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Vitamin D in preventive medicine: Are we ignoring the evidence?

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Vitamin D is metabolised by a hepatic 25-hydroxylase into 25-hydroxyvitamin D (25(OH)D) and by a renal 1alpha-hydroxylase into the vitamin D hormone calcitriol. Calcitriol receptors are present in more than thirty different tissues. Apart from the kidney, several tissues also possess the enzyme 1alpha-hydroxylase, which is able to use circulating 25(OH)D as a substrate. Serum levels of 25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis, adequacy, and toxicity. European children and young adults often have circulating 25(OH)D levels in the insufficiency range during wintertime. Elderly subjects have mean 25(OH)D levels in the insufficiency range throughout the year. In institutionalized subjects 25(OH)D levels are often in the deficiency range. There is now general agreement that a low vitamin D status is involved in the pathogenesis of osteoporosis. Moreover, vitamin D insufficiency can lead to a disturbed muscle function. Epidemiological data also indicate a low vitamin D status in tuberculosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, hypertension, and specific types of cancer. Some intervention trials have demonstrated that supplementation with vitamin D or its metabolites is able: (i) to reduce blood pressure in hypertensive patients; (ii) to improve blood glucose levels in diabetics; (iii) to improve symptoms of rheumatoid arthritis and multiple sclerosis. The oral dose necessary to achieve adequate serum 25(OH)D levels is probably much higher than the current recommendations of 5-15 microg/d.
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Review article
Vitamin D in preventive medicine: are we ignoring the evidence?
Armin Zittermann
Department of Nutrition Science, University of Bonn, Endenicher Allee 11-13, 53115 Bonn, Germany
(Received 28 January 2002 Revised 22 November 2002 Accepted 28 December 2002)
Vitamin D is metabolised by a hepatic 25-hydroxylase into 25-hydroxyvitamin D (25(OH)D) and
by a renal 1a-hydroxylase into the vitamin D hormone calcitriol. Calcitriol receptors are present in
more than thirty different tissues. Apart from the kidney, several tissues also possess the enzyme
1a-hydroxylase, which is able to use circulating 25(OH)D as a substrate. Serum levels of
25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis,
adequacy, and toxicity. European children and young adults often have circulating 25(OH)D
levels in the insufficiency range during wintertime. Elderly subjects have mean 25(OH)D levels
in the insufficiency range throughout the year. In institutionalized subjects 25(OH)D levels are
often in the deficiency range. There is now general agreement that a low vitamin D status is
involved in the pathogenesis of osteoporosis. Moreover, vitamin D insufficiency can lead to a dis-
turbed muscle function. Epidemiological data also indicate a low vitamin D status in tuberculosis,
rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, hypertension, and specific
types of cancer. Some intervention trials have demonstrated that supplementation with vitamin D
or its metabolites is able: (i) to reduce blood pressure in hypertensive patients; (ii) to improve
blood glucose levels in diabetics; (iii) to improve symptoms of rheumatoid arthritis and multiple
sclerosis. The oral dose necessary to achieve adequate serum 25(OH)D levels is probably much
higher than the current recommendations of 5 15 mg/d.
Vitamin D insufficiency: Vitamin D intoxication: Parathyroid hormone: Disease
prevention
Rickets, the clinical outcome of a severe vitamin D
deficiency in infants, was endemic in Europe and North
America during the 19th century and during the first two
decades of the 20th century. Based on the observations
that skin exposure to u.v. light as well as oral vitamin D
intake could cure rickets, several very effective prevention
strategies were performed. The so-called ‘stossprophylaxis’
was based on the administration of high amounts of vita-
min D several times during infancy (Markestad et al.
1987). Moreover, young children were regularly exposed
to artificial u.v. light. Present prophylaxes of rickets
include a daily vitamin D supplement of 10 mg in Germany
(Deutsche Gesellschaft fu
¨
r Erna
¨
hrung et al. 2000), the UK
(Department of Health, 1998), the Netherlands (Health
Council of the Netherlands, 2000), Sweden (Axelsson
et al. 1999), and Finland (National Nutrition Council,
1999). In the USA, the adequate intake for infants is
5 mg/d (Standing Committee on the Scientific Evaluation
of Dietary Reference Intakes, Food and Nutrition Board
and Institute of Medicine, 1997). Nowadays, rickets is
rare in Europe and North America, but there is still a
risk, especially if parents are not aware of preventive
measures or neglect them (Hellebostad et al. 1985;
Hartman, 2000).
There is now growing evidence that the adult European
population is also at risk for an inadequate vitamin D status
(see p. 554555). The present review summarizes the evi-
dence of an involvement of a low vitamin D status in the
pathogenesis of several chronic diseases. Moreover, the
amount of oral vitamin D intake to maintain an adequate
vitamin D status is discussed.
Vitamin D metabolism and actions
Vitamin D can be ingested orally or can be formed
endogenously by the skin after exposure to u.v. B light
Corresponding author: Associate professor Armin Zittermann, fax +49 228 733217, email a.zittermann@uni-bonn.de
Abbreviations: IL, interleukin; MS, multiple sclerosis; 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone; Th, T-helper; TNF-a, tumour-necrosis
factor a; VDR, vitamin D receptor.
British Journal of Nutrition (2003), 89, 552–572 DOI: 10.1079/BJN2003837
q The Author 2003
(wavelength 290315 nm). In the skin, a plateau of daily
vitamin D production is reached after only 30 min of u.v.
B irradiation (Holick, 1994). Increased melanin pigmenta-
tion reduces the efficiency of u.v. B-mediated vitamin D
synthesis and necessitates increases in the exposure time
required to maximize vitamin D formation, but does not
influence the total content of daily vitamin D production.
Orally ingested and endogenously formed vitamin D is
transported to the liver and is there converted to 25-hydro-
xyvitamin D (25(OH)D) (Fig. 1). A strong regulation of
this step does not exist and there is no significant storage
of 25(OH)D in the liver of mammals. 25(OH)D is rapidly
released by the liver into the blood, where it circulates
with a biological half-life of approximately 12 19 d. In
the kidney, 25(OH)D is enzymically converted to the vita-
min D hormone 1,25-dihydroxyvitamin D (calcitriol).
Renal synthesis of calcitriol is homeostatically controlled
by parathyroid hormone (PTH). Synthesis of PTH is regu-
lated by serum concentrations of Ca and P. 25(OH)D can
also be converted by a renal 24-hydroxylase into 24,25-
dihydroxyvitamin D. Circulating 24,25-dihydroxyvitamin
D levels are very strongly correlated with circulating
25(OH)D levels. Circulating 25(OH)D levels are, how-
ever, approximately ten times higher than serum 24,25-
dihydroxyvitamin D levels and are approximately 500
1000 times higher than serum calcitriol levels. Metabolism
of ergocalciferol (vitamin D
2
) and cholecalciferol (vitamin
D
3
) is similar. Oral vitamin D
3
intake results, however, in
a 70 % higher serum 25(OH)D level in comparison with
the same amount of vitamin D
2
(Trang et al. 1998).
Vitamin D metabolites are known as regulators of sys-
temic Ca homeostasis with actions in the intestine, the kid-
neys, and bone. Calcitriol is on a molar basis the most
potent vitamin D metabolite. Calcitriol increases both
intestinal absorption of orally ingested Ca and tubular reab-
sorption of Ca by an active, receptor-mediated process in
order to maintain physiological serum Ca levels.
Calcitriol plays not only a pivotal role in systemic Ca
homeostasis but also in the intracellular Ca homeostasis
of various tissues. Now it is clear that vitamin D receptors
(VDR) exist in more than thirty different tissues (Table 1).
Calcitriol functions as a steroid hormone that binds to a
cytosolic VDR resulting in a selective demasking of the
genome of the nucleolus. Polymorphisms of the VDR
have been described for the endonuclease BmsI, Apa I,
Taq I, and Fok I restriction sites.
The number of genes known to be regulated by calcitriol
is still growing. Apart from a large number of Ca- and
bone-related genes, numerous genes involved in the regu-
lation of the cell cycle or humoral mechanisms
(for example, cytokines involved in the immune or haema-
topoietic system) are also calcitriol-dependent. Calcitriol
can be locally produced in several tissues that possess
VDR and are responsive to this hormone. Consequently,
for calcitriol a paracrine role apart from its Ca-regulating
function has been proposed (Bouillon et al. 1998).
Fig. 1. The major metabolic pathways of vitamin D. Human sources
of vitamin D are skin production of vitamin D
3
by u.v. light and oral
intake of vitamin D
2
and/or vitamin D
3
. Vitamin D is hydroxylated in
the liver into 25-hydroxyvitamin D and in the kidney into the vitamin
D hormone calcitriol. Renal calcitriol synthesis includes activation of
1a-hydroxylase by parathyroid hormone and suppression of the
1a-hydroxylase by high serum levels of ionized Ca. PTH; parathyr-
oid hormone; 24,25(OH)
2
D, 24,25-dihydroxyvitamin D.
