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Vitamin D

Updated on 15th December 2008 by Dr Charles Tweed

Intro
Vitamin D, and in particular Vitamin D3 or cholecalciferol, has received a massive increase in scrutiny and coverage in the last couple of years. It has long been known that adequate Vitamin D levels are required to prevent osteomalacia and rickets [3], but there is a wealth of data emerging about vitamin D’s role in other processes [2]. Vitamin D Receptors have been found in over 200 [2] different cell lines and it is clear that it has important modulating effects in:

Bone health. [3]
Auto-immune disorders. [5, 9, 11]
Multiple sclerosis (MS). [4, 6, 7, 8]
Cardiovascular disease and high blood pressure. [17, 18, 19, 20]
Numerous cancers. [12, 13, 14, 15, 16]
Diabetes. [21, 22]
Psoriasis. [10, 11]
Quite possibly other common health problems. [1, 2]

The biochemistry and related pathways of Vitamin D metabolism is complex, and it is probably unnecessary to spell it out here, but if interested can be found here. In short, you can either get Vitamin D from exposure to sunlight or from your diet. The only food group that contains decent levels of vitamin D are fish, and once again, it’s the oily fish that are the winners:

Herring.
Sardines.
Salmon.

If you live in North America, then you also consume vitamin D in your milk and dairy products. In Europe and the rest of the world you probably don’t and are at risk of having a vitamin D deficiency. The other dietary source is fortified breakfast cereals. Most people’s diet provides inadequate vitamin D. The RDI for adults is 400-800Iu for those under 50 and 600-1200iu for those over. There is a significant body of opinion that is looking to raise this level for the reasons outlined below. Obviously, you are more likely to have a vitamin D deficiency if you do not get exposure to the sun, either because you live in England, or because you cover up for social, religious or fashion reasons. Unfortunately, exposing your skin to UV radiation comes with some negatives:

Increased risk of skin damage and photo-aging.
Increased risk of skin cancers.
Public ridicule if you haven’t been to the gym much and have a fondness for cake and pies.

Given these negatives, it is probably preferable to increase one’s consumption through supplementation. The active ingredient is best given as vitamin D3 or calcitriol. This has been extensively studied and is known to be safe with minimal side effects.

Please see the Google Scholar links below for dynamic, constantly updating data of recent studies so that you can research Vitamin D's benefits for yourself.

Bone health.

Auto-immune disorders

Multiple sclerosis (MS).

Cardiovascular disease and high blood pressure.

Numerous cancers

Diabetes

Psoriasis.

The science
The case for Vitamin D and calcium consumption and maintaining bone mass has been established for many years. This is particularly valid for women heading into the menopause and the both sexes over the age of 60 [3].

Vitamin D is one of the most searched for supplements on the internet, and the rate of searching is increasing. It is being implicated in all sorts of pathologies and perhaps the easiest way of looking at this is to see what happens if you breed a mouse without any vitamin D receptors [1]. I have no idea how hard this must have been but it sounds very tricky. Anyway, here is what happens:

All their hair falls out (alopecia).
They develop a host of auto-immune diseases, particularly:
- Inflammatory bowel disease (crohn’s and ulcerative colitis).
- Type I diabetes.
They develop an increased risk of developing a wide range of cancers.
They also develop cardiovascular problems such as:
- High blood pressure.
- Heart failure.
- Venous thrombo-embolic disorders (blood clots).

Recent media attention has been directed primarily at MS, but it could easily have been any number of auto-immune diseases such as rheumatoid arthritis, type I diabetes or systemic lupus erythematosus [4, 5, 6, 9].

MS is a terrible condition, primarily affecting women, which causes progressive loss of neurological function. The two main theories behind it are the hygiene hypothesis (lack of exposure to environmental antigens causes the immune system to attack itself through boredom) and the sunlight/vitamin D hypothesis, although they are not mutually exclusive. If you look at the incidence of MS it gets more common the further from the equator you get. In addition if you measure the level of vitamin D in the bloodstream, people who get bad and frequent attacks of MS have much lower levels of Vitamin D than controls [7]. Similar findings have been found for type I Diabetes, rheumatoid arthritis and SLE. There is good theoretical reasons why increasing Vitamin D would decrease the chances of developing MS (and other auto-immune disorders) and also decrease the severity and frequency of relapses, if you are unfortunate enough to develop it [8].

