Reviews in Health Care Vol 2, No 2 (2011)
In the last years we observed an increasing number of publications about the vitamin D, due to its recognised therapeutic actions and to the widespread hypovitaminosis D. In addition to the well known skeletal benefits, vitamin D can have multiple effects on other tissues.
- Muscular apparatus: hypovitaminosis D is associated with myopathy, sarcopenia, muscular strength reduction and increased risk of falls. The vitamin D supplementation increases the muscle functionality indexes.
- Cardiovascular system: low levels of vitamin D are related to increased levels of cardiovascular risk factors, heart failure, stroke, and cardiovascular mortality, while a good vitamin D status is associated with a decreased incidence of cardiovascular diseases.
- Diabetes and metabolic syndrome: a good vitamin D status is related to a decreased incidence of type 2 diabetes and metabolic syndrome; a vitamin D supplementation in the early childhood reduces (nearly 30%) the risk of having type 1 diabetes.
- Cancer: vitamin D deficit is associated with breast, colorectal cancer and melanoma relapses. Low and high levels of 25-hydroxy-vitamin D (25(OH)D) are related to a higher neoplastic mortality.
- Infectious diseases: hypovitaminosis D is associated with higher incidence of upper respiratory tract infections and worse interferon response in chronic hepatitis C. Vitamin D supplementation decreases the risk of having type A influence.
- Rheumatic diseases: in rheumatoid arthritis low serum levels of vitamin D metabolites are related to a higher disease activity, while a good vitamin D status is associated with a higher probability of remission or response to therapy and a lower degree of disability.
- Neurologic diseases: associations between vitamin D deficit and risk of multiple sclerosis, depression, cognitive deficits, and Parkinson’s disease have been reported.
There is evidence of the extraskeletal effects of vitamin D, but most derive from observational studies: clinical trials are required the better to determine the therapeutic role of vitamin D.
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A witness to the great interest and several recent acquisitions on vitamin D is the apparent exponential growth in recent years of publications relating to it. Select the publications in PubMed on the basis of the term "vitamin D" in the title, and is between about 300 articles yearly in the early 2000s to more than 1,300 articles in 2010 (Figure 1). In this review we summarize the results of that search by selecting the main and most recent evidence about the potential effects of vitamin D. Extraskeletal
Figure 1. Histogram on the number of publications on PubMed that contain "vitamin D" in the title. It has been a sharp increase over the last 10 years, with a remarkable peak in 2010
The possible clinical relevance of these studies is amplified by the persistence of widespread vitamin D deficiency conditions, especially in Italy. After the first reports in the 90s , which revealed the significant prevalence of severe vitamin D deficiency in our country, especially in the elderly and in the winter months and not limited to long-term care, the problem has also been confirmed recently [2 , 3] and can get to affect more than 70% of older women. Despite the latitude, which would favor the cutaneous synthesis of vitamin D from sun exposure, as early as 1995  and also recently  it was reported that Italy is among the European countries with the lowest serum 25-hydroxy -vitamin D (25 (OH) D), was an expression of vitamin D deficient. The problem does not spare the men in old age , even if it is later than in females .
Lack of vitamin D is not exclusive of the elderly: has also been described in about 1 / 3 of Italian women in the premenopausal age, especially if obese and residents in the southern regions, even at this age significantly associated with reduced bone mineral density .
The clinical significance of this deficiency may be more relevant under certain conditions. One common condition of vitamin D insufficiency has been described recently in patients with rheumatoid arthritis, based on an Italian multicentre study conducted on a case study among the largest in the world . In this study it was observed that most patients have reduced levels of serum 25 (OH) D and that current approaches with additional 400-800 IU / day are sufficient (Figure 2).
Figure 2. Prevalence of vitamin D insufficiency in patients with rheumatoid arthritis. Modified from 
Extraskeletal effects of vitamin D
In addition to the known skeletal effects of vitamin D, also recently confirmed in terms of ability to reduce the risk of fracture under conditions of deficiency, an adequate calcium intake at doses greater than 700-800 IU / day [10,11], it is not surprising that vitamin D may have systemic effects extraskeletal. There are at least four good reasons for considering that:
receptors for vitamin D are present in many tissues;
Vitamin D controls transcription of many genes;
vitamin D endocrine effects not only calciotropic;
activation of vitamin D is not only in the kidney and also intracrini and paracrine effects.