Table 1. Cells with evidence for cytosolic or nuclear
and/or membrane-bound vitamin D receptors (from
Nemere & Farach-Carson, 1998; Norman, 1998,
DeLuca & Cantorna, 2001)
Cell type
Intestinal cells
Muscle cells
Osteoblasts
Distal renal cells
Parathyroid cells
Islet cells, pancreas
Epidermal cells
Circulating monocytes
Transformed B-cells
Activated T-cells
Neurons
Placenta
Skin fibroblasts
Chondrocytes
Colon enterocytes
Liver cells
Prostate cells
Ovarian cells
Keratinocytes of skin
Endocrine cells, stomach
Aortic endothelial cells
Pituitary cells
Vitamin D in preventive medicine 553
The de novo mRNA and protein synthesis induced by the
cytosolic calcitriolVDR complex require periods lasting
hours to days. However, rapid calcitriol actions have also
been observed in several tissues at both the cellular and
subcellular level (Norman, 1998). These calcitriol actions
cannot be explained by receptor hormone interactions
with the genome. Meanwhile, a membrane-bound VDR
has been recognized in different cell lines leading to an
activation of specific intracellular metabolic pathways
within a few minutes. Given the pivotal role of ionized
Ca in muscle contraction, nerve-impulse conduction, and
other physiological phenomena, such a rapid response
could be life-saving for the organism (Nemere & Farach-
Carson, 1998).
There are some studies available indicating that
25(OH)D itself has important physiological functions.
Doseresponse studies indicate a molar potency of calci-
triol relative to 25(OH)D ranging from 125:1 to 400:1 in
increasing Ca absorption from the gut (Barger-Lux et al.
1995). Based on these molar potencies of calcitriol and
25(OH)D and the serum concentrations of the two vitamin
D metabolites (approximately 1:500 to 1:1000) it can be
assumed that 55 to 90 % of the circulating vitamin D
activity is contributed by 25(OH)D (Barger-Lux et al.
1995). In line with this assumption, cross-sectional studies
have demonstrated that serum 25(OH)D levels are a better
indicator for intestinal Ca absorption efficiency than serum
calcitriol levels (Barger-Lux et al. 1995; Zittermann et al.
1998). Consequently, very low 25(OH)D levels as found in
rickets and osteomalacia result in an impaired intestinal Ca
absorption leading to a severe Ca deficit in the human
body. Moreover, 25(OH)D increases: (i) the uptake of
45
Ca into cultured muscle cells (Selles et al. 1994); (ii)
the intracellular Ca re-uptake into the sarcoplasmic reticu-
lum (Poiton et al. 1979); (iii) the intracellular accumulation
of phosphate (Birge & Haddad, 1975). Circulating
25(OH)D also serves as a substrate for the 1a-hydroxylase
of various tissues that possess VDR. The tissues in the
body that are not responsible for regulating extracellular
Ca metabolism probably use circulating 25(OH)D to
make calcitriol (Holick, 2002). Low serum 25(OH)D
levels may thus impair intracellular calcitriol availability.
Several tissues also possess 24-hydroxylase activity result-
ing in a local production of 24,25-dihydroxyvitamin D
from 25(OH)D. It has been hypothesized that 24,25-dihy-
droxyvitamin D is indispensable for normal Ca and
P homeostasis. Consequently, a cellular receptor for
24,25-dihydroxyvitamin D has been postulated by some
investigators (Norman, 1998).
Assessment of vitamin D status
Circulating 25(OH)D levels closely reflect the amount of
sunlight to which the epidermis is exposed and the dietary
intake of vitamin D. There is general agreement that the
serum 25(OH)D level is the best indicator to define vitamin
D deficiency, insufficiency, hypovitaminosis, sufficiency,
and toxicity (Standing Committee on the Scientific Evalu-
ation of Dietary Reference Intakes, Food and Nutrition
Board and Institute of Medicine, 1997; McKenna & Frea-
ney, 1998) (Fig. 2). Nevertheless, it is difficult to clearly
define cut-off values for each stage. There is no doubt
that 25(OH)D levels below 12·5 nmol/l can result in bone
diseases such as rickets in infants and osteomalacia in
adults (Scharla, 1998). There is, however, also evidence
that 25(OH)D levels below 25 nmol/l lead to rickets and
osteomalacia in the long run (Basha et al. 2000). Concen-
trations of 25(OH)D below 4050 nmol/l reflect vitamin D
insufficiency (Malabanan et al. 1998, Need et al. 2000;
Vieth et al. 2001b). Values below this threshold can lead
to functional alterations such as hyperparathyroidism.
In subjects with 25(OH)D levels below 50 nmol/l high
Fig. 2. Stages of vitamin D status. In the vitamin D deficiency range, there is severe hyperparathyroidism, Ca malabsorption, bone diseases
such as rickets in infants and osteomalacia in adults, and myopathy. Vitamin D insufficiency results in mild hyperparathyroidism, low intestinal
Ca absorption rates, reduced bone mineral density, and perhaps subclinical myopathy. In hypovitaminosis D, body stores of vitamin D are low
and parathyroid hormone levels can be slightly elevated. In the range of vitamin D sufficiency no disturbances of vitamin D-dependent func-
tions occur. In the vitamin D toxicity range, there is intestinal Ca hyperabsorption and increased net bone resorption leading to hypercalcae-
mia. 25(OH)D, 25-hydroxyvitamin D.
A. Zittermann554
doses of oral vitamin D can decrease the elevated PTH
levels (Malabanan et al. 1998). It must also be emphasized
that oral Ca intake can suppress PTH levels (Ka
¨
rkkainen
et al. 1997) and oral phosphate intake can increase PTH
levels (Whybro et al. 1998). These nutrients may therefore
influence the vitamin D PTH axis.
Serum calcitriol levels can be affected differently during
vitamin D insufficiency or deficiency. Circulating concen-
trations are often similar to those of vitamin D-replete sub-
jects (Eastwood et al. 1979). The accompanying secondary
hyperparathyroidism can, however, also result in an
increase in serum calcitriol levels (Adams et al. 1982;
Bell et al. 1985). Moreover, even low calcitriol levels
can be observed (Bouillon et al. 1987; Docio et al.
1998), most probably because of an insufficient substrate
availability for the renal 1a-hydroxylase. Consequently,
determination of serum calcitriol levels is not a valid
measure in order to assess vitamin D status.
Serum 25(OH)D concentrations between 50 nmol/l and
80100 nmol/l can be regarded as hypovitaminosis D,
where body stores are already depleted and PTH levels
can be slightly elevated, but are still in the normal range
(McKenna & Freaney, 1998; Lamberg-Allardt et al. 2001).
Circulating 25(OH)D levels between 100 and 200 nmol/l
can be regarded as adequate concentrations, where no dis-
turbances in vitamin D-dependent body functions occur
(Peacock, 1995). A rationale for this assumption is the
observation that subjects with a constantly high u.v. B
exposure living close to the equator have mean 25(OH)D
levels of 107 nmol/l and upper serum levels (+2
SD)of
163 nmol/l throughout the year (Linhares et al. 1984).
Moreover, American bath attendants have serum
25(OH)D levels up to 160 nmol/l (Holmes & Kummerow,
1983).
Vitamin D status in different European population
groups
In general, healthy young adults have marked seasonal
fluctuations in serum 25(OH)D levels with lower concen-
trations in winter than in summer (Table 2). Even children
and adolescents, two groups with various outdoor activities
and frequent exposure to sunlight, have low 25(OH)D
levels in winter (Table 2). The main reason for the low
25(OH)D levels in winter is the fact that vitamin D
status is largely dependent on skin synthesis and that u.v.
B radiation of the sunlight is negligible from October
to April at the latitude of 528N and from November to
February at the latitude of 428N. In contrast, skin synthesis
of vitamin D is possible throughout the year at the latitude
of 328N or closer to the equator (Holick, 1994). Even
premenopausal women living in a sunny country such as
Turkey have very low 25(OH)D levels in summer if suffi-
cient u.v. B irradiation of the skin is not guaranteed
Table 2. Vitamin D status in different European population groups during summer and winter
Mean circulating 25(OH)D
level (nmol/l)
Age group and country Latitude (8North) Summer Winter Reference
Children
Germany 51 84 43 Zittermann (1987)
UK: white children 5060 80 52 Davies et al. (1999)
UK: dark-skinned children 5060 3642* Lawson et al. (1999)
Spain 43·5 75 32 Docio et al. (1998)
Brazil 8 (South) 106 108 Linhares et al. (1984)
Adolescents
Finland 60 63 34 Lehotonen et al. (1999)
France 49 71 21 Guillemant et al. (2001)
Young adults
Norway 70 81 53 Vik et al. (1980)
Finland 60 46 Lamberg-Allardt et al. (2001)
Germany 51 70 30 Zittermann et al. (1998)
Central and Western Europe 4555 68 42 McKenna (1992)k
Turkey (women) 39 Alagol et al. (2000)
Group 1 56†
Group 2 32‡
Group 3
Elderly subjects
Norway 61 47 van der Wielen et al. (1995)
UK 5060 35 23 Hegarty et al. (1994)
Italy 42 28 van der Wielen et al. (1995)
Greece 3538 24 van der Wielen et al. (1995)
Institutionalized subjects
Switzerland 47·5 18 Bischoff et al. (1999a)
France 50 8* Fardellone et al. (1995)
25(OH) D, 25-hydroxyvitamin D.
