The amount of knowledge and information about the role of vitamin D in the human body has increased in recent years. It is considered certain that vitamin D is essential for the absorption of calcium and thus for the formation and maintenance of strong bones. Moreover, the hormone-like, biologically active form of the vitamin appears to be involved through a specific receptor, which is found in many tissues and organs, in the regulation of hundreds of genes. The activation or deactivation of these genes makes sure that protein synthesis is initiated or suppressed, which among other things plays a role in cell division and growth, DNA modification and repair, as well as controlling the immune function and cardiovascular activity. As a result an adequate supply of vitamin D could be required for a variety of bodily functions, and nutrient deficiencies would promote the emergence of diseases. Studies on the targeted delivery of vitamins for disease prevention have provided inconsistent results, and it is often unclear whether a nutrient deficiency is the cause or the result of a disease.
While new findings have lately regularly been published on the possible links between an insufficient or inadequate supply of vitamin D and an increased risk for developing chronic diseases, reviews and analyses of aggregate study data of varying quality report a lack of definite evidence for these connections. Many researchers disagree about whether intake recommendations for vitamin D in the prevention of multifacto- rial chronic diseases such as cardiovascular diseases and cancer should depend on obtaining clear evidence or whether a specific supply could generally be recommen- ded for people diagnosed with inadequate or deficient vitamin D levels in the blood. However, all scientists to agree that vitamin D can only compensate in the prevention or treatment of chronic diseases and not for the various factors of an unhealthy life- style and thus perform miracles.
The role of vitamin D
Preservation of bone, muscular and dental health
Prevention of inflammatory diseases and autoimmune diseases
Prevention of cardiovascular diseases and cancer
Prevention of mental disorders
Preservation of bone, muscular and dental health
The best documented function of vitamin D is the regulation of calcium and bone metabolism. In skin expo- sed to solar radiation (UV-B light) vitamin D3 (cholecalciferol) forms, which is also included in some foods (such as high-fat species of fish, egg yolks and liver); after its conversion into the storage form 25(OH)vita- min D3, it is transformed into the active form 1,25(OH)2D3 (calcitriol). The active vitamin D3 binds to specific vitamin D receptors of intestinal mucosa and promotes the absorption of calcium, which is essential along with phosphorus for healthy bone formation. Vitamin D also promotes bone mineralization and increases the reabsorption of calcium in the kidneys. Too low vitamin D blood levels can lead to impairment of calcium and phosphate metabolism and thus to bone metabolism disorder: Decreased absorption of calcium from the in- testine causes increased release of calcium from the bones (decalcification), allowing bone density decreases and increased risk of bone fracture. Insufficient bodily supply of vitamin D can thus cause bone loss (osteo- porosis) and bone softening (osteomalacia) in adults and bone deformation and stunted growth (rickets) in children. 25-hydroxyvitamin-D3- serum levels of at least 20–30 ng/ml (50–75 nmol/l) are recommended (1, 2). Supply of vitamin D under this target is classified as vitamin D deficiency, and targeted vitamin supple- ments are recommended for the prevention of bone diseases. Supplementation with vitamin D is recommen- ded for the prevention of rickets in infants during the first months of life (3).
According to the European Agency for Food Safety (EFSA), vitamin D not only contributes to the normal de- velopment of bones and teeth in infants and toddlers, as well as to conservation in the further course of life but also to preservation of normal muscle mass and function, plus increased muscle tone can also have a positive effect on bone density (4). In studies vitamin D deficiency has been linked to reduced muscle stren- gth and impaired control of the muscle function as well as increased tendency to fall as a result and thus increased risk of fractures (5). Consequently a sufficient supply of vitamin D helps, especially in older peo- ple, to prevent falls and fractures (4).