The second major breakthrough has been the discovery of associations between vitamin D consumption and the risk of developing cancers. Most work has been done on colon cancer [14] , breast cancer [12, 15] and prostate cancer [13, 16]. It is fair to point out that not all studies have supported a clear association between a reduced vitamin D consumption and an increased risk of developing these cancers, but the majority have. Given the increased level of understanding that vitamin D exerts on the immunomodulating systems, this should not be an unexpected finding. The exact relationship will become clearer over time but we are confident there will be a role for increasing vitamin D RDIs because of it.

As we age the cardiovascular system becomes less flexible and more rigid. Another feature is that it becomes calcified. Both of these pathologies have recently been linked to low vitamin D levels. Not only that, but there are also associations with, high blood pressure, heart failure and kidney failure [17, 18, 19, 20]. There are vitamin D receptors on all of the cells involved with these illnesses and in the lab at least, these effects can be mollified by correcting low vitamin D levels. Intervention studies, to date, have not been performed, but watch this space because they will be coming soon.

Safety
Lastly, is the consideration of side effects and potential negative effects. Fortunately we are on good solid ground, because we have rock solid evidence from multiple studies, to support us. As long as you do not take it in excess of 2,000iu per day the chances of any side effects are vanishingly rare. Allergy to vitamin D has been reported as has a slight increase in daytime sleepiness, but that’s about it. It is safe in pregnancy and breast feeding at normal RDIs of 400-600iu per day.

aging-management.com Buyer's Guide and Recommendation
We recommend consuming more than the current RDIs of vitamin D, given it’s lack of side effects, safety profile and encouraging list of benefits: for adults we suggest 1000iu of vitamin D per day, increasing to 2,000iu per day for post menopausal women and men over 60.

References:

(Back) Vitamin D and human health: lessons from vitamin D receptor null mice. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. Katholieke Universiteit Leuven, Laboratory of Experimental Medicine and Endocrinology, Herestraat 49, O&N 1 bus 902, 3000 Leuven, Belgium. Roger.Bouillon@med.kuleuven.be The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], can now be better evaluated by critical analysis of mice with engineered deletion of the vitamin D receptor (VDR). Absence of a functional VDR or the key activating enzyme, 25-OHD-1alpha-hydroxylase (CYP27B1), in mice creates a bone and growth plate phenotype that mimics humans with the same congenital disease or severe vitamin D deficiency. The intestine is the key target for the VDR because high calcium intake, or selective VDR rescue in the intestine, restores a normal bone and growth plate phenotype. The VDR is nearly ubiquitously expressed, and almost all cells respond to 1,25-(OH)(2)D exposure; about 3% of the mouse or human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system, suggesting a more widespread function. VDR-deficient mice, but not vitamin D- or 1alpha-hydroxylase-deficient mice, and man develop total alopecia, indicating that the function of the VDR and its ligand is not fully overlapping. The immune system of VDR- or vitamin D-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases such as inflammatory bowel disease or type 1 diabetes after exposure to predisposing factors. VDR-deficient mice do not have a spontaneous increase in cancer but are more prone to oncogene- or chemocarcinogen-induced tumors. They also develop high renin hypertension, cardiac hypertrophy, and increased thrombogenicity. Vitamin D deficiency in humans is associated with increased prevalence of diseases, as predicted by the VDR null phenotype. Prospective vitamin D supplementation studies with multiple noncalcemic endpoints are needed to define the benefits of an optimal vitamin D status.
(Back) Mol Aspects Med. 2008 Dec;29(6):361-8. Epub 2008 Sep 2. The vitamin D deficiency pandemic and consequences for nonskeletal health: Mechanisms of action. Holick MF. Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin and Bone Research Laboratory, Boston University Medical Center, Boston, MA, United States. Vitamin D, the sunshine vitamin, is important for childhood bone health. Over the past two decades, it is now recognized that vitamin D not only is important for calcium metabolism and maintenance of bone health throughout life, but also plays an important role in reducing risk of many chronic diseases including type I diabetes, multiple sclerosis, rheumatoid arthritis, deadly cancers, heart disease and infectious diseases. How vitamin D is able to play such an important role in health is based on observation that all tissues and cells in the body have a vitamin D receptor, and, thus, respond to its active form 1,25-dihydroxyvitamin D. However, this did not explain how living at higher latitudes and being at risk of vitamin D deficiency increased risk of these deadly diseases since it was also known that the 1,25-dihydroxyvitamin D levels are normal or even elevated when a person is vitamin D insufficient. Moreover, increased intake of vitamin D or exposure to more sunlight will not induce the kidneys to produce more 1,25-dihydroxyvitamin D. The revelation that the colon, breast, prostate, macrophages and skin among other organs have the enzymatic machinery to produce 1,25-dihydroxyvitamin D provides further insight as to how vitamin D plays such an essential role for overall health and well being. This review will put into perspective many of the new biologic actions of vitamin D and on how 1,25-dihydroxyvitamin D is able to regulate directly or indirectly more than 200 different genes that are responsible for a wide variety of biologic processes. PMID: 18801384 [PubMed - in process]
(Back) Evid Rep Technol Assess (Full Rep). 2007 Aug;(158):1-235.Links Effectiveness and safety of vitamin D in relation to bone health. Cranney A, Horsley T, O'Donnell S, Weiler H, Puil L, Ooi D, Atkinson S, Ward L, Moher D, Hanley D, Fang M, Yazdi F, Garritty C, Sampson M, Barrowman N, Tsertsvadze A, Mamaladze V. OBJECTIVES: To review and synthesize the literature in the following areas: the association of specific circulating 25(OH)D concentrations with bone health outcomes in children, women of reproductive age, postmenopausal women and elderly men; the effect of dietary intakes (foods fortified with vitamin D and/or vitamin D supplementation) and sun exposure on serum 25(OH)D; the effect of vitamin D on bone mineral density (BMD) and fracture or fall risk; and the identification of potential harms of vitamin D above current reference intakes. DATA SOURCES: MEDLINE(R) (1966-June Week 3 2006); Embase (2002-2006 Week 25); CINAHL (1982-June Week 4, 2006); AMED (1985 to June 2006); Biological Abstracts (1990-February 2005); and the Cochrane Central Register of Controlled Trials (2nd Quarter 2006). REVIEW METHODS: Two independent reviewers completed a multi-level process of screening the literature to identify eligible studies (title and abstract, followed