* Not differentiated by season.
Dressed in a style which exposed the usual areas of the skin to sunlight.
Traditional clothing with the skin of the hands and face uncovered.
§ Traditional Islamic style covering the whole body including hands and face.
k Mean level of different studies.
Vitamin D in preventive medicine 555
(Table 2). Moreover, dark-skinned Asian children living in
England have low circulating 25(OH)D levels (Table 2)
supporting the assumption that skin synthesis of vitamin
D is critical for vitamin D status.
Generally, vitamin D status is more troublesome in
elderly subjects in comparison with young adults
(Table 2). Reasons for the low vitamin D status of elderly
subjects are their often modest outdoor activities and the
marked decrease in the capacity of human skin to produce
vitamin D in elderly subjects in comparison with younger
adults (Holick et al. 1989). The vitamin D status of elderly
Norwegians is, however, more favourable in comparison
with elderly subjects from other parts of Europe
(Table 2), probably due to a higher oral vitamin D intake
(see p. 564). The prevalence of serum 25(OH)D levels
below 25 nmol/l is only 18 % in Norway and up to 83 %
in Greece (van der Wielen et al. 1995). Nevertheless, Nor-
wegians have mean 25(OH)D levels clearly below
100 nmol/l in winter and in summer. A very low vitamin
D status is frequently observed in institutionalized elderly
subjects (Table 2).
Associations of low vitamin D status with chronic
diseases
The following sections describe associations between low
vitamin D status and various chronic diseases. At first,
pathogenesis of the diseases is briefly explained. Then,
epidemiological evidence for the vitamin D hypothesis is
presented and available clinical intervention trials are
critically reviewed.
Osteopathy
Severe vitamin D deficiency results in an under-mineraliz-
ation of the growing skeleton and in demineralization of
the adult skeleton leading to rickets and osteomalacia,
respectively. This is due to the marked suppression in
intestinal Ca absorption and the impairment of Ca bal-
ance. There is now general agreement that an insufficient
vitamin D status contributes to osteoporosis of the elderly.
Low 25(OH)D levels are associated with low Ca absorp-
tion rates, hyperparathyroidism and increased bone turn-
over leading to bone loss (Ooms et al. 1995; Peacock,
1995). In elderly subjects, low circulating 25(OH)D
levels are associated with a reduced bone mineral density
at the proximal femur (Ooms et al. 1995; Scharla et al.
1996). It should also be mentioned that low bone mineral
density due to an insufficient vitamin D status can reflect
some stage of osteomalacia. The densitometric measure-
ments only measure bone mineral content and density,
which are low in osteomalacia and osteoporosis.
Even the transient decrease in vitamin D status during
the lack of u.v. B irradiation in wintertime can lead to a
transient loss of spinal bone mineral density in female sub-
jects (Dawson-Hughes et al. 1991). Recent studies have
also demonstrated that even in female adolescents insuffi-
cient 25(OH)D levels are associated with low forearm
bone mineral density (Outila et al. 2001).
Several risk factors for hip fractures are at least in part
related to a low vitamin D status. Incidence of hip fractures
rises ten-fold in white women between the age of 75 and
95. The highest hip fracture rates are found in Northern
Europe. Moreover, there is seasonality in the rates of hip
fractures in the white US population with high rates in
winter and low rates in summer in both sexes
(Peacock, 1995). Patients with hip fractures more often
have serum 25(OH)D levels below 50 nmol/l than
control subjects of this age group (Diamond et al. 1998;
LeBoff et al. 1999).
The results of controlled clinical trials with vitamin D
administration on bone mineral density are inconsistent
(Table 3). An increase in bone mineral density was
observed in studies with vitamin D supplementation of
10·0, 17·5, and 375 mg/week. In studies with 20 mg vitamin
D/d and 15 mg 25(OH)D/d no improvements were
observed. In two out of these latter three studies mean diet-
ary Ca intake was relatively low (530 and 570740 mg/d)
(Hunter et al. 2000; Peacock et al. 2000). It may well be
that the amount of absorbed Ca was still too low to
improve bone mineral density. Bone mineral loss at the
femoral neck, spine, and total body could be prevented
with a combined daily supplement of 17·5 mg vitamin D
and 500 mg Ca (Dawson-Hughes et al. 1997). Moreover,
a long-term randomized large controlled trial has shown
that combined supplements of vitamin D (20 mg/d) and
Ca (1 200 mg/d) were capable of preventing non-vertebral
fractures in healthy ambulatory subjects (Chapuy et al.
1992). The bone density of the proximal femur increased
2·7 % in the vitamin D
3
Ca group and decreased 4·6 %
in the placebo group. It seems probable that the anti-frac-
ture effect of Ca and vitamin D supplementation is not
only due to their effect on bone mineral density. An
increase in 25(OH)D levels may improve neuromuscular
coordination, as measured by body sway, and may thus
decrease the risk of falling and falling-related fractures
(see also p. 555).
Myopathy
It has been assumed already at the beginning of the 20th
century that severe vitamin D deficiency results in a dis-
turbed muscle metabolism (Ritz et al. 1980). Animal
studies have demonstrated that the aktinomyosin content
of myofibrills is reduced during experimental rickets
(Stroder & Arensmeyer, 1965). Moreover, vitamin D
deficiency can impair intracellular Ca metabolism in
muscle cells. The Ca content of mitochondria isolated
from vitamin D-depleted chicks is low (Pleasure et al.
1979) and Ca uptake into the sarcoplasmic reticulum is
reduced during vitamin D deficiency (Curry et al. 1983).
Patients with osteomalacia suffer from muscle weakness
and have low serum levels of muscle enzymes (Ritz et al.
1980; Rimaniol et al. 1994). Supplementation with 357 or
1250 mg vitamin D/d or 50 mg 25(OH)D/d for 1 to 2
months was able to normalize muscle strength in patients
with myopathy (Rimaniol et al. 1994; Ziambaras &
Dagogo-Jack, 1997). Sub-clinical myopathy may even
occur at serum 25(OH)D levels of 10 50 nmol/l (Peacock,
1995). In line with this assumption, leg extension power
was positively correlated with serum 25(OH)D levels in
elderly males and with serum calcitriol levels in the
A. Zittermann556
Table 3. Intervention trials with vitamin D or 25-hydroxyvitamin D (25(OH)D) on bone mineral density (BMD) and fracture risk in post-menopausal women and elderly men
Duration
of
treatment
(years)
Initial serum levels
Change in serum
levels
Reference
Study
design n
Age
(years)
25(OH)D
(nmol/l)
Calcitriol
(pmol/l) Treatment
25(OH)D
(nmol/l)
Calcitriol
(pmol/l) Results
Nordin et al.
(1985)
PC 137 F 2 6574 62 n.d. 375 mg Vitamin D
2
/week +68 n.d. Metacarpal cortical bone loss #
Dawson-Hughes
et al. (1991)
DBPC 249 F 1 Mean
62
97* 74* 10 mg Vitamin D/d† 2 5‡ 0‡ 1 % Less bone loss during
wintertime v. placebo
Ooms et al.
(1995)
DBPC 48 F 2 Mean
80
27 111 10 mg Vitamin D/d +35 +4 Change in BMD at femoral
neck: +1·9 to +2·6 % v. placebo
Dawson-Hughes
et al. (1995)
DBPC 261 F 2 Mean
63
n.d. n.d. 2·5 and 17·5 mg Vitamin D/d n.d. n.d. Change in BMD at femoral
neck: +1·5 % with 17·5 mg
vitamin D v. 2·5 mg vitamin D
Hunter et al.
(2000)
DBPC 158 F 2 4770 71 n.d. 20 mg Vitamin D/d +37 n.d. No effects on BMD v. controls
Patel et al.
(2001)
DBPC 70 F 2 2470 68 n.d. 20 mg Vitamin D/d +25 n.d. No effects on BMD v. controls
Peacock et al.
(2000)
DBPC 438 F
and M
4 75 60·5 103 15 mg 25(OH)D/d +58 2 15 to 2 25 No effects on BMD v. controls
Graafmans et al.
(1996)
PC 81 F 2 81 27 115 10 mg Vitamin D/d +30 +1 Change in BMD +4·4 % and +4·2 %
in the BB and Bb genotype v.
placebo
DBPC, double-blind, placebo-controlled; PC, plaebo-controlled; F, female, M, male; n.d., no data available; # , down.
* Summer values.
Placebo and serum group were given 377 mg Ca/d.
Winter values of the supplemented group v. summer values.
