British Journal of Nutrition (2003), 89, 552–572 DOI: 10.

1079/BJN2003837
q The Author 2003

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 of Dietary Reference Intakes, Food and Nutrition Board
deficiency in infants, was endemic in Europe and North and Institute of Medicine, 1997). Nowadays, rickets is
America during the 19th century and during the first two rare in Europe and North America, but there is still a
decades of the 20th century. Based on the observations risk, especially if parents are not aware of preventive
that skin exposure to u.v. light as well as oral vitamin D measures or neglect them (Hellebostad et al. 1985;
intake could cure rickets, several very effective prevention Hartman, 2000).
strategies were performed. The so-called ‘stossprophylaxis’ There is now growing evidence that the adult European
was based on the administration of high amounts of vita- population is also at risk for an inadequate vitamin D status
min D several times during infancy (Markestad et al. (see p. 554– 555). The present review summarizes the evi-
1987). Moreover, young children were regularly exposed dence of an involvement of a low vitamin D status in the
to artificial u.v. light. Present prophylaxes of rickets pathogenesis of several chronic diseases. Moreover, the
include a daily vitamin D supplement of 10 mg in Germany amount of oral vitamin D intake to maintain an adequate
(Deutsche Gesellschaft für Ernährung et al. 2000), the UK vitamin D status is discussed.
(Department of Health, 1998), the Netherlands (Health
Council of the Netherlands, 2000), Sweden (Axelsson
et al. 1999), and Finland (National Nutrition Council, Vitamin D metabolism and actions
1999). In the USA, the adequate intake for infants is Vitamin D can be ingested orally or can be formed
5 mg/d (Standing Committee on the Scientific Evaluation endogenously by the skin after exposure to u.v. B light

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.
Corresponding author: Associate professor Armin Zittermann, fax +49 228 733217, email [email protected]
 Vitamin D in preventive medicine 553

(wavelength 290 – 315 nm). In the skin, a plateau of daily 25(OH)D levels. Circulating 25(OH)D levels are, how-
vitamin D production is reached after only 30 min of u.v. ever, approximately ten times higher than serum 24,25-
B irradiation (Holick, 1994). Increased melanin pigmenta- dihydroxyvitamin D levels and are approximately 500 –
tion reduces the efficiency of u.v. B-mediated vitamin D 1000 times higher than serum calcitriol levels. Metabolism
synthesis and necessitates increases in the exposure time of ergocalciferol (vitamin D2) and cholecalciferol (vitamin
required to maximize vitamin D formation, but does not D3) is similar. Oral vitamin D3 intake results, however, in
influence the total content of daily vitamin D production. a 70 % higher serum 25(OH)D level in comparison with
Orally ingested and endogenously formed vitamin D is the same amount of vitamin D2 (Trang et al. 1998).
transported to the liver and is there converted to 25-hydro- Vitamin D metabolites are known as regulators of sys-
xyvitamin D (25(OH)D) (Fig. 1). A strong regulation of temic Ca homeostasis with actions in the intestine, the kid-
this step does not exist and there is no significant storage neys, and bone. Calcitriol is on a molar basis the most
of 25(OH)D in the liver of mammals. 25(OH)D is rapidly potent vitamin D metabolite. Calcitriol increases both
released by the liver into the blood, where it circulates intestinal absorption of orally ingested Ca and tubular reab-
with a biological half-life of approximately 12 – 19 d. In sorption of Ca by an active, receptor-mediated process in
the kidney, 25(OH)D is enzymically converted to the vita- order to maintain physiological serum Ca levels.
min D hormone 1,25-dihydroxyvitamin D (calcitriol). Calcitriol plays not only a pivotal role in systemic Ca
Renal synthesis of calcitriol is homeostatically controlled homeostasis but also in the intracellular Ca homeostasis
by parathyroid hormone (PTH). Synthesis of PTH is regu- of various tissues. Now it is clear that vitamin D receptors
lated by serum concentrations of Ca and P. 25(OH)D can (VDR) exist in more than thirty different tissues (Table 1).
also be converted by a renal 24-hydroxylase into 24,25- Calcitriol functions as a steroid hormone that binds to a
dihydroxyvitamin D. Circulating 24,25-dihydroxyvitamin cytosolic VDR resulting in a selective demasking of the
D levels are very strongly correlated with circulating 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).

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
Fig. 1. The major metabolic pathways of vitamin D. Human sources Liver cells
of vitamin D are skin production of vitamin D3 by u.v. light and oral Prostate cells
intake of vitamin D2 and/or vitamin D3. Vitamin D is hydroxylated in Ovarian cells
the liver into 25-hydroxyvitamin D and in the kidney into the vitamin Keratinocytes of skin
D hormone calcitriol. Renal calcitriol synthesis includes activation of Endocrine cells, stomach
1a-hydroxylase by parathyroid hormone and suppression of the Aortic endothelial cells
1a-hydroxylase by high serum levels of ionized Ca. PTH; parathyr- Pituitary cells
oid hormone; 24,25(OH)2D, 24,25-dihydroxyvitamin D.
554 A. Zittermann

The de novo mRNA and protein synthesis induced by the 25(OH)D also serves as a substrate for the 1a-hydroxylase
cytosolic calcitriol– VDR complex require periods lasting of various tissues that possess VDR. The tissues in the
hours to days. However, rapid calcitriol actions have also body that are not responsible for regulating extracellular
been observed in several tissues at both the cellular and Ca metabolism probably use circulating 25(OH)D to
subcellular level (Norman, 1998). These calcitriol actions make calcitriol (Holick, 2002). Low serum 25(OH)D
cannot be explained by receptor –hormone interactions levels may thus impair intracellular calcitriol availability.
with the genome. Meanwhile, a membrane-bound VDR Several tissues also possess 24-hydroxylase activity result-
has been recognized in different cell lines leading to an ing in a local production of 24,25-dihydroxyvitamin D
activation of specific intracellular metabolic pathways from 25(OH)D. It has been hypothesized that 24,25-dihy-
within a few minutes. Given the pivotal role of ionized droxyvitamin D is indispensable for normal Ca and
Ca in muscle contraction, nerve-impulse conduction, and P homeostasis. Consequently, a cellular receptor for
other physiological phenomena, such a rapid response 24,25-dihydroxyvitamin D has been postulated by some
could be life-saving for the organism (Nemere & Farach- investigators (Norman, 1998).
Carson, 1998).
There are some studies available indicating that
Assessment of vitamin D status
25(OH)D itself has important physiological functions.
Dose – response studies indicate a molar potency of calci- Circulating 25(OH)D levels closely reflect the amount of
triol relative to 25(OH)D ranging from 125:1 to 400:1 in sunlight to which the epidermis is exposed and the dietary
increasing Ca absorption from the gut (Barger-Lux et al. intake of vitamin D. There is general agreement that the
1995). Based on these molar potencies of calcitriol and serum 25(OH)D level is the best indicator to define vitamin
25(OH)D and the serum concentrations of the two vitamin D deficiency, insufficiency, hypovitaminosis, sufficiency,
D metabolites (approximately 1:500 to 1:1000) it can be and toxicity (Standing Committee on the Scientific Evalu-
assumed that 55 to 90 % of the circulating vitamin D ation of Dietary Reference Intakes, Food and Nutrition
activity is contributed by 25(OH)D (Barger-Lux et al. Board and Institute of Medicine, 1997; McKenna & Frea-
1995). In line with this assumption, cross-sectional studies ney, 1998) (Fig. 2). Nevertheless, it is difficult to clearly
have demonstrated that serum 25(OH)D levels are a better define cut-off values for each stage. There is no doubt
indicator for intestinal Ca absorption efficiency than serum that 25(OH)D levels below 12·5 nmol/l can result in bone
calcitriol levels (Barger-Lux et al. 1995; Zittermann et al. diseases such as rickets in infants and osteomalacia in
1998). Consequently, very low 25(OH)D levels as found in adults (Scharla, 1998). There is, however, also evidence
rickets and osteomalacia result in an impaired intestinal Ca that 25(OH)D levels below 25 nmol/l lead to rickets and
absorption leading to a severe Ca deficit in the human osteomalacia in the long run (Basha et al. 2000). Concen-
body. Moreover, 25(OH)D increases: (i) the uptake of trations of 25(OH)D below 40– 50 nmol/l reflect vitamin D
45
Ca into cultured muscle cells (Selles et al. 1994); (ii) insufficiency (Malabanan et al. 1998, Need et al. 2000;
the intracellular Ca re-uptake into the sarcoplasmic reticu- Vieth et al. 2001b). Values below this threshold can lead
lum (Poiton et al. 1979); (iii) the intracellular accumulation to functional alterations such as hyperparathyroidism.
of phosphate (Birge & Haddad, 1975). Circulating 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.
 Vitamin D in preventive medicine 555

