Vitamin D

Synonym(s): cholecalciferol, ergocalciferol, vitamin D2, vitamin D3

Nutrient group: Vitamine

Sources and physiological effects

Dietary sources
Vitamin D is a fat-soluble vitamin that is relatively stable to heat but can be damaged by exposure to oxygen and light. Nevertheless, preparation losses are negligible, as only a small part of the daily requirement can be covered by the diet. In animal foods, vitamin D is found in the form of cholecalciferol (vitamin D₃) or as provitamin 7-dehydrocholesterol. Higher vitamin D concentrations are found in cod liver oil and fatty fish such as salmon or herring. Smaller quantities can be found in egg yolk, milk and dairy products. Vegetarian sources are insignificant for vitamin D supply. Only yeasts, mushrooms, spinach and some cabbage vegetables contain traces of vitamin D₂ (ergosterol).
Physiological effects
Bone metabolism	Regulation of the calcium and phosphate balance. Calcium transport and absorption from the intestine Promotion of callus formation through differentiation and maturation of chondrocytes Mineralization and hardening of the bone
Circulation	Antithrombotic effect through activation of thrombomodulin Reduction of blood pressure
Pancreas	Maintain beta cell function (insulin secretion) Protection of pancreatic cells against cytokine-induced apoptosis
Immune system	Stimulation of phagocytosis activity Anticarcinogenic properties through induction of apoptosis and suppression of tumor-induced angiogenesis Inhibition of proinflammatory and promotion of anti-inflammatory cytokines
Skin	Antiproliferative effect by influencing the maturation of keratinocytes

Recommended intake

D-A-CH Recommended nutrient intake (Reference values EFSA and NHI )
	Age	With inadequate endogenous synthesis µg/d
Infants (months)
	0-4	10
	4-12	10
Children (years)
	1-4	20
	4-7	20
	7-10	20
	10-13	20
	13-15	20
Teenagers/adults (years)		Women	Men
	15-19	20	20
	19-25	20	20
	25-51	20	20
	51-65	20	20
	> 65	20	20
Pregnancy	20
Breast-feeding	20
Increased need	Infants/infants, aging, malabsorption (chronic inflammatory bowel disease, short bowel syndrome, pancreatic insufficiency), chronic kidney disease with reduction of endogenous synthesis, diseases such as bronchial asthma, COPD, diabetes mellitus, multiple sclerosis
Special groups at risk of deficiency	Vegetarian/vegan food, people with dark skin, residents of old people's and nursing homes, chronic diseases

Statement DGE 2012:

Vitamin D occupies a special position among vitamins, as it is supplied through nutrition and is also produced by humans themselves through exposure to UVB light (sunlight). In the absence of endogenous synthesis, intake through diet with the usual foods is not sufficient to reach the estimate of an adequate intake which ensures the desired supply (25-hydroxyvitamin D serum concentration of at least 50 nmol/l). The difference to the estimated value must be covered by the endogenous synthesis and/or the intake of a vitamin D preparation. With frequent exposure to the sun, the desired supply can be achieved without taking a vitamin D preparation.

Nutrient safety		Vitamin D
UL	Long-term daily intake, where no adverse health effects are expected	100 µg/d = 4000 I.U. (according to EFSA)
NOAEL	Maximum intake, with no observed adverse effect.	250 µg/d (according to EFSA)
Safety	EFSA has looked at the safety of vitamin D.

EFSA Health Claims

Health claims		EFSA opinion
Vitamin D	Contributes to a normal absorption/utilization of calcium and phosphorus Contributes to a normal calcium level in the blood Contributes to the preservation of normal bone Contributes to the preservation of normal teeth Has a function in cell division Contributes to the maintenance of normal muscle function Contributes to a normal function of the immune system

Status according to Austrian Nutrition Report 2012

Vitamin D status in children

Fig. 1: Vitamin D status assessment compared to vitamin D intake in school children (7 - 14 years), by sex

Vitamin D status in adults

Fig. 2: Vitamin D status evaluation compared to vitamin D intake in adults (18 - 64 years), by sex

Vitamin D status in seniors

Fig. 2: Vitamin D status evaluation in comparison to vitamin D intake in seniors (65 - 80 years), by sex