Vitamin D in preventive medicine 557
whole group of males and females. The males had mean
25(OH)D levels of 90 (
SD 87·5) nmol/l and the females
had mean 25(OH)D levels of 68 (
SD 53) nmol/l (Bischoff
et al. 1999b) indicating that a large number of subjects
had an insufficient vitamin D status. A recent study has
brought forward evidence that a low vitamin D status
also contributes to the pathogenesis of congestive heart
failure, a disease resulting in cardiac muscle weakness
due to impaired myocardial contractility. Circulating
levels of NT-proANP, a biochemical indicator of conges-
tive heart failure severity, were inversely correlated with
serum 25(OH)D levels (r
2
0·16, P, 0·001; Zittermann
et al. 2003).
Supplemental studies have demonstrated that doses of
5 mg calitriol/d or 10 mg vitamin D/d had no effects on
parameters of muscle function (Table 4). A daily sup-
plement of very high doses of vitamin D and also doses
of 20 mg vitamin D/d could, however, significantly
improve muscle function in subjects with low initial
25(OH)D levels (Table 4). It should also be mentioned
that in both intervention trials the 20 mg vitamin D/d was
combined with a daily supplement of 1 200 mg Ca. Prob-
ably, the combined effect of 20 mg vitamin D with high
doses of oral Ca was responsible for the beneficial effects
in these studies.
Infections
There is mounting evidence for a pivotal role of vitamin D
in the immune system. Monocytes, the leucocytes with the
highest phagocytosis capacity, continuously exprime the
vitamin D receptor (Bhalla et al. 1983). Calcitriol is able
to induce the differentiation of monocytes into macro-
phages (Provvedini et al. 1986). Macrophages represent
the first unspecific defence line of the immune system.
Calcitriol increases the activity of lysosomal enzymes in
macrophages and facilitate cytotoxic activity by enhancing
the rate of phagocytosis. This latter effect is mediated by
an enhanced expression of specific Fc-surface receptors
(Boltz-Nitulescu et al. 1995) and by an increased respirat-
ory burst (Cohen et al. 1986). Macrophages possess the
enzyme 1a-hydroxylase and are, thus, able to produce cal-
citriol from 25(OH)D (Rigby, 1988). Activity of this
enzyme is enhanced in activated macrophages leading to
a marked increase of the local calcitriol concentration
(Pryke et al. 1990).
Data relating infectious diseases to vitamin D status are
scanty. However, there is some evidence from epidemiolo-
gical data for a link between low vitamin D status and an
increased risk for infections. The prevalence of acute res-
piratory infections was 81 % in Egyptian infants with nutri-
tional rickets in comparison with 58 % in the control group
(Lawson et al. 1987). In 500 Ethiopian children with pneu-
monia the incidence of rickets was thirteen times higher
compared with 500 healthy children indicating that
severe vitamin D deficiency was frequent in the patients
with pneumonia (Muhe et al. 1997). Moreover, Rehman
(1994) has published in a letter the results of a supplemen-
tation study with 150 mg vitamin D/week and 650 mg Ca/d
in children who had previously repeatedly suffered from
respiratory diseases. Treatment was performed for 6 weeks
and resulted in the absence of infectious disease for the fol-
lowing 6 months. Therapy also normalized the enhanced
alkaline phosphatase and increased Ca serum levels, indi-
cating that a sub-clinical vitamin D deficiency was respon-
sible for the frequent infections.
Vitamin D status also seems to be involved in the risk of
tuberculosis (Chan, 2000). Mycobacterium tuberculosis is
an intracellular pathogen that resides predominantly
within the macrophage. Reduced monocyte-macrophage
function plays an important role in the pathogenesis of
tuberculosis (Davies, 1985). Cross-sectional studies have
indicated that patients with tuberculosis have lower
25(OH)D levels in comparison with control subjects
(Davies et al. 1985, 1988; Chan et al. 1994). Serum
25(OH)D levels of the tuberculosis patients and the con-
trols were 16 and 27 nmol/l, 46 and 69 nmol/l, and 52
and 95 nmol/l, respectively. Moreover, the prevalence of
tuberculosis is enhanced in nursing-home residents (Woo
et al. 1996). In the UK the incidence is high in Asian immi-
grants and especially in those immigrants living in the UK
for only a short time. Obviously, Asians are infected in
their country of origin, where the infection does not lead
to overt disease due to plentiful sunlight and sufficient
skin vitamin D synthesis. Migration towards a more north-
ern latitude then results in an impaired vitamin D status.
The outbreaks of tuberculosis usually occur within the
first 5 years after arrival. The requirement of an infection
with M. tuberculosis can also explain the low incidence
of tuberculosis among Asians born in the UK (Chan,
2000). It has recently been demonstrated that the VDR gen-
otype at the Taq1 restriction site influences susceptibility to
tuberculosis indicating a role of vitamin D in the pathogen-
esis of the disease (Wilkinson et al. 2000).
Inflammatory and autoimmune diseases
Experimental studies have demonstrated that calcitriol has
a modulating effect on the specific immune system.
Briefly, macrophage-derived cytokines induce resting
T-helper (Th) cells to differentiate into Th0 cells. Under
the influence of additional factors such as exogenous cyto-
kines and co-stimulatory molecules expressed by antigen-
presenting cells, these Th0 cells further differentiate into
Th1 or into Th2 cells. Both T-cell subsets secrete a specific
cytokine profile. These cytokines are involved in the pro-
liferation and differentiation of T- and B-cells (Lemire
et al. 1985; Provvedini et al. 1989; Mu
¨
ller et al. 1991b).
Calcitriol can inhibit the synthesis of mRNA of the macro-
phages-derived cytokines interleukin (IL)-1, IL-6, IL-12
and tumour-necrosis factor a (TNF-a) (Mu
¨
ller et al.
1991a; D’Ambrosio et al. 1998). Moreover, calcitriol can
decrease the antigen-presenting activity of macrophages
to lymphocytes by a reduction of the expression of
MHC-II molecules on the cell surface (Rigby et al.
1990). Calcitriol can also suppress the IL-2 secretion of
Th1 cells (Lemire et al. 1995).
Rheumatoid arthritis. Rheumatoid arthritis is charac-
terized by the infiltration of T lymphocytes, macrophages
and plasma cells into the synovium, and the initiation of
a chronic inflammatory state that involves overproduction
of pro-inflammatory cytokines such as TNF-a and
A. Zittermann558
IL-6 and a dysregulated Th1-type response. Rheumatoid
arthritis patients have elevated levels of C-reactive protein,
a biochemical indicator of inflammation. Epidemiological
data indicate that more than 60 % of rheumatic patients
have 25(OH)D levels below 50 nmol/l (Aguado et al.
2000) and that 16 % have levels in the range of vitamin
D deficiency (, 12·5 nmol/l; Kro
¨
ger et al. 1993). In the
general population, the risk for progression of osteoarthritis
is already enhanced at a serum 25(OH)D level below
85 nmol/l and a vitamin D intake below 9·7 mg/d (McAlin-
don et al. 1996). Serum calcitriol levels are reduced in
patients with a high disease activity compared with a low
actual disease activity (Oelzner et al. 1998). Calcitriol is
able to markedly suppress disease activity in an animal
model of rheumatoid arthritis (DeLuca & Cantorna,
2001). Intervention trials with 1 mg1a-vitamin D/d
could, however, not demonstrate a significant effect on dis-
ease outcome in rheumatoid arthritis patients. In contrast,
administration of 2 mg1a-vitamin D/d and also the treat-
ment with relatively high doses of vitamin D and
25(OH)D were able to significant improve pain symptoma-
tology (Table 5).
While treatment with 1 mg1a-vitamin D/d resulted only
in a non-significant decrease in C-reactive protein, IL-6,
and TNF-a levels (Hein & Oelzner, 2000), administration
of 2 mg1a-vitamin D/d was able to significantly reduce
serum C-reactive protein levels (Andjelkovic et al. 1999).
Unfortunately, C-reactive protein and cytokines were not
measured in the earlier studies performed with 25(OH)D
and vitamin D.
Inflammatory bowel diseases. Serum concentrations of
25(OH)D levels are low in patients with inflammatory
bowel diseases such as ulcerative colitis and Crohn’s dis-
ease (Jahnsen et al. 2002). Even newly diagnosed patients
have lower 25(OH)D in comparison with controls (Lamb
et al. 2002). Moreover, geographic variations of inflamma-
tory bowel disease within the USA suggest that the amount
of vitamin D available may be an important factor influen-
cing disease development (Podolsky, 1991; Sonnenberg
et al. 1991). The vitamin D hypothesis has been tested in
an experimental model of IL-10 knockout mice (Cantorna
et al. 2000). These animals spontaneously develop symp-
toms similar to those of human inflammatory bowel disease.
The IL-10 knockout mice rapidly developed diarrhoea and
cachexia and had a high mortality rate when they were
made vitamin D-deficient. In contrast, vitamin D-sufficient
IL-10 knockout mice did not develop diarrhoea, waste or
die. Moreover, supplementation with vitamin D or calcitriol
significantly ameliorated symptoms (Cantorna et al. 2000).