doses of oral vitamin D can decrease the elevated PTH observation that subjects with a constantly high u.v. B
levels (Malabanan et al. 1998). It must also be emphasized exposure living close to the equator have mean 25(OH)D
that oral Ca intake can suppress PTH levels (Kärkkainen levels of 107 nmol/l and upper serum levels (+2 SD ) of
et al. 1997) and oral phosphate intake can increase PTH 163 nmol/l throughout the year (Linhares et al. 1984).
levels (Whybro et al. 1998). These nutrients may therefore Moreover, American bath attendants have serum
influence the vitamin D –PTH axis. 25(OH)D levels up to 160 nmol/l (Holmes & Kummerow,
Serum calcitriol levels can be affected differently during 1983).
vitamin D insufficiency or deficiency. Circulating concen-
trations are often similar to those of vitamin D-replete sub-
Vitamin D status in different European population
jects (Eastwood et al. 1979). The accompanying secondary
groups
hyperparathyroidism can, however, also result in an
increase in serum calcitriol levels (Adams et al. 1982; In general, healthy young adults have marked seasonal
Bell et al. 1985). Moreover, even low calcitriol levels fluctuations in serum 25(OH)D levels with lower concen-
can be observed (Bouillon et al. 1987; Docio et al. trations in winter than in summer (Table 2). Even children
1998), most probably because of an insufficient substrate and adolescents, two groups with various outdoor activities
availability for the renal 1a-hydroxylase. Consequently, and frequent exposure to sunlight, have low 25(OH)D
determination of serum calcitriol levels is not a valid levels in winter (Table 2). The main reason for the low
measure in order to assess vitamin D status. 25(OH)D levels in winter is the fact that vitamin D
Serum 25(OH)D concentrations between 50 nmol/l and status is largely dependent on skin synthesis and that u.v.
80 – 100 nmol/l can be regarded as hypovitaminosis D, B radiation of the sunlight is negligible from October
where body stores are already depleted and PTH levels to April at the latitude of 528N and from November to
can be slightly elevated, but are still in the normal range February at the latitude of 428N. In contrast, skin synthesis
(McKenna & Freaney, 1998; Lamberg-Allardt et al. 2001). of vitamin D is possible throughout the year at the latitude
Circulating 25(OH)D levels between 100 and 200 nmol/l of 328N or closer to the equator (Holick, 1994). Even
can be regarded as adequate concentrations, where no dis- premenopausal women living in a sunny country such as
turbances in vitamin D-dependent body functions occur Turkey have very low 25(OH)D levels in summer if suffi-
(Peacock, 1995). A rationale for this assumption is the 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 50–60 80 52 Davies et al. (1999)
UK: dark-skinned children 50–60 36– 42* 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 45–55 68 42 McKenna (1992)k
Turkey (women) 39 Alagol et al. (2000)
Group 1 56†
Group 2 32‡
Group 3 9§
Elderly subjects
Norway 61 – 47 van der Wielen et al. (1995)
UK 50–60 35 23 Hegarty et al. (1994)
Italy 42 – 28 van der Wielen et al. (1995)
Greece 35–38 – 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.
556 A. Zittermann