Detailed information

Vitamin D - endogenous synthesis by sunlight

Vitamin D is ingested through food or is formed in the skin from 7-dehydrocholesterol under the influence of UV-B radiation. Cholecalciferol (vitamin D₃) produces the biologically active vitamin D forms, especially calcitriol, during metabolism in the liver and kidneys.¹ The main part of the daily vitamin D requirement must be covered by endogenous synthesis, which depends on the position or angle of incidence of the sun's rays. In the winter months, no vitamin D formation is possible in the skin north of the 42nd degree of latitude in winter. A simple rule of thumb for judging whether the intensity of solar radiation is sufficient for vitamin D self-synthesis is to compare one's shadow with one's body length: if the shadow is longer than one's own, the radiation intensity is too low. This means that no vitamin D synthesis is possible in northern latitudes during the entire winter. But even in summer the radiation is not sufficient after 4pm. Staying outdoors after work doesn't help here. In order to produce vitamin D, it is necessary to go out into the sun during alunch break.

Limiting factors of vitamin D self-synthesis

The body's own formation of vitamin D in the skin is also affected by other influencing factors. These include cold temperatures, advanced age, a dark skin type or the use of sun protection factors. The body's own production is almost completely switched of when skin creams, make-ups or sun milk with a sun protection factor of over 8 are used. The risk groups are mainly persons with low UV exposure such as hospitalized or elderly persons and persons with dark skin color as well as persons who for various reasons do not expose their skin to the sun.^{2, 3, 4} Based on this knowledge, the German Nutrition Society recommends supplementation with vitamin D in the absence of self-synthesis (e.g. during the winter months, bed rest).

Vitamin D is a critical nutrient

The German Nutrition Report 2008 states that 91% of women and 82% of men do not consume sufficient vitamin D in their diet, which is why vitamin D is officially considered a critical nutrient.⁵ A regular supplementation of 20 - 25 μg/d vitamin D is a suitable measure to normalize an insufficient vitamin D status, as it occurs mainly in winter months.⁶ Inadequate vitamin D status is associated with an increased risk of various diseases such as prostate, colon and breast cancer, diabetes mellitus, cardiovascular disease, osteoporosis or multiple sclerosis.⁷ Due to inadequate care in regions with low solar irradiation, a large number of experts recommend a supplementary intake of at least 1000 I.U. vitamin D₃ daily in healthy adults in order to achieve a preventive, ideal Calcidiol serum level of 32-64 ng/ml or 80-160 nmol/l. Although vitamin D₃ can be formed in the skin using UV light, studies show that on average 57% of men and 58% of women do not reach the minimum level of 20 ng/ml – in the winter months even up to 90%. According to current calculations, a targeted improvement in vitamin D status in the German population could be accompanied by healthcare savings of up to 37.5 billion euros per year.⁸

Numerous tissues are vitamin D-dependent

Vitamin D is involved in the regulation of the calcium balance. On the skeletal system, vitamin D increases mineralization by activating osteoblasts and inhibits calcium release by reducing parathyroid secretion of parathyroid hormone.¹ While vitamin D was long regarded as a vitamin needed purely for bone health, an overwhelming number of studies now show that the effect of vitamin D far exceeds the preventive and therapeutic effects for osteoporosis. Current studies show that an inadequate vitamin D status not only increases mortality, but is also an important etiological factor in the pathogenesis of numerous non-skeletal diseases. According to current studies, these include inflammatory bowel diseases, autoimmune diseases, infections as well as cardiovascular, oncological and neurocognitive diseases. Vitamin D unfolds its physiological effects by binding to vitamin D receptors. So far, they have been found in more than 36 cell species.⁸

Lower vitamin D status increases risk of disease

Inadequate vitamin D status is associated with an increased risk of various diseases such as prostate, colon and breast cancer, diabetes mellitus, cardiovascular disease, osteoporosis or multiple sclerosis.³ Studies have shown that the length of illness also correlate with a lowered vitamin D level. In the Biogena vitamin D study, for example, participants with values below 50 nmol/l had an average of 9.2 days of infections in winter, whereas those with values above 50 nmol/l were only ill on 3.4 days due to infection and had therefore statistically significant (p<0.05) shorter illnesses.⁹

Vitamin D and Diabetes mellitus

An optimization of the vitamin D status can probably reduce the risk of developing type 1 diabetes. Finnish newborns who received 2000 I.U./d vitamin D₃ in the first year of life had - over a period of 30 years - a DM-1 risk that was about 80 % lower than that of children on lower doses of supplements.¹⁰Even with impaired glucose tolerance in adulthood, optimization of vitamin D levels improves insulin sensitivity in people who had a previous deficiency. The islet cells of the pancreas require vitamin D for normal insulin secretion. Deficiency may be associated with impaired glucose tolerance, impaired insulin secretion and reduced insulin sensitivity.¹⁰ An increase in vitamin D serum values through supplementation leads to an improvement in insulin secretion in type 2 diabetics of up to 34 %¹² and should possibly be considered in future as an accompanying therapy.¹³