by full text review, and categorization of study design per key question). To minimize bias, study design was limited to randomized controlled trials (RCTs) wherever possible. Study criteria for question one were broadened to include observational studies due to a paucity of available RCTs, and question four was restricted to systematic reviews to limit scope. Data were abstracted in duplicate and study quality assessed. Differences in opinion were resolved through consensus or adjudication. If clinically relevant and statistically feasible, meta-analyses of RCTs on vitamin D supplementation and bone health outcomes were conducted, with exploration of heterogeneity. When meta-analysis was not feasible, a qualitative systematic review of eligible studies was conducted. RESULTS: 167 studies met our eligibility criteria (112 RCTs, 19 prospective cohorts, 30 case-controls and six before-after studies). The largest body of evidence on vitamin D status and bone health was in older adults with a lack of studies in premenopausal women and infants, children and adolescents. The quality of RCTs was highest in the vitamin D efficacy trials for prevention of falls and/or fractures in older adults. There was fair evidence of an association between low circulating 25(OH)D concentrations and established rickets. However, the specific 25(OH)D concentrations associated with rickets is uncertain, given the lack of studies in populations with dietary calcium intakes similar to North American diets and the different methods used to determine 25(OH)D concentrations. There was inconsistent evidence of an association of circulating 25(OH)D with bone mineral content in infants, and fair evidence that serum 25(OH)D is inversely associated with serum PTH. In adolescents, there was fair evidence for an association between 25(OH)D levels and changes in BMD. There were very few studies in pregnant and lactating women, and insufficient evidence for an association between serum 25(OH)D and changes in BMD during lactation, and fair evidence of an inverse correlation with PTH. In older adults, there was fair evidence that serum 25(OH)D is inversely associated with falls, fair evidence for a positive association with BMD, and inconsistent evidence for an association with fractures. The imprecision of 25(OH)D assays may have contributed to the variable thresholds of 25(OH)D below which the risk of fractures, falls or bone loss was increased. There was good evidence that intakes from vitamin D-fortified foods (11 RCTs) consistently increased serum 25(OH)D in both young and older adults. Eight randomized trials of ultraviolet (UV)-B radiation (artificial and solar exposure) were small and heterogeneous with respect to determination of the exact UV-B dose and 25(OH)D assay but there was a positive effect on serum 25(OH)D concentrations. It was not possible to determine how 25(OH)D levels varied by ethnicity, sunscreen use or latitude. Seventy-four trials examined the effect of vitamin D(3) or D(2) on 25(OH)D concentrations. Most trials used vitamin D(3), and the majority enrolled older adults. In three trials, there was a greater response of serum 25(OH)D concentrations to vitamin D(3) compared to vitamin D(2), which may have been due to more rapid clearance of vitamin D(2) in addition to other mechanisms. Meta-analysis of 16 trials of vitamin D(3) was consistent with a dose-response effect on serum 25(OH)D when comparing daily doses of <400 IU to doses >/= 400 IU. An exploratory analysis of the heterogeneity demonstrated a significant positive association comparable to an increase of 1 - 2 nmol/L in serum 25(OH)D for every 100 additional units of vitamin D although heterogeneity remained after adjusting for dose. Vitamin D(3) in combination with calcium results in small increases in BMD compared to placebo in older adults although quantitative synthesis was limited due to variable treatment durations and BMD sites. The evidence for fracture reduction with vitamin D supplementation was inconsistent across 15 trials. The combined results of trials using vitamin D(3) (700 - 800 IU daily) with calcium (500 - 1,200 mg) was consistent with a benefit on fractures although in a subgroup analysis by setting, benefit was primarily in elderly institutionalized women (fair evidence from two trials). There was inconsistent evidence across 14 RCTs of a benefit on fall risk. However, a subgroup analysis showed a benefit of vitamin D in postmenopausal women, and in trials that used vitamin D(3) plus calcium. In addition, there was a reduction in fall risk with vitamin D when six trials that adequately ascertained falls were combined. Limitations of the fall and fracture trials included poor compliance with vitamin D supplementation, incomplete assessment of vitamin D status and large losses to follow-up. We did not find any systematic reviews that addressed the question on the level of sunlight exposure that is sufficient to maintain serum 25(OH)D concentrations but minimizes risk of melanoma and non-melanoma skin cancer. There is little evidence from existing trials that vitamin D above current reference intakes is harmful. In