Physiology, in fact, teaches us that vitamin D receptors are present in several extraskeletal tissues (Table I) .
Cancer cells (if any)
B and T lymphocytes
Pancreatic ? cell
Table I. Almost ubiquitous distribution of receptors for vitamin D
Second should be considered not calciotropic endocrine functions of vitamin D activated in the kidney . In particular, the endocrine activity of 1, 25 (OH) 2D produced in the kidney is expressed not only in skeletal but also controls the renin-angiotensin system and insulin secretion (Figure 3) .
Figure 3. Activation and renal and extrarenal effects intracrini, paracrine and endocrine effects of vitamin D
In third place is known extrarenal activation of vitamin D . In particular it has been documented 1-alpha-hydroxylase activity in cells of the monocyte-macrophage and epithelial , from which intracrine and paracrine functions (Figure 3). In the cells of the monocyte-macrophage activation 1-alpha-hydroxylase of vitamin D leads to the production of a protein called cathelicidin bactericidal functions and paracrine modulation of T and B lymphocytes In some epithelial cells the existence of an alpha-1-hydroxylase allows for the autonomous production of 1,25 (OH) 2D, or calcitriol, which induces the synthesis of proteins that inhibit angiogenesis and induce apoptosis, thereby regulating the cell proliferation. To confirm the importance of intracrine and paracrine function of vitamin D has been estimated that there is mostly the 80-95% of the metabolic consumption of vitamin D daily . Inside the cells with 1-alpha-hydroxylase activity is also provided for 24-hydroxylase activity in order to regulate any endogenous overproduction of calcitriol by the production of an inactive metabolite of vitamin D, said calcitroico acid  . Therefore we understand, from this point of view, as it appears preferable to rely primarily on supplementation with vitamin D rather than its active metabolites in order to exploit all its physiological functions in place and adjusted.
Finally, a further demonstration of the potential extraskeletal effects, was recently reported that vitamin D regulates the expression of more than 200 genes and in particular related to some autoimmune diseases or cancer .
Regarding the possible effects of vitamin D appear on your muscles, it should be noted that receptors for vitamin D are present on muscle cells and that their expression tends to decrease with age . Has long been known that vitamin D can stimulate the production of muscle proteins, but also is able to activate some mechanisms of calcium transport in sarcoplasmic reticulum essential in muscle contraction. Under conditions of hypovitaminosis D were often described pictures of myopathy of proximal muscles of the limbs (eg. Difficulty rising from a chair, functional impotence in bringing your arms above your head), of sarcopenia and reduced muscle strength, with disorders 'balance and leading to an increased risk of falls and thus fractures, especially in old age.
Recently it was observed that vitamin D status also affects the functional recovery in the post-hip fracture : patients with serum 25 (OH) D above 25 nmol / l (or 9 ng / ml) had a better physical performance and a lower risk of falls.
An association between hypovitaminosis D and subsequent physical decline assessed on the basis of some tests of physical performance has been documented particularly in women : the time needed to get up 5 times from a chair or stand up, walk 3 meters and return to sit were significantly worse after 2 ½ years, particularly in female subjects with baseline 25 (OH) D in the lowest quartile.
It was also shown an association between certain genetic polymorphisms of the receptor for vitamin D and risk of falling: in particular there was a significantly increased risk in subjects carrying the polymorphism for B Bsm1 receptor for vitamin D . The increased risk of falls could be attributed to the worst conditions of balance and muscle strength, actually documented in these subjects .
There is evidence that the administration of vitamin D is able to improve muscle strength? In a recent randomized, controlled clinical trial it was observed that daily administration of 1,000 IU of vitamin D in older women improves muscle function in the subgroup of patients weak and slow . A recent meta-analysis showed a trend of borderline significance with regard to the relationship between vitamin D supplementation and functional indexes, particularly at the level of the proximal muscles of the lower limbs , as expected, the significance is largely achieved when you go additional to those most lacking, namely with the baseline serum 25 (OH) D lower than 25 nmol / l.