Multiple sclerosis. Multiple sclerosis (MS) is a
demyellinating disease of the central nervous system that
is debilitating and can be fatal (Hayes et al. 1997). Mani-
festation of the disease is typically between the years of 20
and 40. It appears that the pathological demyellinating of
the central nervous system is caused by T-cell-mediated
autoimmune processes. These alterations are obviously
promoted by a genetic component and by virus infections
and traumas. The prevalence of MS is nearly zero close to
the equator and is markedly increased in regions of more
northern latitudes (Dichgans & Diener, 1987). Moreover,
there is a North to South gradient of the MS prevalence
in the USA (Schwartz, 1992). Exceptions from this general
North to South gradient in the MS prevalence of the
Northern hemisphere are some Swiss districts at high alti-
tude (. 2000 m), Greenland and the costal regions of
Norway. In these regions a low MS prevalence was
reported (Dichgans & Diener, 1987; Hayes et al. 1997).
Results are consistent with the hypothesis that an
inadequate vitamin D status is an important pathogenetic
factor in MS. Annual u.v. B irradiation is more intensive
in Swiss districts of high altitude than in regions of low
altitudes. In Greenland and at the costal regions of
Norway there is a traditionally high consumption of vita-
min D-rich fatty fish (Hayes et al. 1997). A study set up
to investigate bone health in MS patients revealed a preva-
lence of insufficient serum 25(OH)D levels (, 50 nmol/l)
in 77 % of the patients (Nieves et al. 1994). Experimental
studies have shown that diets high in Ca and calcitriol can
completely suppress the induction of autoimmune ence-
phalomyelitis, which is a model of MS (Cantorna et al.
1996). Moreover, calcitriol can prevent the progression
of autoimmune encephalomyelitis when Ca is high, but
not when Ca is low in the diet (Cantorna et al. 1999).
An intervention study in MS patients has demonstrated
that daily supplementation with 16 mg Ca/kg body
weight, 10 mg Mg/kg body weight and 125 mg vitamin
D/d for 1 2 years was able to decrease the relapse rate
of MS patients compared with the expected exacerbations
(Goldberg et al. 1986). Several mechanisms have been
held responsible for the beneficial effects of vitamin D
in MS including an inhibition of inflammatory T-helper
cells, an inhibition of the production of inflammatory cyto-
kines by activated macrophages, an enhanced production
of anti-inflammatory cytokines, and an anti-proliferative
action in lymphocytes by the expression of VDR (Hayes
et al. 1997). In line with these assumptions it has recently
been demonstrated that vitamin D supplementation is able
to reduce IL-2 mRNA in peripheral blood mononuclear
cells of MS patients (Cantorna et al. 2001).
Hypertension, cardiovascular diseases and diabetes
mellitus
Hypertension. Essential hypertension is related to several
disturbances in systemic and cellular Ca metabolism.
Extracellular ionized or ultrafiltrable Ca levels are
decreased while intracellular cytosolic Ca concentrations
are increased (McCarron et al. 1987). Dietary Ca intake
is often lower (McCarron et al. 1987) and renal Ca loss
is higher in hypertensive than in normotensive subjects
(Strazzullo, 1991; MacGregor & Cappuccio, 1993) indicat-
ing a renal Ca leak. Epidemiological studies have demon-
strated a weak inverse association between serum
25(OH)D levels and diastolic blood pressure in population
groups with mean 25(OH)D levels of 30 50 nmol/l
(Scragg et al. 1992). Moreover, Afro-Americans have a
significantly higher prevalence of diastolic hypertension
(Dustan, 1990) and have lower 25(OH)D levels (Harris &
Dawson-Hughes, 1998) compared with white Americans.
In clinical trials, daily administration of 5 mg vitamin D
showed no effects on blood pressure in normotensive
subjects (Table 6). Some but not all studies have, however,
Vitamin D in preventive medicine 559
Table 4. Intervention studies with vitamin D or calcitriol on parameters of muscle function such as muscle strength, body sway, and/or falls
Initial serum levels
Change in serum
levels
Reference
Study
design
Duration of treat-
ment (months) n
Mean age
(years)
25(OH)D
(nmol/l)
Calcitriol
(pmol/l) Treatment
25(OH)D
(nmol/l)
Calcitriol
(pmol/l) Results
Grady et al. (1991) PC 6 98 69 60 86 0·5 mg Calcitriol/d n.d. +0 No improvement
Graafmans et al. (1996) PC 7 354 . 70 n.d. n.d. 10 mg Vitamin D/d n.d. n.d. No improvement
Glerup et al. (2000) PC 6 55 32 6·7 108 2800 mg Vitamin D/month +28 +15 Improved maximal voluntary
knee extension
Pfeifer et al. (2000) DBPC 2 148 74 26 91 20 mg Vitamin D/d* +40 +36 Decrease in body sway
and number of falls
Bischoff et al. (2001) DBPC 6 122 84 12 n.d. 20 mg Vitamin D/d n.d. n.d. Improved functional
measures and decrease
in number of falls
PC, Placebo-controlled; DBPC, double-blind, placebo-controlled; 25(OH)D, 25-hydroxyvitamin D; n.d., no data available.
* An additional Ca supplement of 1 200 mg/d was given to the placebo and the verum group.
Table 5. Intervention trials with vitamin D and its metabolites on disease activity in patients with rheumatoid arthritis
Reference Study design
Duration of
treatment n
Age
(years)
Initial serum levels
Change in serum
levels
25(OH) D
(nmol/l)
Calcitriol
(pmol/l) Treatment
25(OH)D
(nmol/l)
Calcitriol
(pmol/l) Results
Hein & Oelzner (2000) Open trial 8 weeks 20 2678 n.d. 95 1 mg1a-Vitamin D/d n.d. +5 No effects
Yamauchi et al. (1989) DBPC 16 weeks 140 n.d. n.d. 1 or 2 mg1a-Vitamin D/d n.d. n.d. No effects
Andjelkovic et al. (1999) Open trial 3 months 19 2371 n.d. n.d. 2 mg1a-Vitamin D/d n.d. n.d. Decreased disease activity
Brohult & Jonson (1973) DBPC 12 years 49 1869 n.d. n.d. 2500 mg Vitamin D/d n.d. n.d. Decreased disease activity
Dottori et al. (1982) PC 30 d 45 20 64 n.d. n.d. 50 mg 25(OH)D/d n.d. n.d. Improved pain symtomatology
DBPC, double-blind, placebo-controlled; PC, placebo-controlled; 25(OH)D, 25-hydroxyvitamin D; n.d., no data available.
A. Zittermann560
demonstrated a blood pressure-lowering effect with 0·75 or
1·0 mg1a-vitamin D/d in hypertensive patients (Table 6).
Short-term supplementation with 20 mg vitamin D/d (in
combination with a supplement of 1 200 mg Ca/d) was
able to significantly reduce diastolic blood pressure. A
reduction in diastolic and systolic blood pressure was
observed in mildly hypertensive patients after 6 weeks of
u.v. B exposure but not after u.v. A exposure (Table 6).
A normalization of the enhanced intracellular Ca levels
seems to be an important measure in order to reduce
blood pressure. This can explain the therapeutic effects
of Ca channel blockers in hypertensive patients (McCarron
et al. 1987). A low adenylate cyclase activity can result in
a decreased Ca re-uptake into the sarcoplasmic reticulum
(Curry et al. 1974) and can contribute to an accumulation
of intracellular free Ca, and to an increase in vascular reac-
tivity and blood pressure (McCarron et al. 1987). Activity
of the intracellular adenylate cyclase is calcitriol-dependent
(Nemere et al. 1993) and improvement of the activity of
this enzyme may thus reduce free cellular Ca
concentrations.
Cardiovascular diseases. Dyslipoproteinaemia, dis-
turbed glucose tolerance, and an increase in blood coagu-
lation factors, blood viscosity, and leucocyte counts are
important risk factors for the development of arteriosclero-
sis (Mendall et al. 1997). There is now increasing evidence
that arteriosclerosis is a low-grade systemic inflammatory
disease. An increase in serum C-reactive protein levels is
an important indicator of inflammatory reactions and also
of the risk of developing arteriosclerosis (van Lente,
2000). Synthesis of C-reactive protein is regulated by
IL-6 and TNF-a (Mendall et al. 1997). Animal studies
have demonstrated that IL-6 accelerates arteriosclerosis
(Huber et al. 1999). Calcitriol can suppress the secretion
of TNF-a and IL-6 in vitro in a dose-dependent manner
(Mu
¨
ller et al. 1992). We have recently observed an inverse
association between TNF-a and 25(OH)D levels in human
subjects (r 0·30, P, 0·01; Zittermann et al. 2003). Epide-
miological investigations brought forward evidence for an
inverse association between myocardial infarction and
plasma 25-hydroxyvitamin D
3
levels (Scragg et al. 1990).
Moreover, the nadir of 25(OH)D levels in the UK during
wintertime (Hegarty et al. 1994) is paralleled by an
increased cardiovascular morbidity (Douglas et al. 1991).