most trials, reports of hypercalcemia and hypercalciuria were not associated with clinically relevant events. The Women's Health Initiative study did report a small increase in kidney stones in postmenopausal women aged 50 to 79 years whose daily vitamin D(3) intake was 400 IU (the reference intake for 50 to 70 years, and below the reference intake for > 70 years) combined with 1000 mg calcium. The increase in renal stones corresponded to 5.7 events per 10,000 person-years of exposure. The women in this trial had higher calcium intakes than is seen in most post-menopausal women. CONCLUSIONS: The results highlight the need for additional high quality studies in infants, children, premenopausal women, and diverse racial or ethnic groups. There was fair evidence from studies of an association between circulating 25(OH)D concentrations with some bone health outcomes (established rickets, PTH, falls, BMD). However, the evidence for an association was inconsistent for other outcomes (e.g., BMC in infants and fractures in adults). It was difficult to define specific thresholds of circulating 25(OH)D for optimal bone health due to the imprecision of different 25(OH)D assays. Standard reference preparations are needed so that serum 25(OH)D can be accurately and reliably measured, and validated. In most trials, the effects of vitamin D and calcium could not be separated. Vitamin D(3) (>700 IU/day) with calcium supplementation compared to placebo has a small beneficial effect on BMD, and reduces the risk of fractures and falls although benefit may be confined to specific subgroups. Vitamin D intake above current dietary reference intakes was not reported to be associated with an increased risk of adverse events. However, most trials of higher doses of vitamin D were not adequately designed to assess long-term harms. PMID: 18088161 [PubMed - indexed for MEDLINE]
(Back) Nutr Rev. 2008 Oct;66(10 Suppl 2):S135-8. Vitamin D and multiple sclerosis: an update. Cantorna MT. The Center for Immunology and Infectious Disease, Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. mxc69@psu.edu Observational studies document a positive relationship between vitamin D from the environment (sunlight or diet), circulating vitamin D status, and improved symptoms or prevention of multiple sclerosis (MS). Experimental animal models of MS reproduce the beneficial effects of vitamin D and 1,25(OH)(2)D(3). The geographical distribution of MS can be explained by both the hygiene hypothesis and the vitamin D hypothesis. It therefore seems more likely that both hypotheses may be correct and that there are interactions between multiple environmental factors like vitamin D and the rate of infection that might explain the etiology of MS. The effects of vitamin D on the immune system and in the CNS have begun to be described and there is some information on the mechanisms underlying the effects of vitamin D in MS. A need exists for better understanding of the interactions of the environmental factors on MS, communication with the physicians treating MS patients as to the benefits of vitamin D, and clinical interventions with both vitamin D and analogs of 1,25(OH)(2)D(3). PMID: 18844840 [PubMed - in process]
(Back) Curr Opin Rheumatol. 2008 Sep;20(5):532-7.Click here to read Links Vitamin D in systemic lupus erythematosus. Kamen D, Aranow C. Medical University of South Carolina, USA. PURPOSE OF REVIEW: There is growing interest in the contribution of vitamin D deficiency to autoimmunity. It is therefore timely to review the immunologic actions of vitamin D and the evidence linking vitamin D deficiency to autoimmune disease in animal models and to systemic lupus erythematosus in epidemiologic studies. RECENT FINDINGS: A number of recent studies have highlighted the association between systemic lupus erythematosus and vitamin D deficiency. Vitamin D deficiency skews the immunologic response towards loss of tolerance. Adding vitamin D in vitro reverses immunologic abnormalities characteristic of systemic lupus erythematosus. SUMMARY: Multiple systemic lupus erythematosus cohorts have low vitamin D levels. The physiologic and clinical consequences of vitamin D deficiency in systemic lupus erythematosus are not entirely known. Prospective studies of vitamin D in systemic lupus erythematosus are limited, but most cross-sectional studies show an inverse relationship between levels of vitamin D and disease activity. This suggests that repletion of vitamin D may have benefits beyond bone health for patients with systemic lupus erythematosus. PMID: 18698173 [PubMed - indexed for MEDLINE]