One meta-analysis that included data from 20 randomized controlled trials, however, concluded that supple- mentation with vitamin D, with or without calcium, in elderly subjects would not reduce the number of falls by even 15% (6). As a result, there would be no reason to prescribe vitamin D supplements for fall prevention. Experts noted that this finding stands in contrast to the results of other meta-analyses, like the data analysis of the US Prevention Services Task Force (USPSTF) for example (7) and the Cochrane Collaboration (8), according to which a targeted intake of vitamin D is recommended for the prevention of bone fractures in adults in nursing homes. While very specific recommendations for the use of vitamin D supplements for the prevention of fractures were derived from the USPSTF and Cochrane analyses, the new data analysis focu- ses on the number of falls, which is based on a relatively unusual sequential meta-analysis. Although fractu- res usually result from falls, not all falls result in fractures. The influence of the number of falls as the para- meter for the effectiveness of supplemental vitamin D intake (6) is much less significant than analysis of risk of fall-related fractures (7, 8). Therefore, according to the experts, the results of the new meta-analysis on the existing recommendations for the use of vitamin D supplements to prevent (fall-related) fractures in adults with insufficient vitamin D intakes change nothing.
For synthesis of vitamin D to occur a person must remain under the sun’s rays for a sufficiently long time (15–30 minutes) with at least 25% of skin exposed (such as hands, arms and face), as well as there being a high concentration of UV-B rays. Especially the latter condition is only available during certain months in northern latitudes. Because foods that contain high doses of vitamin D (e.g., fatty fish) are often insufficiently consumed, large parts of the population in the north western hemisphere have to low to poor (less than 25–30 nmol/L) vitamin D levels (9, 10). Since an optimal supply to reach recommended blood concentrations for bone growth or for the preservation of bone health (11,12) can not be achieved by many people, the intake of vitamin D through supplements may be recommended. According to the EFSA, 800 UI (20 µg) of vitamin D should be consumed daily from all sources for the prevention of bone or muscle weakening (4).
The importance of an adequate supply of vitamin D for a healthy calcium and phosphate metabolism is relevant for the formation and maintenance of healthy teeth as well. Thanks to vitamin D, calcium and phosphate are stored in dental bone (dentin) and enamel, where they contribute significantly to the growth
of teeth and the hardness of tooth enamel. A study with expectant mothers has shown that infants whose mothers were well supplied during the pregnancy with vitamin D had much less frequently incomplete or incorrect development of enamel matrix in the embryonic tooth stage (enamel hypoplasia) or developed early childhood cavities far less often (13).
Prevention of inflammatory diseases and autoimmune diseases
It is considered certain that an adequate supply of vitamin D contributes to a normal immune system and a healthy inflammatory response (14). Experimental results indicate that vitamin D activates immune system’s killer cells – the T-cells – and thus enables the fight against pathogens (15). Furthermore, vitamin D seems not only involved in fighting infections but also in reigning in excessive immune reactions, which occur with autoimmune diseases or in organ rejection after transplants. In both cases, activated T cells multiply explo- sively, producing inflammation, which can have devastating consequences for the body. There is ever more evidence to suggest that vitamin D affects the immune system at the genetic level. In a randomized control- led study, subjects who were vitamin D deficient at the beginning of the study received daily doses of 400 IU (10 micrograms) vitamin D or 2,000 IU (50 micrograms) over a period of three months (16). Meanwhile, immune cells were sampled from all participants at the beginning and at the end of the study and gene expression analysis was carried out. The results of the study showed that taking vitamin D resulted in a significant change in the activity of 291 genes, whose functions were related to 160 biological signal path- ways to autoimmune, infectious as well as cardiovascular diseases and cancer. It is assumed that the active form of vitamin D (calcitriol) penetrates into the nucleus, where it bindes to the vitamin D receptor (VDR), which in turn responds with a vitamin A -dependent receptor. The resulting receptor complex can bind to small DNA sequences, which are distributed across the entire genome, and trigger a cascade of molecular interactions that regulate the transcription of certain genes (17, 18).