(Table 2). Moreover, dark-skinned Asian children living in rises ten-fold in white women between the age of 75 and
England have low circulating 25(OH)D levels (Table 2) 95. The highest hip fracture rates are found in Northern
supporting the assumption that skin synthesis of vitamin Europe. Moreover, there is seasonality in the rates of hip
D is critical for vitamin D status. fractures in the white US population with high rates in
Generally, vitamin D status is more troublesome in winter and low rates in summer in both sexes
elderly subjects in comparison with young adults (Peacock, 1995). Patients with hip fractures more often
(Table 2). Reasons for the low vitamin D status of elderly have serum 25(OH)D levels below 50 nmol/l than
subjects are their often modest outdoor activities and the control subjects of this age group (Diamond et al. 1998;
marked decrease in the capacity of human skin to produce LeBoff et al. 1999).
vitamin D in elderly subjects in comparison with younger The results of controlled clinical trials with vitamin D
adults (Holick et al. 1989). The vitamin D status of elderly administration on bone mineral density are inconsistent
Norwegians is, however, more favourable in comparison (Table 3). An increase in bone mineral density was
with elderly subjects from other parts of Europe observed in studies with vitamin D supplementation of
(Table 2), probably due to a higher oral vitamin D intake 10·0, 17·5, and 375 mg/week. In studies with 20 mg vitamin
(see p. 564). The prevalence of serum 25(OH)D levels D/d and 15 mg 25(OH)D/d no improvements were
below 25 nmol/l is only 18 % in Norway and up to 83 % observed. In two out of these latter three studies mean diet-
in Greece (van der Wielen et al. 1995). Nevertheless, Nor- ary Ca intake was relatively low (530 and 570– 740 mg/d)
wegians have mean 25(OH)D levels clearly below (Hunter et al. 2000; Peacock et al. 2000). It may well be
100 nmol/l in winter and in summer. A very low vitamin that the amount of absorbed Ca was still too low to
D status is frequently observed in institutionalized elderly improve bone mineral density. Bone mineral loss at the
subjects (Table 2). 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,
Associations of low vitamin D status with chronic
a long-term randomized large controlled trial has shown
diseases
that combined supplements of vitamin D (20 mg/d) and
The following sections describe associations between low Ca (1 200 mg/d) were capable of preventing non-vertebral
vitamin D status and various chronic diseases. At first, fractures in healthy ambulatory subjects (Chapuy et al.
pathogenesis of the diseases is briefly explained. Then, 1992). The bone density of the proximal femur increased
epidemiological evidence for the vitamin D hypothesis is 2·7 % in the vitamin D3 –Ca group and decreased 4·6 %
presented and available clinical intervention trials are in the placebo group. It seems probable that the anti-frac-
critically reviewed. 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
Osteopathy
coordination, as measured by body sway, and may thus
Severe vitamin D deficiency results in an under-mineraliz- decrease the risk of falling and falling-related fractures
ation of the growing skeleton and in demineralization of (see also p. 555).
the adult skeleton leading to rickets and osteomalacia,
respectively. This is due to the marked suppression in
Myopathy
intestinal Ca absorption and the impairment of Ca bal-
ance. There is now general agreement that an insufficient It has been assumed already at the beginning of the 20th
vitamin D status contributes to osteoporosis of the elderly. century that severe vitamin D deficiency results in a dis-
Low 25(OH)D levels are associated with low Ca absorp- turbed muscle metabolism (Ritz et al. 1980). Animal
tion rates, hyperparathyroidism and increased bone turn- studies have demonstrated that the aktinomyosin content
over leading to bone loss (Ooms et al. 1995; Peacock, of myofibrills is reduced during experimental rickets
1995). In elderly subjects, low circulating 25(OH)D (Stroder & Arensmeyer, 1965). Moreover, vitamin D
levels are associated with a reduced bone mineral density deficiency can impair intracellular Ca metabolism in
at the proximal femur (Ooms et al. 1995; Scharla et al. muscle cells. The Ca content of mitochondria isolated
1996). It should also be mentioned that low bone mineral from vitamin D-depleted chicks is low (Pleasure et al.
density due to an insufficient vitamin D status can reflect 1979) and Ca uptake into the sarcoplasmic reticulum is
some stage of osteomalacia. The densitometric measure- reduced during vitamin D deficiency (Curry et al. 1983).
ments only measure bone mineral content and density, Patients with osteomalacia suffer from muscle weakness
which are low in osteomalacia and osteoporosis. and have low serum levels of muscle enzymes (Ritz et al.
Even the transient decrease in vitamin D status during 1980; Rimaniol et al. 1994). Supplementation with 357 or
the lack of u.v. B irradiation in wintertime can lead to a 1250 mg vitamin D/d or 50 mg 25(OH)D/d for 1 to 2
transient loss of spinal bone mineral density in female sub- months was able to normalize muscle strength in patients
jects (Dawson-Hughes et al. 1991). Recent studies have with myopathy (Rimaniol et al. 1994; Ziambaras &
also demonstrated that even in female adolescents insuffi- Dagogo-Jack, 1997). Sub-clinical myopathy may even
cient 25(OH)D levels are associated with low forearm occur at serum 25(OH)D levels of 10– 50 nmol/l (Peacock,
bone mineral density (Outila et al. 2001). 1995). In line with this assumption, leg extension power
Several risk factors for hip fractures are at least in part was positively correlated with serum 25(OH)D levels in
related to a low vitamin D status. Incidence of hip fractures elderly males and with serum calcitriol levels in the
 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

Change in serum
Duration Initial serum levels levels
of
Study treatment Age 25(OH)D Calcitriol 25(OH)D Calcitriol
Reference design n (years) (years) (nmol/l) (pmol/l) Treatment (nmol/l) (pmol/l) Results

Nordin et al. PC 137 F 2 65–74 62 n.d. 375 mg Vitamin D2/week +68 n.d. Metacarpal cortical bone loss #
(1985)
Dawson-Hughes DBPC 249 F 1 Mean 97* 74* 10 mg Vitamin D/d† 25‡ 0‡ 1 % Less bone loss during
et al. (1991) 62 wintertime v. placebo
Ooms et al. DBPC 48 F 2 Mean 27 111 10 mg Vitamin D/d +35 +4 Change in BMD at femoral
(1995) 80 neck: +1·9 to +2·6 % v. placebo
Dawson-Hughes DBPC 261 F 2 Mean n.d. n.d. 2·5 and 17·5 mg Vitamin D/d n.d. n.d. Change in BMD at femoral
et al. (1995) 63 neck: +1·5 % with 17·5 mg
vitamin D v. 2·5 mg vitamin D
Hunter et al. DBPC 158 F 2 47–70 71 n.d. 20 mg Vitamin D/d +37 n.d. No effects on BMD v. controls
(2000)
Patel et al. DBPC 70 F 2 24–70 68 n.d. 20 mg Vitamin D/d +25 n.d. No effects on BMD v. controls
(2001)
Peacock et al. DBPC 438 F 4 75 60·5 103 15 mg 25(OH)D/d +58 215 to 225 No effects on BMD v. controls
Vitamin D in preventive medicine

(2000) and M
Graafmans et al. PC 81 F 2 81 27 115 10 mg Vitamin D/d +30 +1 Change in BMD +4·4 % and +4·2 %
(1996) 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.
557
558 A. Zittermann