The importance covered by the myopathy of vitamin D deficiency in causing falls in the elderly has been confirmed by the demonstration of reducing the risk of falls following administration of adequate doses of vitamin D, which was documented in three recent independent meta-analysis [23 -25]. A separate meta-analysis of the Cochrane Collaboration has confirmed that the administration of vitamin D in combination with calcium reduces 29% the incidence of falls . The lack of significance of the result with the only vitamin D can be attributed to the type used in vitamin D (ergocalciferol rather than cholecalciferol or D3 or D2) and the insufficient dosage. In fact it has been observed in another meta-analysis to obtain a significant reduction in risk of falls should be given at least 800 IU of vitamin D daily (or equivalent doses weekly or monthly) and reach levels of 25 (OH) D serum higher and 60 nmol / l, preferably obtained, as is known, using the D3 .
Recently it has been surprisingly reported an increased incidence of falls and fractures, especially in the first 3 months of dosing in one day than 500,000 IU of vitamin D in women over seventy . However, this is generally not subject deficient, and therefore the results of this study are not applicable to reality, such as the Italian elderly population, which is instead known in a consistent lack of vitamin D. Another possible interpretation of the unexpected increase in the incidence of falls observed in this study can be found in the paradoxical potential extraskeletal benefits of vitamin D which, being able to increase the active life of the elderly, would ultimately expose more traumatic to pitfalls. However, currently some uncertainties remain about the maximum desirable levels of vitamin D was recently reported increased risk of the frail elderly syndrome (muscle wasting, weakness, low energy, slowness, low physical activity) under both low and high levels serum 25 (OH) D .
There are many pathogenic mechanisms by which vitamin D deficiency could lead to an increase in cardiovascular problems  (Figure 4).
Figure 4. Possible pathogenesis of the association between vitamin D deficiency and cardiovascular risk
In the presence of low levels of vitamin D were observed on average higher levels of systolic blood pressure, as well as in the presence of other, better-known risk factors for hypertension . The risk of hypertension increases with decreasing levels of 25 (OH) D . Although this meta-analysis of available studies on the effects of administration of vitamin D on blood pressure shows a decreasing trend, although not significant, regardless of dosage or association with calcium . This may derive from inadequate doses and case studies so far investigated. Even with regard to heart rate, an indirect indicator of heart failure, low serum 25 (OH) D act as the best-known cardiovascular risk factors, ie overweight, low physical activity and smoking . It was reported that serum 25 (OH) D could be a marker or modulator of several important functional parameters in patients with heart failure . In hypertensive patients, levels of 25 (OH) D below 15 ng / ml were associated with an increased risk of cardiovascular disease than double  and men with such a lack of vitamin D had a doubled risk of myocardial infarction in the ten subsequent years than those who had normal levels of 25 (OH) D . 3-5 times higher risk of dying from heart failure or sudden cardiac death have been reported in patients with 25 (OH) D below 25 nmol / l compared to those with serum levels above 75 nmol / l, of course, after correction for all other known cardiovascular risk factors . The incidence of stroke was 33% lower in subjects with 25 (OH) D above average .
Please note that an association was observed between low serum levels of vitamin D and mortality [37-40], especially cardiovascular [38-40], and that these levels were also associated with laboratory abnormalities indicative of inflammation, altered cell adhesion and oxidative stress . A meta-analysis also demonstrated that administration of vitamin D can significantly reduce overall mortality . Recent meta-analysis confirmed a significant reduction of more than 30% incidence of cardiovascular disease in people with a good vitamin D , with an obvious negative correlation between relative risk and serum 25 (OH) D [31 ]. However, the meta-analysis is currently feasible only shows a nonsignificant trend in the effect estimate of vitamin D supplementation against cardiovascular events, although this can be clearly attributed to the scarcity of studies available to date and inadequate dosages [ 43]. In January 2010 he was finally initiated a trial (VITAL, Vitamin D and omega-3 trial), sponsored by the National Institutes of Health, in order to assess whether the administration of 2,000 IU / day of vitamin D and / or 1 g of Fish oil (polyunsaturated fatty acids omega-3) are actually able to reduce the risk of heart disease and stroke. Concomitant calcium supplementation does not seem to make a positive contribution in this direction , and indeed has been recently reported that calcium supplementation in the absence of vitamin D increase the risk of myocardial infarction .
Two meta-analysis consensus that a good vitamin D status, evaluated as vitamin D intake  as well as serum 25 (OH) D , is associated with a reduced incidence of diabetes type 2 and metabolic syndrome.