Vitamin D and cancer

Epidemiological studies show that decreased calcidiol levels are associated with increased cancer incidence and mortality.¹⁴In particular, the influence on colon, prostate and breast cancer risk is well documented. For example, low levels of calcidiol and calcitriol are associated with a 5 to 7-fold increased risk of breast cancer. The long-term prognosis in cancer also seems to be improved by an adequate vitamin D level,¹⁵ whereby the interaction with calcium is an additional important factor.¹⁶

Cardiovascular diseases

Vitamin D₃ regulates myocardial calcium homeostasis, cardiac muscle performance and blood pressure. Various studies document an inverse correlation between vitamin D₃ levels and cardiovascular mortality^{17, 18} In a large-scale cross-sectional study, vitamin D deficiency was associated with a 2.8-fold increased risk of death from heart failure and a 5-fold increased risk of sudden cardiac death compared to a good status (calcidiol greater than/equal to 75 nmol/l).¹⁷

Vitamin D and occurrence of infections

A number of studies document the preventive and therapeutic role of vitamin D₃ in respiratory diseases such as influenza or colds. Low calcidiol levels (<75 nmol/l) appear to contribute significantly to the spread of colds, especially in the low light season.^{19, 20} The 2011 Biogena vitamin D study also showed a significant correlation between vitamin D levels and number of sick days: the lower the vitamin D levels, the higher the number of sick days in the previous winter.⁹

Multiple Sclerosis and neurological diseases

For years now, alatitude dependent inverse correlation between UV-B light exposure and MS incidence has been known. Studies showed subclinical vitamin D₃ deficiency (< 50 nmol/l) in 48% of MS patients. Vitamin D appears not only to prevent the development of MS²¹, but also to slow the progression of the disease.²² An increase of the active vitamin D₃-metabolite 25(OH)D3 in serum by 10 nmol/l leads to a reduction of MS-induced disability in women with MS by 19 %.²³In a recent study with 49 MS patients, the influence of high vitamin D doses (14000 I.U./d + 1200 mg calcium/d) on the relapse rate was investigated. Under vitamin D therapy, the relapse rate after one year dropped by 41%. The degree of disability according to the EDSS scale also declined slightly. However, the results were not significant due to the small number of patients. Studies also document the preventive effect of vitamin D on neurological diseases such as depression, Parkinson's or dementia.²⁴In depression, a meta-analysis also found that daily supplementation of more than 2 800 I. E. vitamin D was associated with a reduction in incidence and better treatment of the condition.²⁵

Bone diseases

In osteomalacia and osteoporosis, vitamin D supplementation can significantly reduce bone loss and thus the risk of fracture. A regular supplementation of vitamin D together with calcium shows a maintenance and improvement of bone mineralization, especially in older women and men.^{26, 27}

Musculature

A inadeqaute supply of vitamin D has been shown to lead to impaired muscle function in older people. People with very low vitamin D levels (< 15 ng/ml) benefit especially from vitamin D supplementation.²⁸

Kidney

In the kidney, calcidiol forms the hormonally active calcitriol, which is why normal kidney function is a prerequisite for vitamin D metabolism. In a German study, 80 % of patients with terminal renal insufficiency had a severe vitamin D deficiency.²⁹

Anti-Aging

A good vitamin D status generally seems to reduce the risk of age-related diseases. In addition, studies show that a good vitamin D status is associated with a higher telomere length (= “lifetime clock“ of a cell) regardless of age.²⁹

Vitamin D deficiency and dementia

A worldwide unique study by the University of Australia in collaboration with the National Health and Medical Research Council showed that there is a direct link between dementia and a vitamin D deficiency using genetic tests with data from 294 514 participants from the UK Biobank. They found that low vitamin D levels (25 nmol/L) were associated with lower brain volume and increased risk of dementia. According to the researchers, up to 17% of dementia cases could also be prevented in some populations if everyone had normal vitamin D levels of 50 nmol/L.³⁰

Vitamin D status and medication

It is known that various drug groups can interfere with vitamin D metabolism. Antiepileptic drugs, antituberculotic drugs (isoniazid, rifampicin), corticosteroids (e.g. prednisolone, dexamethasone) and diuretics (thiazides) increase the risk of osteoporotic changes, not least because they inhibit vitamin D formation and activation.³¹