whole group of males and females. The males had mean and resulted in the absence of infectious disease for the fol-
25(OH)D levels of 90 (SD 87·5) nmol/l and the females lowing 6 months. Therapy also normalized the enhanced
had mean 25(OH)D levels of 68 (SD 53) nmol/l (Bischoff alkaline phosphatase and increased Ca serum levels, indi-
et al. 1999b) indicating that a large number of subjects cating that a sub-clinical vitamin D deficiency was respon-
had an insufficient vitamin D status. A recent study has sible for the frequent infections.
brought forward evidence that a low vitamin D status Vitamin D status also seems to be involved in the risk of
also contributes to the pathogenesis of congestive heart tuberculosis (Chan, 2000). Mycobacterium tuberculosis is
failure, a disease resulting in cardiac muscle weakness an intracellular pathogen that resides predominantly
due to impaired myocardial contractility. Circulating within the macrophage. Reduced monocyte-macrophage
levels of NT-proANP, a biochemical indicator of conges- function plays an important role in the pathogenesis of
tive heart failure severity, were inversely correlated with tuberculosis (Davies, 1985). Cross-sectional studies have
serum 25(OH)D levels (r 2 0·16, P, 0·001; Zittermann indicated that patients with tuberculosis have lower
et al. 2003). 25(OH)D levels in comparison with control subjects
Supplemental studies have demonstrated that doses of (Davies et al. 1985, 1988; Chan et al. 1994). Serum
0·5 mg calitriol/d or 10 mg vitamin D/d had no effects on 25(OH)D levels of the tuberculosis patients and the con-
parameters of muscle function (Table 4). A daily sup- trols were 16 and 27 nmol/l, 46 and 69 nmol/l, and 52
plement of very high doses of vitamin D and also doses and 95 nmol/l, respectively. Moreover, the prevalence of
of 20 mg vitamin D/d could, however, significantly tuberculosis is enhanced in nursing-home residents (Woo
improve muscle function in subjects with low initial et al. 1996). In the UK the incidence is high in Asian immi-
25(OH)D levels (Table 4). It should also be mentioned grants and especially in those immigrants living in the UK
that in both intervention trials the 20 mg vitamin D/d was for only a short time. Obviously, Asians are infected in
combined with a daily supplement of 1 200 mg Ca. Prob- their country of origin, where the infection does not lead
ably, the combined effect of 20 mg vitamin D with high to overt disease due to plentiful sunlight and sufficient
doses of oral Ca was responsible for the beneficial effects skin vitamin D synthesis. Migration towards a more north-
in these studies. 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
Infections
with M. tuberculosis can also explain the low incidence
There is mounting evidence for a pivotal role of vitamin D of tuberculosis among Asians born in the UK (Chan,
in the immune system. Monocytes, the leucocytes with the 2000). It has recently been demonstrated that the VDR gen-
highest phagocytosis capacity, continuously exprime the otype at the Taq1 restriction site influences susceptibility to
vitamin D receptor (Bhalla et al. 1983). Calcitriol is able tuberculosis indicating a role of vitamin D in the pathogen-
to induce the differentiation of monocytes into macro- esis of the disease (Wilkinson et al. 2000).
phages (Provvedini et al. 1986). Macrophages represent
the first unspecific defence line of the immune system.
Inflammatory and autoimmune diseases
Calcitriol increases the activity of lysosomal enzymes in
macrophages and facilitate cytotoxic activity by enhancing Experimental studies have demonstrated that calcitriol has
the rate of phagocytosis. This latter effect is mediated by a modulating effect on the specific immune system.
an enhanced expression of specific Fc-surface receptors Briefly, macrophage-derived cytokines induce resting
(Boltz-Nitulescu et al. 1995) and by an increased respirat- T-helper (Th) cells to differentiate into Th0 cells. Under
ory burst (Cohen et al. 1986). Macrophages possess the the influence of additional factors such as exogenous cyto-
enzyme 1a-hydroxylase and are, thus, able to produce cal- kines and co-stimulatory molecules expressed by antigen-
citriol from 25(OH)D (Rigby, 1988). Activity of this presenting cells, these Th0 cells further differentiate into
enzyme is enhanced in activated macrophages leading to Th1 or into Th2 cells. Both T-cell subsets secrete a specific
a marked increase of the local calcitriol concentration cytokine profile. These cytokines are involved in the pro-
(Pryke et al. 1990). liferation and differentiation of T- and B-cells (Lemire
Data relating infectious diseases to vitamin D status are et al. 1985; Provvedini et al. 1989; Müller et al. 1991b).
scanty. However, there is some evidence from epidemiolo- Calcitriol can inhibit the synthesis of mRNA of the macro-
gical data for a link between low vitamin D status and an phages-derived cytokines interleukin (IL)-1, IL-6, IL-12
increased risk for infections. The prevalence of acute res- and tumour-necrosis factor a (TNF-a) (Müller et al.
piratory infections was 81 % in Egyptian infants with nutri- 1991a; D’Ambrosio et al. 1998). Moreover, calcitriol can
tional rickets in comparison with 58 % in the control group decrease the antigen-presenting activity of macrophages
(Lawson et al. 1987). In 500 Ethiopian children with pneu- to lymphocytes by a reduction of the expression of
monia the incidence of rickets was thirteen times higher MHC-II molecules on the cell surface (Rigby et al.
compared with 500 healthy children indicating that 1990). Calcitriol can also suppress the IL-2 secretion of
severe vitamin D deficiency was frequent in the patients Th1 cells (Lemire et al. 1995).
with pneumonia (Muhe et al. 1997). Moreover, Rehman Rheumatoid arthritis. Rheumatoid arthritis is charac-
(1994) has published in a letter the results of a supplemen- terized by the infiltration of T lymphocytes, macrophages
tation study with 150 mg vitamin D/week and 650 mg Ca/d and plasma cells into the synovium, and the initiation of
in children who had previously repeatedly suffered from a chronic inflammatory state that involves overproduction
respiratory diseases. Treatment was performed for 6 weeks of pro-inflammatory cytokines such as TNF-a and
 Vitamin D in preventive medicine 559