There are so far on the other hand some evidence of the usefulness of supplementation with vitamin D in type 2 diabetes  Although there are eight trials that evaluated the effects of vitamin D supplementation on glycemic parameters, only 2 were classified as being of good quality, the doses used were probably too low, compliance was often poor and only in small subgroups were investigated in serum 25 (OH) D. However, in patients with congestive fasting blood glucose, daily supplementation with 700 IU of vitamin D3 and 500 mg of calcium reduced the anticipated deterioration with age, fasting blood glucose and an index of insulin resistance . It is planning a trial (Evaluation thiazolidinedione Intervention with vitamin D, TIDE) conducted in 16,000 patients with type 2 diabetes who also has among its objectives to evaluate the effects of administration in these patients than 1,000 IU / day of vitamin D3.
With regard to the type 1 diabetes there is a meta-analysis indicates that a reduction of almost 30% of the risk of developing this disease if you take vitamin D supplements in early childhood .
The possibility of some epithelial cells to activate vitamin D, which results in the regulation of intracrina mechanisms involved in the replication and apoptosis, accounts for a number of associations between vitamin D and certain types of cancer. In particular meta-analysis of case-control studies is a clear negative correlation between serum levels of vitamin D and risk of breast cancer [48.49], although not reaching significance for the nested case-control studies [49 ]. The increased risk in a cohort of postmenopausal women was especially evident for values ??of 25 (OH) D below 50 nmol / l . Similar observations are available for cancers of the colon and rectum , which was estimated to reduce incidence by 50% for serum 25 (OH) D above 34 ng / ml . Recently in the European population has been confirmed a lower incidence of almost 30% of colorectal cancers in people with adequate calcium intake that are good values ??prediagnostic of 25 (OH) D . Moreover, in patients with melanoma, those with serum 25 (OH) D greater than about 60 nmol / l to less relapse .
On the relationship between vitamin D status and cancer risk, however, there are reports in the opposite direction. A recent meta-analysis not only showed no relationship between hypovitaminosis D and risk of pancreatic cancer, but reported an increased risk for high levels of 25 (OH) D, greater than 100 nmol / l . The same was also reported increased mortality, and in particular the tumor, both for low serum levels for both high levels of 25 (OH) D . To date there is only one randomized clinical trial that has assessed the effects of vitamin D supplementation on cancer risk: has been reported a significant risk reduction in subjects treated daily with 1,100 IU of vitamin D in combination with calcium, compared to only calcium or placebo .
The potent bactericidal activity of the cathelicidin monocyte-macrophage-induced activation of vitamin D, as well as to justify the historical benefit and solar ultraviolet irradiation against tuberculosis has prompted the analysis of possible correlations between vitamin D status and various conditions infectious diseases, both bacterial and viral infections. In a large American series was actually observed an inverse correlation between the incidence of upper respiratory tract infections and serum 25 (OH) D . The association was particularly evident in patients with COPD or asthma, in which, inter alia, has been recently observed a positive correlation between serum levels of vitamin D and lung function response to corticosteroids . According to a recent major review evidence indicating a potential preventive or therapeutic supplementation with vitamin D regards tuberculosis, viral diseases of the respiratory tract and influenza . Recently in a randomized clinical trial, double-blind placebo was observed that administration of only 1,200 IU of vitamin D3 in children of school age can be reduced by more than 40% the risk of getting influenza A . Under conditions of hypovitaminosis D has also been reported in chronic hepatitis C, a reduced response to interferon treatment  (Table II).