Reference values

Parameters	Substrate	Referece value	Description
25-hydroxy vitamin D₃	Serum/Plasma	50 - 150 nmol/l	Fasting (12h) Main pool of vitamin D₃metabolites in plamsa
1.25-dihydroxy vitamin D₃	Serum/Plasma	Adults 75 - 175 pmol/ Children 100 - 250 pmol/l	Most physiologically active metabolite. Especially renal insufficiency can lead to deficits.
Interpretation
Low values		Vitamin D₃-deficiency, malnutrition, absorption problems, too little UV light
High values		Overdose of vitamin D₃, sarcoidosis, lymphoma
Note on the measurement results
The radioimmunoassay based on a competitive protein binding analysis does not distinguish between 25-hydroxy-vitamin D₃ and 25-hydroxy-vitamin D_2.

Deficiency symptoms

Impact on	Symptoms
General health	Tiredness, weakness, sleep disturbances
Immune system	Increased susceptibility to infections
Bones	Decrease in bone density, rickets, osteopenia With children: Rickets with skeletal deformations, spinal deformations, deceleration of the breakthrough of milk teeth
Cardiovascular system	Calcification of vessels, cardiac insufficiency
Blood	Increase in alkaline phosphatase Insufficient absorption of calcium and phosphate
Nerve system	ECG alterations Tetanic muscle spasms (paw position of hands and feet) In children: increased nervousness and irritability
Glucose metabolism	Reduced insulin secretion and increased risk of type 1 diabetes
Fertility	Fertility problems

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	For the treatment of an insufficient vitamin D status determined by medical diagnosis	2000 I.U.
	Prevention of deficiency during the winter months and in high-risk groups to maintain and normalize vitamin D status	2000 I.U.
	Supportive therapy for vitamin D deficiency and related diseases such as osteomalacia, osteolysis or rickets	2000 I.U.

Pharmacological effects at a high intake	Supportive therapy for cardiovascular disease, low moods, cancer, diabetes, Multiple Sclerosis and for the prevention of dementia	2000 - 4000 I.U.

Administration

General mode of administration
When	Vitamin D as a fat-soluble vitamin should be taken with meals to improve absorption.
Side effects
No side effects are known to date.
Contraindications
Absolute contraindication: Idiopathic hypercalcciuria, hypercalcemia Calcium controlled supplementation: Calcium-containing kidney stones, renal insufficiency, sarcosidosis

Interactions

Drug interactions
Glucocorticoids (e.g. methylprednisolone, dexamethasone)	Lower the level of vitamin D in the body.
Cholesterol-lowering drugs (e.g. Simvastatin)	Vitamin D improves the lipid modulating effect and reduces the risk of myalgia.
Proton pump inhibitors (e.g. Pantoprazole)	Impair the absorption and utilisation of vitamin D.
H₂-blocker (cimetidine)	Cimetidine reduces the conversion of vitamin D to calcidiol.
Antiepileptic drugs (e.g. carbamazepine, lamotrigine, levetiracetam)	Acceleration of vitamin D degradation through enzyme induction and increase in vitamin D excretion
Aromatase inhibitors (e.g. anastrozole, letrozole)	Vitamin D reduces aromatase inhibitors associated myalgia and arthralgia.
Selective estrogen receptor modulators (e.g. tamoxifen)	Combination with vitamin D leads to an increased inhibition of carcinogenesis and has positive effects on bone metabolism.
Estrogens (oral contraceptives, hormone replacement therapy)	Vitamin D can counteract the increased risk of reduced bone density and osteoporosis.
Bisphosphonates (e.g. alendronate)	Therapeutic effect increased by vitamin D.
Vitamin D analogues (e.g. calcitriol)	Dose adjustment of vitamin D due to risk of overdose.
Nutrient interactions
Trace elements	Calcium deficiency leads to an acceleration of vitamin D degradation through enzyme induction. Extremely high doses of vitamin D can lead to an increase in phosphate levels. High phosphate levels can suppress the conversion of calcidiol and calcitriol.

Description and related substances

Description

Fat-soluble vitamin

Related substances

Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are approved. Cholecalciferol is the more active form.