IL-6 and a dysregulated Th1-type response. Rheumatoid in the USA (Schwartz, 1992). Exceptions from this general
arthritis patients have elevated levels of C-reactive protein, North to South gradient in the MS prevalence of the
a biochemical indicator of inflammation. Epidemiological Northern hemisphere are some Swiss districts at high alti-
data indicate that more than 60 % of rheumatic patients tude (. 2000 m), Greenland and the costal regions of
have 25(OH)D levels below 50 nmol/l (Aguado et al. Norway. In these regions a low MS prevalence was
2000) and that 16 % have levels in the range of vitamin reported (Dichgans & Diener, 1987; Hayes et al. 1997).
D deficiency (, 12·5 nmol/l; Kröger et al. 1993). In the Results are consistent with the hypothesis that an
general population, the risk for progression of osteoarthritis inadequate vitamin D status is an important pathogenetic
is already enhanced at a serum 25(OH)D level below factor in MS. Annual u.v. B irradiation is more intensive
85 nmol/l and a vitamin D intake below 9·7 mg/d (McAlin- in Swiss districts of high altitude than in regions of low
don et al. 1996). Serum calcitriol levels are reduced in altitudes. In Greenland and at the costal regions of
patients with a high disease activity compared with a low Norway there is a traditionally high consumption of vita-
actual disease activity (Oelzner et al. 1998). Calcitriol is min D-rich fatty fish (Hayes et al. 1997). A study set up
able to markedly suppress disease activity in an animal to investigate bone health in MS patients revealed a preva-
model of rheumatoid arthritis (DeLuca & Cantorna, lence of insufficient serum 25(OH)D levels (, 50 nmol/l)
2001). Intervention trials with 1 mg 1a-vitamin D/d in 77 % of the patients (Nieves et al. 1994). Experimental
could, however, not demonstrate a significant effect on dis- studies have shown that diets high in Ca and calcitriol can
ease outcome in rheumatoid arthritis patients. In contrast, completely suppress the induction of autoimmune ence-
administration of 2 mg 1a-vitamin D/d and also the treat- phalomyelitis, which is a model of MS (Cantorna et al.
ment with relatively high doses of vitamin D and 1996). Moreover, calcitriol can prevent the progression
25(OH)D were able to significant improve pain symptoma- of autoimmune encephalomyelitis when Ca is high, but
tology (Table 5). not when Ca is low in the diet (Cantorna et al. 1999).
While treatment with 1 mg 1a-vitamin D/d resulted only An intervention study in MS patients has demonstrated
in a non-significant decrease in C-reactive protein, IL-6, that daily supplementation with 16 mg Ca/kg body
and TNF-a levels (Hein & Oelzner, 2000), administration weight, 10 mg Mg/kg body weight and 125 mg vitamin
of 2 mg 1a-vitamin D/d was able to significantly reduce D/d for 1– 2 years was able to decrease the relapse rate
serum C-reactive protein levels (Andjelkovic et al. 1999). of MS patients compared with the expected exacerbations
Unfortunately, C-reactive protein and cytokines were not (Goldberg et al. 1986). Several mechanisms have been
measured in the earlier studies performed with 25(OH)D held responsible for the beneficial effects of vitamin D
and vitamin D. in MS including an inhibition of inflammatory T-helper
Inflammatory bowel diseases. Serum concentrations of cells, an inhibition of the production of inflammatory cyto-
25(OH)D levels are low in patients with inflammatory kines by activated macrophages, an enhanced production
bowel diseases such as ulcerative colitis and Crohn’s dis- of anti-inflammatory cytokines, and an anti-proliferative
ease (Jahnsen et al. 2002). Even newly diagnosed patients action in lymphocytes by the expression of VDR (Hayes
have lower 25(OH)D in comparison with controls (Lamb et al. 1997). In line with these assumptions it has recently
et al. 2002). Moreover, geographic variations of inflamma- been demonstrated that vitamin D supplementation is able
tory bowel disease within the USA suggest that the amount to reduce IL-2 mRNA in peripheral blood mononuclear
of vitamin D available may be an important factor influen- cells of MS patients (Cantorna et al. 2001).
cing disease development (Podolsky, 1991; Sonnenberg
et al. 1991). The vitamin D hypothesis has been tested in
Hypertension, cardiovascular diseases and diabetes
an experimental model of IL-10 knockout mice (Cantorna
mellitus
et al. 2000). These animals spontaneously develop symp-
toms similar to those of human inflammatory bowel disease. Hypertension. Essential hypertension is related to several
The IL-10 knockout mice rapidly developed diarrhoea and disturbances in systemic and cellular Ca metabolism.
cachexia and had a high mortality rate when they were Extracellular ionized or ultrafiltrable Ca levels are
made vitamin D-deficient. In contrast, vitamin D-sufficient decreased while intracellular cytosolic Ca concentrations
IL-10 knockout mice did not develop diarrhoea, waste or are increased (McCarron et al. 1987). Dietary Ca intake
die. Moreover, supplementation with vitamin D or calcitriol is often lower (McCarron et al. 1987) and renal Ca loss
significantly ameliorated symptoms (Cantorna et al. 2000). is higher in hypertensive than in normotensive subjects
Multiple sclerosis. Multiple sclerosis (MS) is a (Strazzullo, 1991; MacGregor & Cappuccio, 1993) indicat-
demyellinating disease of the central nervous system that ing a renal Ca leak. Epidemiological studies have demon-
is debilitating and can be fatal (Hayes et al. 1997). Mani- strated a weak inverse association between serum
festation of the disease is typically between the years of 20 25(OH)D levels and diastolic blood pressure in population
and 40. It appears that the pathological demyellinating of groups with mean 25(OH)D levels of 30 –50 nmol/l
the central nervous system is caused by T-cell-mediated (Scragg et al. 1992). Moreover, Afro-Americans have a
autoimmune processes. These alterations are obviously significantly higher prevalence of diastolic hypertension
promoted by a genetic component and by virus infections (Dustan, 1990) and have lower 25(OH)D levels (Harris &
and traumas. The prevalence of MS is nearly zero close to Dawson-Hughes, 1998) compared with white Americans.
the equator and is markedly increased in regions of more In clinical trials, daily administration of 5 mg vitamin D
northern latitudes (Dichgans & Diener, 1987). Moreover, showed no effects on blood pressure in normotensive
there is a North to South gradient of the MS prevalence subjects (Table 6). Some but not all studies have, however,
 560

Table 4. Intervention studies with vitamin D or calcitriol on parameters of muscle function such as muscle strength, body sway, and/or falls

Change in serum
Initial serum levels levels

Study Duration of treat- Mean age 25(OH)D Calcitriol 25(OH)D Calcitriol

Reference design ment (months) n (years) (nmol/l) (pmol/l) Treatment (nmol/l) (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.
A. Zittermann

Table 5. Intervention trials with vitamin D and its metabolites on disease activity in patients with rheumatoid arthritis

Change in serum
Initial serum levels levels

Duration of Age 25(OH) D Calcitriol 25(OH)D Calcitriol

Reference Study design treatment n (years) (nmol/l) (pmol/l) Treatment (nmol/l) (pmol/l) Results

Hein & Oelzner (2000) Open trial 8 weeks 20 26–78 n.d. 95 1 mg 1a-Vitamin D/d n.d. +5 No effects
Yamauchi et al. (1989) DBPC 16 weeks 140 – n.d. n.d. 1 or 2 mg 1a-Vitamin D/d n.d. n.d. No effects
Andjelkovic et al. (1999) Open trial 3 months 19 23–71 n.d. n.d. 2 mg 1a-Vitamin D/d n.d. n.d. Decreased disease activity
Brohult & Jonson (1973) DBPC 1– 2 years 49 18–69 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.
 Vitamin D in preventive medicine 561