Since the prevalence of cardiovascular diseases is low in
alpine regions of high altitudes and low temperatures
(Scragg, 1981), reasons apart from ambient temperature
must be responsible for the differences in cardiovascular
diseases between different seasons. One factor may be
the low vitamin D availability in winter, while vitamin D
availability is high in alpine regions due to intensive
u.v. B exposure. It is also only an apparent paradox that
Eskimos have a low risk of arteriosclerosis (Feskens &
Kromhout, 1993) although u.v. B irradiation is low in the
region they live. The traditional diet of Eskimos is high
in marine fishes and other sea meat (Feskens & Kromhout,
1993). These foods are very rich in vitamin D (Table 7).
Physical activity and an increased intake of unsaturated
fatty acids are frequently recommended in the prevention
and therapy of cardiovascular diseases. Physical activity
is associated with higher circulating levels of 25(OH)D
and calcitriol compared with a sedentary lifestyle
(Zittermann et al. 2000). Consequently, the beneficial
effect of physical activity may at least in part be explained
by the improvement in vitamin D status. Physiological
amounts of unsaturated fatty acids can reduce the binding
of serum calcitriol to the vitamin D-binding protein by
more than 20 % and can thus increase the bioavailability
of calcitriol. Saturated fatty acids do not show such an
effect (Bouillon et al. 1992).
Diabetes mellitus. The dependence of normal insulin
secretion in pancreatic b-cells on vitamin D has been
known for several decades. Experimental studies have
demonstrated that a reduction in vitamin D activity can
result in both increased insulin resistance and reduced insu-
lin secretion (Boucher, 1998). Epidemiological data have
shown a four- to five-fold higher prevalence of non-insu-
lin-dependent diabetes in dark-skinned Asian immigrants
in comparison with British Caucasians indicating that
low vitamin D status may contribute to the pathogenesis
of diabetes (McKeigue et al. 1992). Moreover, in elderly
subjects the subgroup with the lowest tertile of 25(OH)D
levels had a significantly higher blood glucose increase
and higher blood insulin increase after an oral glucose-tol-
erance test in comparison with the subgroup with the high-
est tertile of 25(OH)D levels (Baynes et al. 1997). Data
indicate that vitamin D insufficiency may result in insulin
resistance. Results are in line with the suggestion that
enhanced levels of TNF-a, a cytokine with is inversely
related to 25(OH)D and calcitriol (see p. 560), promote
insulin resistance (Hotamisligil & Spiegelman, 1994).
A severe vitamin D deficiency probably results in low
serum insulin levels indicating reduced insulin secretion
(Boucher, 1998). In uraemic patients, administration of
1a-vitamin D was able to improve blood glucose levels
and increase serum insulin levels (Table 8). Moreover,
two studies have demonstrated that daily administration
of 50 mg and 1050 2125 mg vitamin D/d was able to
reduce blood glucose levels in patients with osteomalacia.
In another study, however, there was an increase in blood
glucose levels in diabetic patients 8 12 weeks after a
single injection of 2500 mg vitamin D compared with the
pre-treatment value (Table 8). It was assumed by the
authors of that study that the failure to correct diabetes
was probably due to the modest increase of 25(OH)D
levels of only 25 nmol/l (Boucher et al. 1995).
A Norwegian study brought forward evidence that the
daily intake of cod-liver oil during pregnancy can reduce
the risk of diabetes in the offspring (Stene et al. 2000).
Cod-liver oil has a very high vitamin D content (Table 7).
In a more recent Finnish investigation, regular vitamin D
supplementation of 50 mg/d during infancy in the 1960s
was associated with a markedly reduction in the risk of
type 1 diabetes 30 years later in comparison with unsupple-
mented infants (relative risk 0·12). Children suspected of
having rickets during the first year of life had a threefold
increased prevalence of type 1 diabetes in comparison
with those without such a suspicion (Hyppo
¨
nen et al.
2001). In Germany, the incidence of type 1 diabetes in
adolescents is higher in autumn and winter compared
with spring and summer (Statistisches Bundesamt, 1998).
Autoimmune processes are regarded to play an important
Vitamin D in preventive medicine 561
Table 6. Intervention trials with u.v.B irradiation and supplementation with vitamin D and its metabolites on blood pressure in normotensive and hypertensive patients
Initial serum levels Change in serum levels
Reference
Study
design n
Duration of
treatment
Age
(years)
25(OH)D
(nmol/l)
Calcitriol
(pmol/l) Treatment
25(OH)D
(nmol/l)
Calcitriol
(pmol/l) Results
Lind et al. (1987) DBPC 26 H 6 months Mean 63 n.d. n.d. 1 mg1a-Vitamin D/d n.d. n.d. 2 9·2 mmHg diastolic blood
pressure
Lind et al. (1988) DBPC 65 H 12 weeks 6165 n.d. n.d. 0·75 mg1a-Vitamin D/d n.d. n.d. 2 9/ 2 3 mmHg systolic and
diastolic blood pressure
Lind et al. (1989) DBPC 39 H 4 months Mean 51 n.d. n.d. 1 mg1a-Vitamin D/d n.d. n.d. No difference v. controls
Pan et al. (1993) DBPC 58 N 11 weeks 6383 61 n.d. 5 mg Vitamin D
3
+7 n.d. No effects
59 n.d. 5 mgD
3
+800 mg Ca/d +11 n.d.
Scragg et al. (1995) DBPC 189 N 5 weeks 6376 34·5 n.d. 5 mg Vitamin D/d +14 n.d. No effects
Krause et al. (1998) DBPC 18 H 6 weeks 2666 58 n.d. u.v.B irradiation
thrice-weekly
+94 n.d. 2 6/ 2 6 mmHg systolic and
diastolic blood pressure
Pfeifer et al. (2001) DBPC Elderly
women
8 weeks 75 26 91 20 mg Vitamin D/d* +40 +36 26 mmHg systolic
DBPC, double-blind, placebo-controlled; H, hypertensive subjects (blood pressure ^ 140/90); N, normotensive subjects; 25(OH)D, 25-hydroxyvitamin D; n.d., no data available.
* An additional Ca supplement of 1 200 mg/d was given to the placebo and the verum group.
A. Zittermann562
role in the pathogenesis of type 1 diabetes. Again, it should
be mentioned that calcitriol has immunomodulatory prop-
erties (see p. 557). Availability of calcitriol in the cell
may thus influence autoimmune processes. The vitamin
D hypothesis is also in line with results demonstrating
that the risk of type 1 diabetes and of type 2 diabetes is
influenced by the VDR genotype at the BmsI restriction
site (Chang et al. 2000; Ortlepp et al. 2001).
It should be mentioned that hypertension, cardiovascular
diseases, and diabetes mellitus are often associated with
obesity. Obese subjects have an increased risk for low cir-
culating 25(OH)D levels (Bell et al. 1985; Wortsman et al.
2000) due to the storage of vitamin D and 25(OH)D in adi-
pose tissue (Wortsman et al. 2000). The alterations in vita-
min D metabolism of obese subjects in comparison with
lean subjects are also associated with functional alterations
such as elevated PTH levels (Bell et al. 1985; Wortsman
et al. 2000). Obesity might thus contribute to insufficient
circulating 25(OH)D levels.
Cancer
Although carcinogenesis can occur relatively quickly, most
cancers develop over decades making it difficult to perform
reliable human intervention studies on the association
between vitamin D and cancer risk. However, there is
evidence that enhanced sunlight exposure is associated
with lower prostate, breast and colon cancer death rates,
while the historical geographical distribution of rickets
parallels that for these cancer deaths (Guyton et al. 2001).
The strongest epidemiological evidence supporting a
protective role for vitamin D in colon cancer is from pro-
spective studies. Inverse associations for vitamin D
intake and colon or colorectal cancer with relative risks
ranging from 0·33 to 0·74 have been reported (Bostick
et al. 1993; Guyton et al. 2001). Moreover, a nested
casecontrol study based on serum drawn from a cohort
of 25 620 individuals reported that concentrations of
25(OH)D in the range of 65 100 nmol/l were associated
with large reductions in the incidence of colorectal
cancer compared with lower 25(OH)D levels (Garland
et al. 1991).
A reduced risk of breast cancer has been observed in the
NHANES I epidemiological follow-up study with several
measures of sunlight exposure and dietary vitamin D
intake, with relative risks ranging from 0·67 to 0·85. The
risk reductions were highest for women who lived in US
regions of high solar radiation and no reduction was
founds for women who lived in regions of low solar radi-
ation (John et al. 1999). Data are in line with experimental
results suggesting that high amounts of vitamin D and diet-
ary Ca decrease susceptibility to chemically induced mam-
mary neoplasia (Carroll et al. 1991).
Another important observation is that in the USA the
occurrence of prostate cancer and MS have similar geo-
graphical distributions (Schwartz, 1992). The hypothesis
of a vitamin D dependency on prostate cancer has recently
been confirmed by a large nested casecontrol study (Tuo-
himaa et al. 2001). In a 13-year follow-up study of about
19 000 middle-aged Finnish men, prostate cancer risk
was highest among the group of younger men (40 51
years) with low serum 25(OH)D levels. Approximately
one half of the serum samples had 25(OH)D levels
below 50 nmol/l. Low serum 25(OH)D levels, however,
appeared not to increase the risk of prostate cancer in
older men (. 51 years). Data suggest that vitamin D has
a protective role against prostate cancer only before the
andropause, when serum androgen concentrations are
higher. The lowest 25(OH)D concentrations in the younger
men were associated with more aggressive prostate cancer
(Tuohimaa et al. 2001).