(Back) J Cell Biochem. 2008 Oct 1;105(2):338-43.Click here to read Links Vitamin D and multiple sclerosis. Raghuwanshi A, Joshi SS, Christakos S. Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA. Vitamin D is a principal regulator of calcium homeostasis. However, recent evidence has indicated that vitamin D can have numerous other physiological functions including inhibition of proliferation of a number of malignant cells including breast and prostate cancer cells and protection against certain immune mediated disorders including multiple sclerosis (MS). The geographic incidence of MS indicates an increase in MS with a decrease in sunlight exposure. Since vitamin D is produced in the skin by solar or UV irradiation and high serum levels of 25-hydroxyvitamin D (25(OH)D) have been reported to correlate with a reduced risk of MS, a protective role of vitamin D is suggested. Mechanisms whereby the active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) may act to mediate this protective effect are reviewed. Due to its immunosuppressive actions, it has been suggested that 1,25(OH)(2)D(3) may prevent the induction of MS. (c) 2008 Wiley-Liss, Inc. PMID: 18655192 [PubMed - in process]
(Back) Mult Scler. 2008 Nov;14(9):1220-1224. Epub 2008 Jul 24. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R. School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands; Department of Internal Medicine, division of Clinical and Experimental Immunology, University Hospital Maastricht, Maastricht, The Netherlands j.smolders@mumc.nl. BackgroundMultiple Sclerosis is associated with low serum levels of 25-hydroxyvitamin D (25(OH)D). We investigated the association between serum levels of 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)2D), the biologically active metabolite, and clinical MS severity as expressed by EDSS-score and relapse rate.Study-designCross-sectional study.Patients and MethodsSerum samples from 267 MS patients were collected for 25(OH)D and 1,25(OH)2D measurement. Clinical MS parameters at the date of serum sampling were determined. Results: Both metabolite levels were significantly lower in the progressive forms compared to the relapsing remitting (RR)MS phenotype. In RRMS patients (disease course <= 5 years), high 25(OH)D levels were associated with a high chance of remaining relapse-free. Low 25(OH)D levels were associated with high EDSS-scores. 1,25(OH)2D was not directly associated with relapse rate or EDSS-score, and was dependent of age and 25(OH)D level.ConclusionSerum levels of 25(OH)D were associated with both relapse rate and disability in MS patients. These results are suggestive for a disease modulating effect of the serum concentrations of 25(OH)D on MS. The low circulating 1,25(OH)2D levels in progressive MS are due to older age and lower 25(OH)D levels. The potential consequences for vitamin D supplementation in MS will be discussed. PMID: 18653736 [PubMed - as supplied by publisher]
(Back) Neurol Res. 2008 Sep;30(7):710-9. Epub 2008 Jul 15. Examining the evidence: complementary adjunctive therapies for multiple sclerosis. Namaka M, Crook A, Doupe A, Kler K, Vasconcelos M, Klowak M, Gong Y, Wojewnik-Smith A, Melanson M. Faculty of Pharmacy, University of Manitoba, Department of Neurology, Health Sciences Centre, Winnipeg, Manitoba, Canada. namakamp@ms.umanitoba.ca OBJECTIVE: The purpose of this article is to provide a comprehensive overview of the most frequently encountered non-conventional approaches trialed for use in multiple sclerosis (MS). The efficacy and safety of non-conventional approaches ranging from bee venom therapy (BVT) to an array of vitamins and herbal products were discussed and evaluated. METHODS: Relevant English-language articles were identified through searches of MEDLINE (1990-2006), PubMed (1999-2006), Cochrane (1995-2006) and Toxnet (2000-2006). Classification of available literature was conducted according to the evidence based guidelines established by the American Academy of Neurology (AAN). However, due to the non-conventional nature of these treatment approaches, most available literature was derived from anecdotal reports and suboptimal clinical studies, lacking the rigor of evidence-based practice. RESULTS: There is presently only marginal supportive evidence for BVT in MS treatment. The inability to identify and quantify the active component of BVT combined with the associated risk of anaphylaxis has deterred its widespread use. The most promising evidence comes from prophylactic daily supplementation with vitamin D. Despite beneficial reports regarding non-herbal supplements such as alpha-lipoic acid (ALA), luteolin, evening primrose oil and vitamins such as B12, the lack of evidence does not support their prophylactic use. DISCUSSION: Based on available evidence, the prophylactic use of vitamin D is a viable option as an adjunct to conventional medicine. Although there is a lack of conclusive evidence to support the use of other non-conventional treatments, patients are still opting to trial and bare the risks of these products which are accessible without the intervention of a healthcare professional. Controlled, evidence-based trials are essential for healthcare professionals to competently intervene and recommend these products. PMID: 18631428 [PubMed - in process]