demonstrated a blood pressure-lowering effect with 0·75 or and calcitriol compared with a sedentary lifestyle
1·0 mg 1a-vitamin D/d in hypertensive patients (Table 6). (Zittermann et al. 2000). Consequently, the beneficial
Short-term supplementation with 20 mg vitamin D/d (in effect of physical activity may at least in part be explained
combination with a supplement of 1 200 mg Ca/d) was by the improvement in vitamin D status. Physiological
able to significantly reduce diastolic blood pressure. A amounts of unsaturated fatty acids can reduce the binding
reduction in diastolic and systolic blood pressure was of serum calcitriol to the vitamin D-binding protein by
observed in mildly hypertensive patients after 6 weeks of more than 20 % and can thus increase the bioavailability
u.v. B exposure but not after u.v. A exposure (Table 6). of calcitriol. Saturated fatty acids do not show such an
A normalization of the enhanced intracellular Ca levels effect (Bouillon et al. 1992).
seems to be an important measure in order to reduce Diabetes mellitus. The dependence of normal insulin
blood pressure. This can explain the therapeutic effects secretion in pancreatic b-cells on vitamin D has been
of Ca channel blockers in hypertensive patients (McCarron known for several decades. Experimental studies have
et al. 1987). A low adenylate cyclase activity can result in demonstrated that a reduction in vitamin D activity can
a decreased Ca re-uptake into the sarcoplasmic reticulum result in both increased insulin resistance and reduced insu-
(Curry et al. 1974) and can contribute to an accumulation lin secretion (Boucher, 1998). Epidemiological data have
of intracellular free Ca, and to an increase in vascular reac- shown a four- to five-fold higher prevalence of non-insu-
tivity and blood pressure (McCarron et al. 1987). Activity lin-dependent diabetes in dark-skinned Asian immigrants
of the intracellular adenylate cyclase is calcitriol-dependent in comparison with British Caucasians indicating that
(Nemere et al. 1993) and improvement of the activity of low vitamin D status may contribute to the pathogenesis
this enzyme may thus reduce free cellular Ca of diabetes (McKeigue et al. 1992). Moreover, in elderly
concentrations. subjects the subgroup with the lowest tertile of 25(OH)D
Cardiovascular diseases. Dyslipoproteinaemia, dis- levels had a significantly higher blood glucose increase
turbed glucose tolerance, and an increase in blood coagu- and higher blood insulin increase after an oral glucose-tol-
lation factors, blood viscosity, and leucocyte counts are erance test in comparison with the subgroup with the high-
important risk factors for the development of arteriosclero- est tertile of 25(OH)D levels (Baynes et al. 1997). Data
sis (Mendall et al. 1997). There is now increasing evidence indicate that vitamin D insufficiency may result in insulin
that arteriosclerosis is a low-grade systemic inflammatory resistance. Results are in line with the suggestion that
disease. An increase in serum C-reactive protein levels is enhanced levels of TNF-a, a cytokine with is inversely
an important indicator of inflammatory reactions and also related to 25(OH)D and calcitriol (see p. 560), promote
of the risk of developing arteriosclerosis (van Lente, insulin resistance (Hotamisligil & Spiegelman, 1994).
2000). Synthesis of C-reactive protein is regulated by A severe vitamin D deficiency probably results in low
IL-6 and TNF-a (Mendall et al. 1997). Animal studies serum insulin levels indicating reduced insulin secretion
have demonstrated that IL-6 accelerates arteriosclerosis (Boucher, 1998). In uraemic patients, administration of
(Huber et al. 1999). Calcitriol can suppress the secretion 1a-vitamin D was able to improve blood glucose levels
of TNF-a and IL-6 in vitro in a dose-dependent manner and increase serum insulin levels (Table 8). Moreover,
(Müller et al. 1992). We have recently observed an inverse two studies have demonstrated that daily administration
association between TNF-a and 25(OH)D levels in human of 50 mg and 1050 –2125 mg vitamin D/d was able to
subjects (r 0·30, P, 0·01; Zittermann et al. 2003). Epide- reduce blood glucose levels in patients with osteomalacia.
miological investigations brought forward evidence for an In another study, however, there was an increase in blood
inverse association between myocardial infarction and glucose levels in diabetic patients 8– 12 weeks after a
plasma 25-hydroxyvitamin D3 levels (Scragg et al. 1990). single injection of 2500 mg vitamin D compared with the
Moreover, the nadir of 25(OH)D levels in the UK during pre-treatment value (Table 8). It was assumed by the
wintertime (Hegarty et al. 1994) is paralleled by an authors of that study that the failure to correct diabetes
increased cardiovascular morbidity (Douglas et al. 1991). was probably due to the modest increase of 25(OH)D
Since the prevalence of cardiovascular diseases is low in levels of only 25 nmol/l (Boucher et al. 1995).
alpine regions of high altitudes and low temperatures A Norwegian study brought forward evidence that the
(Scragg, 1981), reasons apart from ambient temperature daily intake of cod-liver oil during pregnancy can reduce
must be responsible for the differences in cardiovascular the risk of diabetes in the offspring (Stene et al. 2000).
diseases between different seasons. One factor may be Cod-liver oil has a very high vitamin D content (Table 7).
the low vitamin D availability in winter, while vitamin D In a more recent Finnish investigation, regular vitamin D
availability is high in alpine regions due to intensive supplementation of 50 mg/d during infancy in the 1960s
u.v. B exposure. It is also only an apparent paradox that was associated with a markedly reduction in the risk of
Eskimos have a low risk of arteriosclerosis (Feskens & type 1 diabetes 30 years later in comparison with unsupple-
Kromhout, 1993) although u.v. B irradiation is low in the mented infants (relative risk 0·12). Children suspected of
region they live. The traditional diet of Eskimos is high having rickets during the first year of life had a threefold
in marine fishes and other sea meat (Feskens & Kromhout, increased prevalence of type 1 diabetes in comparison
1993). These foods are very rich in vitamin D (Table 7). with those without such a suspicion (Hyppönen et al.
Physical activity and an increased intake of unsaturated 2001). In Germany, the incidence of type 1 diabetes in
fatty acids are frequently recommended in the prevention adolescents is higher in autumn and winter compared
and therapy of cardiovascular diseases. Physical activity with spring and summer (Statistisches Bundesamt, 1998).
is associated with higher circulating levels of 25(OH)D Autoimmune processes are regarded to play an important
 562

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

Study Duration of Age 25(OH)D Calcitriol 25(OH)D Calcitriol

Reference design n treatment (years) (nmol/l) (pmol/l) Treatment (nmol/l) (pmol/l) Results

Lind et al. (1987) DBPC 26 H 6 months Mean 63 n.d. n.d. 1 mg 1 a-Vitamin D/d n.d. n.d. 29·2 mmHg diastolic blood
pressure
Lind et al. (1988) DBPC 65 H 12 weeks 61– 65 n.d. n.d. 0·75 mg 1a-Vitamin D/d n.d. n.d. 29/ 2 3 mmHg systolic and
diastolic blood pressure
Lind et al. (1989) DBPC 39 H 4 months Mean 51 n.d. n.d. 1 mg 1a-Vitamin D/d n.d. n.d. No difference v. controls
Pan et al. (1993) DBPC 58 N 11 weeks 63– 83 61 n.d. +7 n.d. No effects
A. Zittermann

5 mg Vitamin D3
59 n.d. 5 mg D3+800 mg Ca/d +11 n.d.
Scragg et al. (1995) DBPC 189 N 5 weeks 63– 76 34·5 n.d. 5 mg Vitamin D/d +14 n.d. No effects
Krause et al. (1998) DBPC 18 H 6 weeks 26– 66 58 n.d. u.v.B irradiation +94 n.d. 26/ 2 6 mmHg systolic and
thrice-weekly diastolic blood pressure
Pfeifer et al. (2001) DBPC Elderly 8 weeks 75 26 91 20 mg Vitamin D/d* +40 +36 26 mmHg systolic
women

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.
 Vitamin D in preventive medicine 563

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 für Ernährung 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