Vitamin D is anti-proliferative and promotes cellular
maturation, induces differentiation and apoptosis in many
different cell lines including malignant cells (Feldman
et al. 1995; Guyton et al. 2001). Vitamin D receptors
have been found in the mammary gland, in the colon and
in the prostate (Table 1). Moreover, it is now recognized
that colon, breast, and prostate cells also express the 1a-
hydroxylase to form calcitriol from circulating 25(OH)D
(Holick, 2002). It seems clear that vitamin D must be
viewed as an important cellular anti-tumour substance.
Prevention of vitamin D insufficiency
Preventive measures have to consider that there is a high
risk of vitamin D insufficiency in the whole population
during winter and that the elderly population, and
especially institutionalized subjects, are at increased risk
for vitamin D insufficiency or even deficiency. Available
modes of prevention are threefold: increased exposure to
Table 7. Adequate daily vitamin D intake values by age group for Germany, Austria, and
Switzerland, and vitamin D content of some foods per 100 g edible portion (from Souci et al. 1994;
Deutsche Gesellschaft fu
¨
r Erna
¨
hrung et al. 2000)
Age group Vitamin D adequate intake (mg) Food Vitamin D contact (mg)
Infants 10 Herring 27
Children 5 Eel 20
Adolescents 5 Salmon 16
Adults , 65 years 5 Cod 1·3
Adults . 65 years 10 Butter 1·3
Egg 3
Pork liver
Cod-liver oil 330
Vitamin D in preventive medicine 563
Table 8. Intervention trials with vitamin D and its metabolites on blood glucose and insulin levels in patients with diabetes mellitus and/or disturbed calcium and vitamin D metabolism
Initial serum levels Change in serum levels
Reference
Study
design n
Duration of
treatment
Age
(years)
25(OH)D
(nmol/l)
Calcitriol
(pmol/l) Treatment
25(OH)D
(nmol/l)
Calcitriol
(pmol/l) Results
Rudnicki & Molsted-
Pedersen (1997)
Open trial 20
GD
2 h n.d n.d. 240 Intravenous infusion
of 2 mg calcitriol/m
2
n.d. +115 Blood glucose: 0·8 mmol/l
# after GTT
Ljunghall et al. (1987) PC 65
IP
3 months 6165 93 110 0·75 mg1a-Vitamin D/d +12 +5 No improvement
Boucher et al. (1995) Open trial 22
DP
812 weeks n.d. 9 n.d. Single intramuscular
injection of 2500 mg
Vitamin D
+25 n.d. Blood glucose,1·8 mmol/l " ;
specific insulin, 43 mU/l
" after GTT
Kocian (1992) Open trial 61
OP
6 weeks n.d. n.d. n.d. 10502125 mg Vitamin
D/d and 470 700 mg
Ca/d
n.d. n.d. Blood glucose, 1·5 mmol/l
# after GTT
Kumar et al. (1994) Case
report
1
HP
5 months 65 6·8 30 50 mg Vitamin D/d +46 +88 Blood glucose, 1·6 mmol/l
# ; insulin, 29 mU/l
" after GTT
Tu
¨
rk et al. (1992) PC 31
UP
8 weeks 17 66 n.d. 44 0·5 mg Calcitriol/d n.d. +103 Blood glucose, 1·1 mmol/l
# ; insulin, 78 mIU/l
" after GTT
Allegra et al. (1994) Open trial 17
UP
3 weeks Mean
50
n.d. 44 0·5 mg Calcitriol/d n.d. +37 Blood glucose, 1·1 mmol/l
# ; insulin, 13m IU/l
" after GTT
PC, placebo-controlled; GD, patients with gestational diabetes; IP, patients with impaired glucose tolerance; DP, vitamin D-deficient patients with impaired glucose tolerance; OP, patients with osteomalacia; HP, hypo-
calcaemic patient; UP uraemic patients; 25(OH)D, 25-hydroxyvitamin D; GTT, glucose tolerance test; n.d., no data available; # , down; " , up.
A. Zittermann564
u.v. light; dermal vitamin D application; increased oral
vitamin D intake.
A general recommendation from health authorities of a
higher sunlight exposure of the free-living population
during winter may be largely ineffective due to the lack
of u.v. B irradiation. In addition, there are valid concerns
about photo-ageing and skin cancer if u.v. B exposure is
increased, for example, between spring and autumn
(McKenna, 1992). The vitamin D status of elderly people
may be enhanced by skin exposure to artificial u.v. light,
but provision of fluorescent lighting in wards has resulted
in inconsistent responses and can be associated with com-
plications; namely skin burns, keratoconjunctivitis, and
cataracts (McKenna, 1992).
Similar to the administration of oestrogens, dermal
application of vitamin D might be a useful individual
measure to achieve constant levels of this steroid substance
during several weeks. However, such a measure has not yet
been tested in clinical trials.
Adequate daily oral vitamin D intake could be an easy
and effective measure to maintain a physiological vitamin
D status. Adequate intake values are 5 10 mg/d (National
Nutrition Council, 1999; Deutsche Gesellschaft fu
¨
r
Erna
¨
hrung et al. 2000; Health Council of the Netherlands,
2000) and 15 mg vitamin D/d for elderly subjects with
insufficient skin vitamin D synthesis (Health Council of
the Netherlands, 2000). In Germany the mean vitamin D
intake is 3 mg/d in females and 4 mg/d in males (Heseker
et al. 1994). In The Netherlands vitamin D intakes are
also below 5 mg/d (Health Council of the Netherlands,
2000). In middle-aged Finnish females and males mean
vitamin D intake is 4·7 and 5·6 mg/d respectively (Lam-
berg-Allardt et al. 2001). Norwegians have a high con-
sumption of vitamin D-rich fatty fish (Hayes et al. 1997)
and usually consume cod-liver oil during their whole life-
span. This may explain the ‘relatively’ high 25(OH)D
levels in elderly Norwegians during wintertime (Table 2).
The low vitamin D intake in several European countries
is due to the fact that only a few foods are naturally good
sources of vitamin D and some fishes alone can substan-
tially contribute to an adequate nutritional supply of vita-
min D (Table 7). Moreover, only a few foods are
fortified with low amounts of vitamin D in Europe; for
example, margarine, vegetable oil, cereals, breakfast bev-
erages, and breads (Lips et al. 1996). The European
Union is therefore supporting a project towards a strategy
for optimal vitamin D fortification named OPTIFORD
(Andersen et al. 2001).
It must be emphasized that currently no recommended
intake level for vitamin D exists. The adequate intake
values are crude estimates in order to prevent vitamin D-
dependent diseases such as rickets and osteomalacia. We
are probably ignoring the evidence that a much higher
oral vitamin D intake than 515 mg/d is necessary to main-
tain adequate circulating 25(OH)D levels in the absence of
u.v. B irradiation of the skin. Dose response studies with
daily doses of oral vitamin D have demonstrated that 10,
25, 100 and 250 mg vitamin D result in a mean increase
of circulating 25(OH)D levels of 45, 48, 56, and
112 nmol/l, respectively (Vieth, 1999; Vieth et al.
2001a). Data from Tables 3, 4, 6 and 8 indicate that
vitamin D intakes of 5, 10, 20 and 50 mg/d increase
mean serum 25(OH)D levels by 714, 3035, 2540,
and 46 nmol/l respectively. Results suggest that the
increase of 25(OH)D following a vitamin D supplement
of 10 mg is often too low to maintain a 25(OH)D level
above 50 nmol/l or even above 100 nmol/l. In line with
this assumption mean circulating 25(OH)D levels were
only 17·5 nmol/l in veiled ethnic Danish Moslem women
although their estimated daily vitamin D intake was
13·5 mg/d (Glerup et al. 2000). Moreover, in Finnish ado-
lescent girls daily supplementation with 10 mg Vitamin
D
2
was not able to increase serum 25(OH)D levels
during the winter. Supplementation with 20 mg vitamin
D/d resulted in a 25(OH)D level which was only
14 nmol/l higher in comparison with the unsupplemented
group (Lehtonen-Veromaa et al. 2002). In Danish perime-
nopausal women who took vitamin D supplements at least
during wintertime, serum 25(OH)D levels were only
8·5 nmol/l higher than in non-users (Brot et al. 2001).
Together, these data indicate that in the absence of u.v.
