for
pregnane X receptor can potentially trigger all of the negative the fat-soluble vitamin D to be absorbed. Furthermore vitamin
consequences of a vitamin D deficiency. But the effects of PXR D can be taken daily or the total amount can be taken once a
on bone homeostasis are tissue specific and signal specific, and week or even once a month as long as the total is the same i.e.,
drug-induced osteomalacia may be far more complicated than 3000 IUs daily or 21 000 IUs weekly or 90 000 IUs monthly are
just a phenomenon of enhanced CYP3A4 (or CYP24A1) expres- equally effective in maintaining serum 25(OH)D levels in the
sion and induced 25(OH)D and 1α,25(OH) 2D catabolism. A desired range of 40–60 ng/mL.
drug-induced vitamin D deficiency manifests mainly at the level To guarantee vitamin D sufficiency there are a variety of strat-
of bone and muscle metabolism.132-134 egies to both treat and prevent vitamin D deficiency. One simple
strategy that is effective is to fill the empty vitamin D tank with
Comment: As a general rule, the vitamin D status of all patients under-
50 000 IUs of vitamin D once a week for 8–12 weeks.3,142 This
going long-term medication regimens should be monitored in view of is equivalent to ingesting approximately 6600 IUs daily. To pre-
the fact that not all of the agonists of the pregnane X receptor in phar- vent recurrence of vitamin D deficiency 50 000 IUs of vitamin D
maceutical substances that can degrade vitamin D have been described once every 2 weeks (equivalent to 3300 IUs daily) forever is effec-
to date, often this patients need more vitamin D to achieve an optimum tive in maintaining a healthy vitamin D status without causing
25(OH)D status of 40–60 ng/ml or 100–150 nmol/l!
toxicity.142 Even young children have been effectively treated for
vitamin D deficiency with 50 000 IUs of vitamin D weekly for 6
weeks or 2000 IUs of vitamin D daily.143
Treatment Strategies
Concluding Remarks
Sensible sun exposure is the least expensive and most effi-
cient way of obtaining an adequate amount of vitamin D. It has Closer attention should be paid to vitamin D deficiency in
been estimated that a healthy adult in a bathing suit exposed to medical and pharmaceutical practice than has been the case hith-
one minimal erythemal dose (MED) of sunlight is equivalent erto. The data available to date on vitamin D from experimental,
to ingesting about 20 000 IUs of vitamin D.3,52 Thus the skin ecological, case-control, retrospective and prospective observa-
has a large capacity to produce vitamin D. Because time of day, tional studies, as well as smaller intervention studies, are signifi-
season of the year and latitude along with degree of skin pig- cant and confirm the sunshine vitamin’s essential role in a variety
mentation has a dramatic effect on the cutaneous production of of physiological and preventative functions, including neuropsy-
vitamin D there is no simple recommendation as to how much chiatric disorders. The results of these studies justify the recom-
time to be exposed to obtain an adequate amount of vitamin D. mendation to improve the general vitamin D status in children
However for example if a person knows that they are going to get and adults by means of a healthy approach to sunlight exposure,
a light pinkness to their skin 24 h later, i.e., a MED, by being consumption of foods containing vitamin D and supplementa-
exposed to 30 min of sun in their locale, the recommendation tion with vitamin D preparations. Nevertheless, in a number of
is to expose arms, legs and abdomen and back when possible for fields, we must await the results of controlled and randomized
about 10–15 min followed by good sun protection. One way to interventional studies involving the use of vitamin D in suffi-
determine how much vitamin D a child or adult is producing is ciently high doses, which are still pending and can be expected to
to use a free app dminder.info which not only provides the user be published in the coming years.1,2,135-137

www.landesbioscience.com Dermato-Endocrinology e2-343

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