role in the pathogenesis of type 1 diabetes. Again, it should intake, with relative risks ranging from 0·67 to 0·85. The
be mentioned that calcitriol has immunomodulatory prop- risk reductions were highest for women who lived in US
erties (see p. 557). Availability of calcitriol in the cell regions of high solar radiation and no reduction was
may thus influence autoimmune processes. The vitamin founds for women who lived in regions of low solar radi-
D hypothesis is also in line with results demonstrating ation (John et al. 1999). Data are in line with experimental
that the risk of type 1 diabetes and of type 2 diabetes is results suggesting that high amounts of vitamin D and diet-
influenced by the VDR genotype at the BmsI restriction ary Ca decrease susceptibility to chemically induced mam-
site (Chang et al. 2000; Ortlepp et al. 2001). mary neoplasia (Carroll et al. 1991).
It should be mentioned that hypertension, cardiovascular Another important observation is that in the USA the
diseases, and diabetes mellitus are often associated with occurrence of prostate cancer and MS have similar geo-
obesity. Obese subjects have an increased risk for low cir- graphical distributions (Schwartz, 1992). The hypothesis
culating 25(OH)D levels (Bell et al. 1985; Wortsman et al. of a vitamin D dependency on prostate cancer has recently
2000) due to the storage of vitamin D and 25(OH)D in adi- been confirmed by a large nested case – control study (Tuo-
pose tissue (Wortsman et al. 2000). The alterations in vita- himaa et al. 2001). In a 13-year follow-up study of about
min D metabolism of obese subjects in comparison with 19 000 middle-aged Finnish men, prostate cancer risk
lean subjects are also associated with functional alterations was highest among the group of younger men (40 – 51
such as elevated PTH levels (Bell et al. 1985; Wortsman years) with low serum 25(OH)D levels. Approximately
et al. 2000). Obesity might thus contribute to insufficient one half of the serum samples had 25(OH)D levels
circulating 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
Cancer
a protective role against prostate cancer only before the
Although carcinogenesis can occur relatively quickly, most andropause, when serum androgen concentrations are
cancers develop over decades making it difficult to perform higher. The lowest 25(OH)D concentrations in the younger
reliable human intervention studies on the association men were associated with more aggressive prostate cancer
between vitamin D and cancer risk. However, there is (Tuohimaa et al. 2001).
evidence that enhanced sunlight exposure is associated Vitamin D is anti-proliferative and promotes cellular
with lower prostate, breast and colon cancer death rates, maturation, induces differentiation and apoptosis in many
while the historical geographical distribution of rickets different cell lines including malignant cells (Feldman
parallels that for these cancer deaths (Guyton et al. 2001). et al. 1995; Guyton et al. 2001). Vitamin D receptors
The strongest epidemiological evidence supporting a have been found in the mammary gland, in the colon and
protective role for vitamin D in colon cancer is from pro- in the prostate (Table 1). Moreover, it is now recognized
spective studies. Inverse associations for vitamin D that colon, breast, and prostate cells also express the 1a-
intake and colon or colorectal cancer with relative risks hydroxylase to form calcitriol from circulating 25(OH)D
ranging from 0·33 to 0·74 have been reported (Bostick (Holick, 2002). It seems clear that vitamin D must be
et al. 1993; Guyton et al. 2001). Moreover, a nested viewed as an important cellular anti-tumour substance.
case – control study based on serum drawn from a cohort
of 25 620 individuals reported that concentrations of
Prevention of vitamin D insufficiency
25(OH)D in the range of 65 –100 nmol/l were associated
with large reductions in the incidence of colorectal Preventive measures have to consider that there is a high
cancer compared with lower 25(OH)D levels (Garland risk of vitamin D insufficiency in the whole population
et al. 1991). during winter and that the elderly population, and
A reduced risk of breast cancer has been observed in the especially institutionalized subjects, are at increased risk
NHANES I epidemiological follow-up study with several for vitamin D insufficiency or even deficiency. Available
measures of sunlight exposure and dietary vitamin D modes of prevention are threefold: increased exposure to
 564

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

Study Duration of Age 25(OH)D Calcitriol 25(OH)D Calcitriol

Reference design n treatment (years) (nmol/l) (pmol/l) Treatment (nmol/l) (pmol/l) Results

Rudnicki & Molsted- Open trial 20 2h n.d n.d. 240 Intravenous infusion n.d. +115 Blood glucose: 0·8 mmol/l
Pedersen (1997) GD of 2 mg calcitriol/m2 # after GTT
Ljunghall et al. (1987) PC 65 3 months 61– 65 93 110 0·75 mg 1a-Vitamin D/d +12 +5 No improvement
IP
Boucher et al. (1995) Open trial 22 8 –12 weeks n.d. 9 n.d. Single intramuscular +25 n.d. Blood glucose,1·8 mmol/l " ;
DP injection of 2500 mg specific insulin, 43 mU/l
Vitamin D " after GTT
Kocian (1992) Open trial 61 6 weeks n.d. n.d. n.d. 1050– 2125 mg Vitamin n.d. n.d. Blood glucose, 1·5 mmol/l
OP D/d and 470 700 mg # after GTT
A. Zittermann

Ca/d
Kumar et al. (1994) Case 1 5 months 65 6·8 30 50 mg Vitamin D/d +46 +88 Blood glucose, 1·6 mmol/l
report HP # ; insulin, 29 mU/l
" after GTT
Türk et al. (1992) PC 31 8 weeks 17– 66 n.d. 44 0·5 mg Calcitriol/d n.d. +103 Blood glucose, 1·1 mmol/l
UP # ; insulin, 78 mIU/l
" after GTT
Allegra et al. (1994) Open trial 17 3 weeks Mean n.d. 44 0·5 mg Calcitriol/d n.d. +37 Blood glucose, 1·1 mmol/l
UP 50 # ; 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.
 Vitamin D in preventive medicine 565