Author, year [ref]
Ginde, 2009 
Measurement of the association between levels of 25 (OH) D and URTI
The levels of 25 (OH) D were inversely associated with recent URTI (p <0.001), assessed by a percentage equal to:
24% for 25 (OH) D <10 ng / ml
20% for 10 ng / ml ? 25 (OH) D <30 ng / ml
17% for 25 (OH) D ? 30 ng / ml
Sutherland, 2010 
Determine the effect of vitamin D on the phenotype and the response to GCs in asthma
In asthma low levels of vitamin D are associated with reduced lung function (22.7 ml increase in FEV1 for each ng / ml increase in vitamin D, p = 0.02), with increased airway hyperresponsiveness (required 1.03 vs 1.92 mg / ml of methacholine to induce a reduction in FEV1 of 20%, p = 0.01) and a reduced response to GC (0.05 times increase of MKP-1 for each ng / ml of vitamin D increase, P = 0.02)
Urashima, 2010 
Determine the effect of vitamin D supplementation on the incidence of influenza A season in school children
The vitamin D3 supplementation in the winter reduces the incidence of influenza A in children of school age (10.8% vs 18.6%, p = 0.04) and incidence of asthma attacks in asthmatic children (2 / 167 vs 12/167, P = 0.006)
Petta, 2010 
To investigate the role of 25 (OH) D in the progression of chronic hepatitis C and virological response to interferon-based therapy
Patients with genotype 1 HCV have serum 25 (OH) D levels (perhaps due to reduced expression of CYP27A1) (p <0.001). Low levels of vitamin D correlate with severe fibrosis and low rates of virologic response to interferon-based therapy
Table II. Summary of recent major studies that have investigated the role of vitamin D in infectious diseases and asthma
25 (OH) D = 25-hydroxyvitamin D; FEV1 = Forced expiratory volume in the 1st second; GC = glucocorticoids; HCV = Hepatitis C Virus, MKP-1 = mitogen-activated protein Kinase Phosphatase-1, URTI = Upper Respiratory Tract Infections
Patients with autoimmune diseases, including many, but not only, of a rheumatic nature, often have serum 25 (OH) D indicative of a serious deficiency and on average lower than those found in healthy controls . it was observed that subjects with greater dietary intake of vitamin D are less exposed to the risk of developing an autoimmune disease such as rheumatoid arthritis , but this has not been confirmed in a subsequent study . The discrepancy is due to the lack of accuracy in assessing the status of vitamin D, both studies estimated on the basis of food intake that is, as noted, only 10-20% of the endogenous vitamin D. Other studies have observed an inverse correlation between serum levels of 1,25 (OH) 2D  or 25 (OH) D  and disease activity in rheumatoid arthritis. It is unclear whether a state of hypovitaminosis D in active rheumatoid arthritis can especially be simply the result of a state of disability associated with impairment in particular exposure to the sun, or be a contributing cause of the inflammation and disability. In an Italian multicentre study of patients with rheumatoid arthritis we observed a positive correlation between vitamin D status and likelihood of remission or response to therapy and a negative correlation with the degree of disability . These correlations remained significant even after adjustment for major determinants of serum 25 (OH) D (sun exposure, body mass index and age). This fact suggests that vitamin D may play a role in the control of disease in rheumatoid arthritis and in alleviating the consequences of disability conditions.
Already in the past, low levels of serum 25 (OH) D were seen to associate with the worsening of coxarthrosis and gonarthrosis, though not always. Recently it was confirmed that men with vitamin D deficiency have double the risk of having radiographic signs of osteoarthritis of the hip  and was documented with nuclear magnetic resonance that the cartilage volume in women with knee arthritis is positively associated with levels serum 25 (OH) D, both at baseline and longitudinally . Please note that receptors for vitamin D are present in human articular chondrocytes and that a lack of vitamin D may impair the ability of the subchondral bone to withstand the traumatic insult.
In some studies it was also noted that low levels of vitamin D, despite adjustment for many covariates as possible, are associated with a significantly increased risk of chronic low back pain  or diffuse , particularly in women, reasons for the moment unclear.
Finally, in systemic lupus erythematosus [71.72] and in systemic sclerosis  vitamin D status appears to influence certain clinical manifestations.
In neurological extremely interesting, even if still uncertain clinical significance are also reports of an association of vitamin D deficiency with risk of multiple sclerosis, depression, cognitive impairment and Alzheimer's disease [74-77].
Implications for further research
There is a clear need for clinical trials that specifically assess the systemic effects of supplementation with vitamin D deficiency conditions. It will not be easy, however, for ethical reasons and lead them to interpret the results, because as of now it seems appropriate to avoid conditions of vitamin D insufficiency, especially considering the low cost and good safety profile of a preventive intervention.
In conclusion, there are many available evidence relating to potential clinical effects of vitamin D. Extraskeletal However you will notice that many of the observations, resulting from observational studies show associations between vitamin D status and pathologies in which you can not even define the role of cause or effect. Furthermore, it seems clear need for clinical trials that specifically assess the systemic effects of supplementation with vitamin D. However, given the serious deficiency Italian state, especially in old age, it appears to me having to pay greater attention to prevention of vitamin D deficiency, taking into account the favorable cost-benefits and potential of the known safety profile. The finding of high prevalence of hypovitaminosis D even in the most recent epidemiological data shows a lack or inadequacy of preventive treatments so far undertaken in this regard.
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