B exposure the oral vitamin D demand is probably far
above the present recommendation of 10 mg/d and may
be up to 100 mg/d in order to maintain adequate circulating
25(OH)D levels (Heaney, 2000). Only those traditional
diets with a regular intake of cod-liver oil and/or sea
foods such as salmon, herring, and eel are able to provide
such high amounts of vitamin D daily (Table 7). This also
means that intervention trials with oral vitamin D sup-
plements must obviously include much higher doses than
the currently often-used 520 mg/d. Due to the relatively
small increase in serum 25(OH)D levels and relatively
low Ca absorption rates, vitamin D intakes of 520 mg/d
alone may be inadequate to significantly improve the
amount of absorbed Ca. A simple increase in oral Ca just
as well as a high vitamin D intake can increase the
amount of absorbed Ca. This may explain why some
improvements in fracture prevalence, muscle function
and blood pressure have been achieved with daily sup-
plements of 20 mg vitamin D in combination with
1200 mg Ca/d (Chapuy et al. 1992; Pfeifer et al. 2000,
2001). Nevertheless, it is doubtful whether high oral Ca
intake alone can beneficially influence intracellular Ca
and cytokine metabolism. It is therefore encouraging that
oral doses of vitamin D or 25(OH)D ^ 50 mg/d were
able to improve the disease outcome in patients with rheu-
matoid arthritis (Dottori et al. 1982) and MS (Goldberg
et al. 1986). Moreover, administration of 50 mg vitamin
D/d to infants can obviously markedly reduce the preva-
lence of type 1 diabetes in later life (Hyppo
¨
nen et al.
2001). Data are a further indication that currently used
oral vitamin D doses are probably much too low in the pre-
vention and therapy of vitamin D-related diseases.
Vitamin D intoxication
There are no reports of vitamin D intoxication in healthy
adults after intensive sunlight exposure. Vitamin D in the
skin reaches a plateau after only 15 30 min of u.v. B
exposure. Then, vitamin D-inactive substances such as
lumisterol and tachysterol are produced, which do not
reach the systemic circulation. Thus, the maximum
Vitamin D in preventive medicine 565
25(OH)D level corresponding to an intensive u.v. B
exposure can be regarded as an upper safe level (Fig. 2).
The changes in circulating calcitriol levels during
intoxication are generally small (Markestad et al. 1987;
Jacobus et al. 1992). Nevertheless, increases in serum
calcitriol have been reported and might contribute to the
symptoms of vitamin D intoxication such as hypercalcae-
mia (Standing Committee on the Scientific Evaluation of
Dietary Reference Intakes, Food and Nutrition Board and
Institute of Medicine, 1997). Hypercalcaemia results
primarily from intestinal Ca hyperabsorption and to a
lesser degree from Ca release from bone (Chesney,
1989). The hypercalcaemia induced by high oral doses of
vitamin D can lead to nephrocalcinosis and coronary scler-
osis (Hesse & Jahreis, 1990).
In all cases of vitamin D intoxication 25(OH)D levels
were clearly above 200 nmol/l. Levels up to 1000 nmol/l
and more have been observed (Markestad et al. 1987;
Jacobus et al. 1992). All these instances of intoxication
were the result of an excessive oral intake of vitamin D
2
or vitamin D
3
. They are the result of an unregulated intes-
tinal vitamin D uptake in association with an uncontrolled
hepatic 25-hydroxylation leading to high circulating
25(OH)D levels. Vitamin D intoxication has been
described in British infants during the late 1940s and
early 1950s after heavy enrichment of dried milk powder
together with vitamin D-enriched cereals and in addition
to the recommendation of a daily vitamin D supplement
of 17·5 20·0 mg (Chesney, 1989). Moreover, the ‘stoss
prophylaxis’ in the former German Democratic Republic
against rickets with intermittent doses as high as 15 mg
vitamin D
2
was associated with symptoms of vitamin D
intoxication such as hypercalcaemia and serum 25(OH)D
levels of several hundred nmol/l (Markestad et al. 1987).
In adults, vitamin D intoxication has been observed after
the administration of very high therapeutic vitamin D
3
doses (Lilienfeld-Toal et al. 1978), in association with an
over-the-counter supplement that contained 26 to 430
times the vitamin D
3
amount listed by the manufacturer
(Koutka et al. 2001), and in association with an acciden-
tally excessive overfortification of consumers’ milk with
vitamin D
3
(Jacobus et al. 1992; Blank et al. 1995). There
are no reports in the literature about vitamin D intoxication
with traditionally consumed foods (Chesney, 1989).
The US Standing Committee on the Scientific Evalu-
ation of Dietary Reference Intakes, Food and Nutrition
Board and Institute of Medicine (1997) has defined a toler-
able upper intake level of 25 mg vitamin D/d for infants
and of 50 mg vitamin D/d for children aged . 1 year and
for adults (Standing Committee on the Scientific
Evaluation of Dietary Reference Intakes, Food and Nutri-
tion Board and Institute of Medicine, 1997). However,
evidence for the threshold of 25 mg/d in infants is not
well documented. Most of the occurrences of intoxication
occurred during a time when circulating 25(OH)D could
not be measured. Consequently, insufficient data of mini-
mal vitamin D intake, corresponding serum 25(OH)D
levels, and toxic effects are available in infants. Moreover,
recent investigations suggest that an oral vitamin D intake
up to 100 mg/d is safe in the adult population. No changes
in serum and urinary Ca levels have been observed with
that dose. The highest individual 25(OH)D level after
administration of 100 mg vitamin D/d was 140 nmol/l
(Vieth et al. 2001a) and was, thus, in the range also seen
during intensive u.v. B-exposure.
Conclusions
Calcitriol is a very potent steroid hormone and is, on a
molar basis, the most effective vitamin D metabolite.
Nevertheless, an adequate serum 25(OH)D level is also
necessary to achieve full physiological vitamin D activity.
Obviously, the serum 25(OH)D level and not the serum
calcitriol level is the best indicator for vitamin D insuffi-
ciency, adequacy, or toxicity.
Because only a few foods, especially some fatty fishes,
naturally contain vitamin D in relevant amounts circulating
25(OH)D levels normally largely depend on u.v. B
exposure. In tropical and subtropical regions, where more
than 90 % of human evolution took place, u.v. B irradiation
is abundant throughout the year. Reasons for a low vitamin
D status in Europe are: (i) the seasonal lack of u.v. B
irradiation; (ii) low outdoor activities; (iii) the ageing pro-
cess leading to a reduced vitamin D synthesis in the skin;
(iv) the low vitamin D content of most foods. Probably,
the prevalence of a low vitamin D status will increase in
future due to the rising number of elderly individuals in
European societies, and due to the migration of dark-
skinned people and veiled women to Europe. The relevance
of the frequently low vitamin D status is not completely
clear. However, there is growing evidence for the contri-
bution of a circulating 25(OH)D level below 50 nmol/l to
the development of various chronic diseases which are fre-
quent in Western societies. Current estimations for an ade-
quate oral intake are obviously much too low to achieve an
optimal vitamin D status and thus to effectively prevent
chronic vitamin D-dependent diseases.
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... Experimental studies involving knockout mice lacking active vitamin D receptors revealed elevated levels of renin and angiotensin II in the mice's blood, which caused a significant rise in blood pressure and subsequent cardiac hypertrophy [85][86][87][88]. Figure 3 is a schematic representation of the main pleiotropic systemic effects of vitamin D. the mice's blood, which caused a significant rise in blood pressure and subsequent cardiac hypertrophy [85][86][87][88]. Figure 3 is a schematic representation of the main pleiotropic systemic effects of vitamin D. Figure 3. Pleiotropic effect of vitamin D. CKD, chronic kidney disease; EGFR, epidermal growth factor receptor; ESRD, end-stage renal disease; IF/TA, interstitial fibrosis/tubular atrophy; IL-6, interleukin 6; RAAS, renin-angiotensin-aldosterone system; TGF-α, transforming growth factor alpha. ...
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... Vitamin D, a steroid hormone, plays the main role in the immune system [12,13]. Vitamin D influences many reactions against the normal immune response to pathogens. ...
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We evaluated the prevalence and association of Vitamin D deficiency with glycemic control and CVD risk in T2DM patients. Serum 25 (OH)D3, lipid profile, glucose panel, HbA1c, serum insulin, and HOMA-IR were assessed in 93 T2DM patients and 69 controls. 10 years and lifetime ASCVD risk scores were calculated. The levels of 25(OH)D3 were significantly low in T2DM patients compared to the control. T2DM patients with hypovitaminosis D displayed significantly increased FBG, insulin, and HOMA-IR compared to normovitaminosis. Their lifetime and 10-year ASCVD risk scores were significantly higher regardless of vitamin D deficiency levels ( P = 0.006 ; P = 0.023 ) in comparison to patients with sufficient levels of vitamin D. Among patients, the lifetime and 10 years of ASCVD risk showed a significant negative correlation with serum 25(OH)D3 and HDLc ( P = 0.037 ; 0.018) ( P = 0.0001 ), respectively, and significant positive correlation with T2DM duration, serum insulin, and HOMA-IR ( P = 0.018 ; 0.0001) ( P = 0.002 ; 0.001) ( P = 0.005 ; 0.001), respectively. The 10-year ASCVD risk exhibited a significant positive correlation with FBG ( P = 0.003 ) and HbA1c ( P = 0.009 ). T2DM duration was a predictor of vitamin D deficiency among T2DM patients (β = 0.22; CI = 0.002–0.04). There is a considerable association between lifetime and 10 years of ASCVD risk with hypovitaminosis D in T2DM, regardless of the deficiency levels which could be predicted by the diabetes duration.