Increasingly, experimental results indicate that vitamin D plays a role in the innate and acquired immune system, where it acts as an immunomodulator and reduces inflammation. The active form of vitamin D sup- ports the function of helper cells (T cells, white blood cells) of the immune system, suppressing the inflam- matory activity of dendritic cells (immune cells), initiates antibacterial activities of all immune cells and regulates the production of cytokines (proteins regulating cell growth and differentiation) in favor of an anti-inflammatory immune response (19). Targeted intake of vitamin D might be especially beneficial therapeutically for inflammatory bowel disease like ulcerative colitis or Crohn’s disease. Inflammatory syndromes occur in muscle disorders (myopathies) that go hand in hand with muscle atrophy and muscle weakness (20). Calcitriol and receptors distributed over the genome, like the VDR, seem to play a role in the signal transduction of the skeletal as well as the cardial functions. A faulty regulation of the VDR can nega- tively affect muscle metabolism and muscle structure integrity. Further research is needed to determine to what degree vitamin D supplementation can undo inflammation-induced muscle atrophy or prevent it.
Moreover laboratory and animal studies as well as observational studies increasingly indicate a correlation between low vitamin D3 levels and the incidence of autoimmune diseases such as rheumatoid arthritis (often accompanied with cardiovascular problems), multiple sclerosis and diabetes mellitus type 1 and 2 (18, 21– 24). The anti-inflammatory and immunomodulatory properties of calcitriol also seem to be of importance in these chronic diseases.
With regard to the prevention and treatment of infections, especially those of the upper respiratory tract (25) and in particular influenzal infections (26), the findings of experimental, epidemiological and randomized controlled trials indicate that a targeted intake of vitamin D might make a lot of sense (27). Especially in the cold, dark seasons when there is less sunlight, during which vitamin D levels can drop and the immune sys- tem may require support.
Prevention of cardiovascular diseases and cancer
The focal point for preventive effects of vitamin D for heart and cardiovascular health is atherosclerosis. It is assumed that inflammatory processes underlie all stages of atherosclerosis – from the first emergence of a plaque and its growth to rupture and the formation of blood clots. Increasingly narrowing blood vessels are a major cause of high blood pressure and life-threatening events such as a heart attack. The anti-inflammatory properties of vitamin D suggest that it could contribute to prevention or reduction of inflammation on the inside of vascular walls (endothelium) and thereby aid in the treatment of atherosclerosis. Low vitamin D levels seem to occur in conjunction with increased inflammation (28) and greater risk of atheroscleroses and heart attack. In addition, low vitamin D levels in the blood could be associated with an increased risk of developing severe forms of coronary heart disease: For subjects with vitamin D deficiency, the disease rate was almost double that of participants with normal blood levels (29). Vitamin D deficiency has also been linked to a 20% higher emergence of severe forms of coronary heart disease. A randomized controlled trial with patients who had suffered an acute heart attack showed that subjects who received daily supplements of 4000 IU of vitamin D for five days, the increase of inflammatory cytokines and other parameters in the blood (such as adhesion molecules) could be reduced after the coronary event (30). Diabetics have an increased risk of developing cardiac and vascular diseases. This could possibly be countered in type 2 diabetic patients with vitamin D doses that work against the formation of atherosclerotic plaque, as a clinical study has shown (31). Randomized controlled studies clearly demonstrating a preventive effect of vitamin D against atheros- clerosis and its consequences have yet to be carried out (32), as are studies that demonstrate a possible positive effect of vitamin D against inflammation-induced heart failure (20).
Inflammatory processes are also involved in the development of cancers in addition to a variety of other factors. Since in addition to its anti-inflammatory effect vitamin D crucially contributes to well functioning cell division, the vitamin may be effective against cancer development (14). Studies have observed a link bet- ween low vitamin D levels and an increased likelihood of prostate cancer (33) or esophageal cancer (34). In addition daily intakes of 4000 IU of vitamin D3 or maintaining an average vitamin D level of 82 nmol/l in serum could significantly reduce the risk of a prostate cancer diagnosis by biopsy (35). While findings of in vitro and in vivo studies and epidemiological studies of various types of cancer, such as colorectal and breast cancer, indicate a possible reduction of cancer risk (36) and an increase in the survival rate of cancer pati- ents (37), randomized controlled trials have not yet given confirmation.