u.v. light; dermal vitamin D application; increased oral vitamin D intakes of 5, 10, 20 and 50 mg/d increase
vitamin D intake. mean serum 25(OH)D levels by 7 –14, 30 – 35, 25– 40,
A general recommendation from health authorities of a and 46 nmol/l respectively. Results suggest that the
higher sunlight exposure of the free-living population increase of 25(OH)D following a vitamin D supplement
during winter may be largely ineffective due to the lack of 10 mg is often too low to maintain a 25(OH)D level
of u.v. B irradiation. In addition, there are valid concerns above 50 nmol/l or even above 100 nmol/l. In line with
about photo-ageing and skin cancer if u.v. B exposure is this assumption mean circulating 25(OH)D levels were
increased, for example, between spring and autumn only 17·5 nmol/l in veiled ethnic Danish Moslem women
(McKenna, 1992). The vitamin D status of elderly people although their estimated daily vitamin D intake was
may be enhanced by skin exposure to artificial u.v. light, 13·5 mg/d (Glerup et al. 2000). Moreover, in Finnish ado-
but provision of fluorescent lighting in wards has resulted lescent girls daily supplementation with 10 mg Vitamin
in inconsistent responses and can be associated with com- D2 was not able to increase serum 25(OH)D levels
plications; namely skin burns, keratoconjunctivitis, and during the winter. Supplementation with 20 mg vitamin
cataracts (McKenna, 1992). D/d resulted in a 25(OH)D level which was only
Similar to the administration of oestrogens, dermal 14 nmol/l higher in comparison with the unsupplemented
application of vitamin D might be a useful individual group (Lehtonen-Veromaa et al. 2002). In Danish perime-
measure to achieve constant levels of this steroid substance nopausal women who took vitamin D supplements at least
during several weeks. However, such a measure has not yet during wintertime, serum 25(OH)D levels were only
been tested in clinical trials. 8·5 nmol/l higher than in non-users (Brot et al. 2001).
Adequate daily oral vitamin D intake could be an easy Together, these data indicate that in the absence of u.v.
and effective measure to maintain a physiological vitamin B exposure the oral vitamin D demand is probably far
D status. Adequate intake values are 5– 10 mg/d (National above the present recommendation of 10 mg/d and may
Nutrition Council, 1999; Deutsche Gesellschaft für be up to 100 mg/d in order to maintain adequate circulating
Ernährung et al. 2000; Health Council of the Netherlands, 25(OH)D levels (Heaney, 2000). Only those traditional
2000) and 15 mg vitamin D/d for elderly subjects with diets with a regular intake of cod-liver oil and/or sea
insufficient skin vitamin D synthesis (Health Council of foods such as salmon, herring, and eel are able to provide
the Netherlands, 2000). In Germany the mean vitamin D such high amounts of vitamin D daily (Table 7). This also
intake is 3 mg/d in females and 4 mg/d in males (Heseker means that intervention trials with oral vitamin D sup-
et al. 1994). In The Netherlands vitamin D intakes are plements must obviously include much higher doses than
also below 5 mg/d (Health Council of the Netherlands, the currently often-used 5 –20 mg/d. Due to the relatively
2000). In middle-aged Finnish females and males mean small increase in serum 25(OH)D levels and relatively
vitamin D intake is 4·7 and 5·6 mg/d respectively (Lam- low Ca absorption rates, vitamin D intakes of 5 – 20 mg/d
berg-Allardt et al. 2001). Norwegians have a high con- alone may be inadequate to significantly improve the
sumption of vitamin D-rich fatty fish (Hayes et al. 1997) amount of absorbed Ca. A simple increase in oral Ca just
and usually consume cod-liver oil during their whole life- as well as a high vitamin D intake can increase the
span. This may explain the ‘relatively’ high 25(OH)D amount of absorbed Ca. This may explain why some
levels in elderly Norwegians during wintertime (Table 2). improvements in fracture prevalence, muscle function
The low vitamin D intake in several European countries and blood pressure have been achieved with daily sup-
is due to the fact that only a few foods are naturally good plements of 20 mg vitamin D in combination with
sources of vitamin D and some fishes alone can substan- 1200 mg Ca/d (Chapuy et al. 1992; Pfeifer et al. 2000,
tially contribute to an adequate nutritional supply of vita- 2001). Nevertheless, it is doubtful whether high oral Ca
min D (Table 7). Moreover, only a few foods are intake alone can beneficially influence intracellular Ca
fortified with low amounts of vitamin D in Europe; for and cytokine metabolism. It is therefore encouraging that
example, margarine, vegetable oil, cereals, breakfast bev- oral doses of vitamin D or 25(OH)D ^ 50 mg/d were
erages, and breads (Lips et al. 1996). The European able to improve the disease outcome in patients with rheu-
Union is therefore supporting a project towards a strategy matoid arthritis (Dottori et al. 1982) and MS (Goldberg
for optimal vitamin D fortification named OPTIFORD et al. 1986). Moreover, administration of 50 mg vitamin
(Andersen et al. 2001). D/d to infants can obviously markedly reduce the preva-
It must be emphasized that currently no recommended lence of type 1 diabetes in later life (Hyppönen et al.
intake level for vitamin D exists. The adequate intake 2001). Data are a further indication that currently used
values are crude estimates in order to prevent vitamin D- oral vitamin D doses are probably much too low in the pre-
dependent diseases such as rickets and osteomalacia. We vention and therapy of vitamin D-related diseases.
are probably ignoring the evidence that a much higher
oral vitamin D intake than 5 –15 mg/d is necessary to main-
Vitamin D intoxication
tain adequate circulating 25(OH)D levels in the absence of
u.v. B irradiation of the skin. Dose– response studies with There are no reports of vitamin D intoxication in healthy
daily doses of oral vitamin D have demonstrated that 10, adults after intensive sunlight exposure. Vitamin D in the
25, 100 and 250 mg vitamin D result in a mean increase skin reaches a plateau after only 15 – 30 min of u.v. B
of circulating 25(OH)D levels of 45, 48, 56, and exposure. Then, vitamin D-inactive substances such as
112 nmol/l, respectively (Vieth, 1999; Vieth et al. lumisterol and tachysterol are produced, which do not
2001a). Data from Tables 3, 4, 6 and 8 indicate that reach the systemic circulation. Thus, the maximum
566 A. Zittermann

25(OH)D level corresponding to an intensive u.v. B that dose. The highest individual 25(OH)D level after
exposure can be regarded as an upper safe level (Fig. 2). administration of 100 mg vitamin D/d was 140 nmol/l
The changes in circulating calcitriol levels during (Vieth et al. 2001a) and was, thus, in the range also seen
intoxication are generally small (Markestad et al. 1987; during intensive u.v. B-exposure.
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- Conclusions
mia (Standing Committee on the Scientific Evaluation of Calcitriol is a very potent steroid hormone and is, on a
Dietary Reference Intakes, Food and Nutrition Board and molar basis, the most effective vitamin D metabolite.
Institute of Medicine, 1997). Hypercalcaemia results Nevertheless, an adequate serum 25(OH)D level is also
primarily from intestinal Ca hyperabsorption and to a necessary to achieve full physiological vitamin D activity.
lesser degree from Ca release from bone (Chesney, Obviously, the serum 25(OH)D level and not the serum
1989). The hypercalcaemia induced by high oral doses of calcitriol level is the best indicator for vitamin D insuffi-
vitamin D can lead to nephrocalcinosis and coronary scler- ciency, adequacy, or toxicity.
osis (Hesse & Jahreis, 1990). Because only a few foods, especially some fatty fishes,
In all cases of vitamin D intoxication 25(OH)D levels naturally contain vitamin D in relevant amounts circulating
were clearly above 200 nmol/l. Levels up to 1000 nmol/l 25(OH)D levels normally largely depend on u.v. B
and more have been observed (Markestad et al. 1987; exposure. In tropical and subtropical regions, where more
Jacobus et al. 1992). All these instances of intoxication than 90 % of human evolution took place, u.v. B irradiation
were the result of an excessive oral intake of vitamin D2 is abundant throughout the year. Reasons for a low vitamin
or vitamin D3. They are the result of an unregulated intes- D status in Europe are: (i) the seasonal lack of u.v. B
tinal vitamin D uptake in association with an uncontrolled irradiation; (ii) low outdoor activities; (iii) the ageing pro-
hepatic 25-hydroxylation leading to high circulating cess leading to a reduced vitamin D synthesis in the skin;
25(OH)D levels. Vitamin D intoxication has been (iv) the low vitamin D content of most foods. Probably,
described in British infants during the late 1940s and the prevalence of a low vitamin D status will increase in
early 1950s after heavy enrichment of dried milk powder future due to the rising number of elderly individuals in
together with vitamin D-enriched cereals and in addition European societies, and due to the migration of dark-
to the recommendation of a daily vitamin D supplement skinned people and veiled women to Europe. The relevance
of 17·5– 20·0 mg (Chesney, 1989). Moreover, the ‘stoss of the frequently low vitamin D status is not completely
prophylaxis’ in the former German Democratic Republic clear. However, there is growing evidence for the contri-
against rickets with intermittent doses as high as 15 mg bution of a circulating 25(OH)D level below 50 nmol/l to
vitamin D2 was associated with symptoms of vitamin D the development of various chronic diseases which are fre-
intoxication such as hypercalcaemia and serum 25(OH)D quent in Western societies. Current estimations for an ade-
levels of several hundred nmol/l (Markestad et al. 1987). quate oral intake are obviously much too low to achieve an
In adults, vitamin D intoxication has been observed after optimal vitamin D status and thus to effectively prevent
the administration of very high therapeutic vitamin D3 chronic vitamin D-dependent diseases.
doses (Lilienfeld-Toal et al. 1978), in association with an
over-the-counter supplement that contained 26 to 430
times the vitamin D3 amount listed by the manufacturer
(Koutka et al. 2001), and in association with an acciden-
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