(Back) Autoimmun Rev. 2007 Nov;7(1):59-64. Epub 2007 Aug 14. Vitamin D in rheumatoid arthritis. Cutolo M, Otsa K, Uprus M, Paolino S, Seriolo B. Research Laboratory and Academic Clinical Unit of Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 6 - 16132 Genova, Italy. mcutolo@unige.it The discovery of the vitamin D receptor (VDR) in the cells of the immune system and the fact that activated dendritic cells produce the vitamin D hormone suggested that vitamin D could have immunoregulatory properties. VDR, a member of the nuclear hormone receptor superfamily, was identified in mononuclear cells, dendritic cells, antigen-presenting cells, and activated T-B lymphocytes. In synthesis, the most evident effects of the D-hormone on the immune system seem to be in the downregulation of the Th1-driven autoimmunity. Low serum levels of vitamin D3 might be partially related, among other factors, to prolonged daily darkness (reduced activation of the pre vitamin D by the ultra violet B sunlight), different genetic background (i.e. vitamin D receptor polymorphism) and nutritional factors, and explain to the lattitute-related prevalence of autoimmune diseases such as rheumatoid arthritis (RA), by considering the potential immunosuppressive roles of vitamin D. 25(OH)D3 plasma levels have been found inversely correlated at least with the RA disease activity showing a circannual rhythm (more severe in winter). Recently, greater intake of vitamin D was associated with a lower risk of RA, as well as a significant clinical improvement was strongly correlated with the immunomodulating potential in vitamin D-treated RA patients. PMID: 17967727 [PubMed - indexed for MEDLINE]
(Back) Exp Dermatol. 2008 Aug;17(8):633-9. Epub 2008 Jun 28. The vitamin D pathway: a new target for control of the skin's immune response? Schauber J, Gallo RL. Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany. juergen.schauber@med.uni-muenchen.de The surface of our skin is constantly challenged by a wide variety of microbial pathogens, still cutaneous infections are relatively rare. Within cutaneous innate immunity the production of antimicrobial peptides (AMPs) is a primary system for protection against infection. Many AMPs can be found on the skin, and these include molecules that were discovered for their antimicrobial properties, and other peptides and proteins first known for activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first families of AMPs discovered on the skin. They are now known to have two distinct functions; they have direct antimicrobial activity and will initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Dysfunction of cathelicidin is relevant in the pathogenesis of several cutaneous diseases including atopic dermatitis where cathelicidin induction is suppressed, rosacea, where cathelicidin peptides are abnormally processed to forms that induce cutaneous inflammation and a vascular response, and psoriasis, where a cathelicidin peptide can convert self-DNA to a potent stimulus of an autoinflammatory cascade. Recent work has unexpectedly identified vitamin D3 as a major factor involved in the regulation of cathelicidin expression. Therapies targeting the vitamin D3 pathway and thereby cathelicidin may provide new treatment modalities in the management of infectious and inflammatory skin diseases. PMID: 18573153 [PubMed - indexed for MEDLINE]
(Back) Curr Drug Targets. 2008 Apr;9(4):345-59. Cellular and molecular mechanisms involved in the action of vitamin D analogs targeting vitiligo depigmentation. Birlea SA, Costin GE, Norris DA. Department of Dermatology, Fitzsimmons Campus, Aurora, Mail Stop 8127, PO Box 6511, Aurora, CO 80045, USA. The active metabolite of vitamin D3 - 1,25-(OH)2D3 - exerts most of its physiological and pharmacological actions through its nuclear receptor (VDR), regulating the transcriptional machinery of a variety of cell types. Basic research motivated by the detection of VDR in numerous target cells, has indicated potential therapeutic applications of VDR ligands in osteoporosis, cancer, secondary hyperparathyroidism and autoimmune diseases such as psoriasis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes and multiple sclerosis. In recent years vitamin D analogs, particularly calcipotriol and tacalcitol, have been used as topical therapeutic agents in vitiligo, an autoimmune pigmentary disorder characterized by aberrant loss of functional melanocytes from involved epidermis. The presence of cytotoxic T cells targeting melanocyte antigens and imbalance of the cytokine network were described as characteristics of the disease, eventually leading to melanocyte damage and death. Vitamin D ligands are designed to target the local immune response in vitiligo, acting on specific T cell activation, mainly by inhibiting the transition of T cells from early to late G1 phase and by inhibiting the expression of several pro-inflammatory cytokines genes, such as those encoding tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma). Vitamin D(3) compounds are known to influence melanocyte maturation and differentiation and also to up-regulate melanogenesis through pathways activated by specific ligand receptors, such as endothelin receptor and c-kit. In this review we summarize the complex pathogenetic rationale of vitamin D analogs in vitiligo depigmentation. Understanding the cellular and molecular mechanisms through which vitamin D targets the epidermal melanin unit is of great interest for identification of new effective therapeutic combination(s) that might induce repigmentation in vitiligo. PMID: 18393827 [PubMed - indexed for MEDLINE]