In three meta-analyses the results of previously performed meta-analyses (38) and (39) randomized con- trolled studies were compiled partly in combination with the results of observational studies (38, 40). A data analysis concluded that among the numerous targeted vitamin D intakes that have the potential to influence health parameters, only one (positive influence of birth weight of the child through raising the vitamin D levels of the mother in late-stage pregnancy) had sufficient probative force; while potentially positive impact was shown, for example, on birth weight in general as well as the prevention of dental cavities in children (38). The second study assessed the results of several studies on vitamin D in the prevention of cardiovas- cular diseases, cancer and resulting deaths in adults in a sequential meta-analysis (39). The results were assessed with reference to their authenticity by competent researchers as insufficient: Vitamin D intakes by means of dietary supplements (with and without calcium) showed a reduction of disease risk by not more than 15% for all indicators. Finally, a third overview summed up the results of numerous studies on the possible link between vitamin D blood concentrations of subjects and their risk of death, cardiovascular disease or cancer (40). The meta-analysis showed a connection between low vitamin D levels and increased risk of mortality. The use of nutritional supplements with vitamin D3 (but not with vitamin D2) led to a reduction in the risk of death in general. In comments (9, 10) referring to the studies, experts ensure that the conclusions are at odds with the comprehensive analyses and evaluations of the Institute of Medicine, whose report indicates the sufficiently proven need for 25-hydroxyvitamin D levels to be between 30 and
50 nmol/L for maintaining bone health (11) a value that many people could not achieve without supplemental vitamin D intakes. As a target for maintaining bone health, vitamin D values over 50 nmol/L were recom- mended (12). A boost in vitamin D intake ultimately only makes sense if deficits exist. Unfortunately, say the experts, the majority of studies failed to check the subjects with regard to their nutritional status at the beginning of the study. This was the case, they say, for almost all the studies that were included in the above-mentioned meta-analysis. General conclusions based on meta-analyses are problematic, because the results of various studies (various study designs, study periods, groups of participants and used doses of vitamin D) are pooled together and distorted. Added to that is the fact that the randomized placebo-control- led study design borrowed from the evidence-based medicine – the gold standard for drug testing – is quite limited for research on nutrients.
Prevention of mental disorders
Both the vitamin D receptor and an enzyme that transfers vitamin D into its active form, can be found in many regions of the brain, where they seem to affect the metabolism of neurotransmitters (dopamine, epinephrine, norepinephrine and serotonin). Experimental findings suggest that vitamin D could counteract a lack of dopamine and serotonin in the brain and thus fight depression (41). Low vitamin D levels apparently go hand in hand with an increased risk of developing depressive symptoms (42). Although the underlying mechanisms of this relationship still require ongoing exploration, two clinical studies have shown that vitamin D supplementation could help reduce depressive symptoms (43, 44). From daily vitamin D intakes of 800 IU, effects were observed that were comparable to anti-depressant medications, along with an increase of vitamin D levels. There is more evidence that also showed that women whose vitamin D levels were too low during pregnancy may have increased risk of postnatal pregnancy depression (45).
Current research has identified three genes that are abnormally expressed in cases of autism and which are regulated directly by vitamin D (46). Also low levels of the hormone oxytocin are measured in autistic children. Oxytocin contri- butes to the development of social behavior and seems to be controlled directly by vitamin D. In addition, recent studies have pointed out a possible connection between optimal vitamin D blood levels (60–80 ng/ml) and better quality sleep, less nocturnal insomnia as well as tiredness during the day (47). Further studies are needed to gain more knowledge about the detailed mechanisms that may be responsible for the beneficial effects of vitamin D.