References

¹Hahn, A. et al. Ernährung. Physiologische Grundlagen, Prävention, Therapie. 2006.
²Lappe, J. M. et al. 2007. Vitamin D and calcium supplementation reduces cancer risk. Am J Clin Nutr. 85:1586–1591.
³ Holick, M. F. 1995. Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr. 61(3 Suppl):638S–645S.
⁴Grant, W. B., Holick, M. F. 2005. Benefits and Requirements of Vitamin D for Optimal Health: A Review. Altern Med Rev. 10(2):94–111.
⁵ Max Rubner Institut. Nationale Verzehrsstudie II. Bundesministerium für Ernährung, Landwirtschaft und Verbraucherschutz Deutschland, 2008.
⁶Nelson, M. L. et al. 2009. Supplements of 20 microg/d cholecalciferol optimized serum 25-hydroxyvitamin D concentrations in 80 % of premenopausal women in winter. J Nutr. 139(3):540-6. doi: 10.3945/jn.108.096180.
⁷ Holick, M. F. 2004. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 80(6 Suppl):1678S-88S.
⁸Gröber, U. 2010. Vitamin D3, ein altes Vitamin im neuen Licht. Medizinische Monatsschrift für Pharmazeuten. 33(10): 376-83.
⁹Sinnißbichler, T., Viebahn, I. Vitamin D gesucht – Defizite gefunden. Biogena Studie 2011.
¹⁰ Hyppönen, E. et al. 2001. Inake of vitamin D and risk of type 1 diabetes: a birth cohort study. Lancet. 358: 1500-3.
¹¹ Gröber, U. Orthomolekulare Medizin: Ein Leitfaden für Apotheker und Ärzte, 3. unveränderte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2008.
¹² Borissova, A. M. et al. 2003. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract. 57(4):258-61.
¹³ Aggarwal, A., Kállay, E. 2016. Cross Talk between the Calcium-Sensing Receptor and the Vitamin D System in Prevention of Cancer. Front Physiol. 7:451. doi: 10.3389/fphys.2016.00451.
¹⁴Guyton, K. Z. et al. 2001. Cancer chemoprevention using natural vitamin D und synthetic analogs. Ann Rev Pharmacol Toxicol. 41:421-42.
¹⁵ Lowe, L. C. et al. 2005. Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer. 41:1164-9. doi: 10.1016/j.ejca.2005.01.017.
¹⁶ Mitri, J., Pittas, A. G. 2014. Vitamin D and Diabetes. Endocrinology and Metabolism Clinics of North America. 43(1), 205–232
¹⁷ Pilz, S. et al. 2008. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrin Metab. 93:3927-35. doi: 10.1210/jc.2008-0784.
¹⁸ Dobnig, H. et al. 2008. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 168:1340-9. doi: 10.1001/archinte.168.12.1340.
¹⁹ Aloia, J. F., Li-Ng, M. 2008. Epidemic influenza and vitamin D (letter). Epidemiol Infect. 135:1095-6.
²⁰ Sundaram, M. E., Coleman, L. A. 2012. Vitamin D and Influenza. Advances in Nutrition: An International Review Journal. 3(4): 517-525. doi: 10.3945/an.112.002162.
²¹ Raghuwanshi, A. et al. 2008. Vitamin D and multiple sclerosis. J Cell Biochem. 105(2):338-43. doi: 10.1002/jcb.21858.
²² Smolders, J. et al. 2008. Vitamin D as an immune modulator in multiple sclerosis. A Review. J Neuroimmunol. 194(1-2):7–17.
²³ Kragt, J. J. et al. 2009. Higher levels of 25-hydroxyvitamin D are associated with lower incidence of multiple sclerosis only in women. Mult Scler. 15(1): 9–15.
²⁴ Lemke, D. 2011. Wirkung von Vitamin D auf Nerven und Gehirn. Vitamin D Update an der Charité, Berlin April 2011.
²⁵ Xie, F. et al. 2022. Effect of vitamin D supplementation on the incidience and prognosis of depression: An updated meta-analysis based on randomized controlled trials. Front Public Health. 10:903547
²⁶Cranney, A. et al. 2007. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess. (158):1–235.
²⁷ Dobnig, H. 2011. Wirkung von Vitamin D auf Muskulatur und Fitness. Vitamin D Update an der Charité, Berlin April 2011.
²⁸ Krause, R. 2011. Vitamin D und Niere. Vitamin D Update an der Charité, Berlin April 2011.
²⁹ Richards, J. B. et al. 2007. Higher serum vitamin D concentrations are associated with longer leuocyte telomere lengh in women. Am J Clin Nutr. 86:1420-5. doi:
³⁰ Navale, S. S. et al. 2022. Vitamin D and brain health: an oberservational and Mendelian randomization study. Am J Clin Nutr. nqac107. oi: 10.1093/ajcn/nqac107.
³¹ Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.

References Interactions
¹ Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.
² Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
³ Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.