(Back) Best Pract Res Clin Endocrinol Metab. 2008 Aug;22(4):587-99. Vitamin D and breast cancer risk. Colston KW. Division of Cellular and Molecular Medicine, St George's University of London, Cranmer Terrace, London SW17 0RE, UK. kcolston@sghms.ac.uk In addition to its important role in the maintenance of the skeleton, there is mounting evidence that vitamin D has effects on other body systems, and that adequate supplies of vitamin D are likely to be required for optimal health. Vitamin D is obtained both from dietary sources and from cutaneous synthesis with exposure to sunlight. Some epidemiological studies have indicated that vitamin D deficiency and decreased exposure to solar UVB radiation increase the risk of some cancers, including breast cancer. The active metabolite of vitamin D, 1,25-dihydroxy-vitamin D(3), is synthesized primarily in the kidney, and has been shown in laboratory studies to have potent anti-proliferative effects on breast cancer cells. Normal and neoplastic breast tissues contain the vitamin D receptor, and gene ablation studies have implicated the receptor in normal breast development. Several polymorphisms have been identified in the vitamin D receptor gene, and these have been associated with risk of breast cancer in some studies. Local synthesis of 1,25-dihydroxyvitamin D(3) in breast tissue may contribute to maintenance of normal cell function, which could be impaired in vitamin D deficiency. PMID: 18971120 [PubMed - in process]
(Back) Am J Pathol. 2008 Nov;173(5):1589-90 Vitamin D may reduce prostate cancer metastasis by several mechanisms including blocking Stat3. Grant WB. PMID: 18948436 [PubMed - indexed for MEDLINE]
(Back) Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2800-7. Calcium, dairy foods, vitamin D, and colorectal cancer risk: the Fukuoka Colorectal Cancer Study. Mizoue T, Kimura Y, Toyomura K, Nagano J, Kono S, Mibu R, Tanaka M, Kakeji Y, Maehara Y, Okamura T, Ikejiri K, Futami K, Yasunami Y, Maekawa T, Takenaka K, Ichimiya H, Imaizumi N. Department of Epidemiology and International Health, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. mizoue@ri.imcj.go.jp Epidemiologic evidence supporting a protective role of calcium and vitamin D in colorectal carcinogenesis has been accumulating in Western populations, but it is limited in Asian populations, whose intake of calcium is relatively low. We investigated the association of intakes of these nutrients with colorectal cancer risk in Japanese. Study subjects were participants of a large-scale case-control study in Fukuoka, Japan. Diet was assessed through interview regarding 148 dietary items by showing typical foods or dishes on the display of a personal computer. In a multivariate analysis adjusting for potential confounding variables, calcium intake was significantly, inversely associated with colorectal cancer risk (P for trend=0.01); the odds ratio for the highest versus lowest quintile of calcium intake was 0.64 (95% confidence interval, 0.45-0.93). Higher levels of dietary vitamin D were significantly associated with decreased risk of colorectal cancer among those who had fewer chances of sunlight exposure at work or in leisure (P for trend=0.02). A decreased risk of colorectal cancer associated with high calcium intake was observed among those who had higher levels of vitamin D intake or among those who had a greater chance of daily sunlight exposure, but not among those with medium or lower intake of vitamin D or among those with potentially decreased sunlight exposure. These results add to support for a joint action of calcium and vitamin D in the prevention of colorectal carcinogenesis. PMID: 18843026 [PubMed - in process]
(Back) Am J Epidemiol. 2008 Oct 15;168(8):915-24. Epub 2008 Aug 27. Vitamin D from dietary intake and sunlight exposure and the risk of hormone-receptor-defined breast cancer. Blackmore KM, Lesosky M, Barnett H, Raboud JM, Vieth R, Knight JA. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 60 Murray Street, Box 18, Toronto, Ontario, Canada M5T3L9. blackmore@mshri.on.ca Evidence has emerged for a role of vitamin D in the development of breast cancer, and there is some suggestion that its antiproliferative effect is greater in hormone-receptor-positive cells. Few epidemiologic studies have considered the association between vitamin D and hormone-receptor-defined breast cancer, and the results are conflicting. Considering 759 cases and 1,135 controls from a case-control study (Ontario, Canada, 2003-2005), the authors examined the association between vitamin D intake at specific ages and combined estrogen-receptor- (ER) and progesterone-receptor- (PR) defined breast cancer. While increased intake of vitamin D (from the sun and diet) was most consistently associated with a significantly reduced risk of ER+/PR+ tumors (e.g., odds ratio = 0.76, 95% confidence interval: 0.59, 0.97 for use of cod liver oil during adolescence), comparable nonsignificant associations were found for receptor-negative (ER-/PR-) (odds ratio = 0.74, 95% confidence interval: 0.53, 1.04) and mixed (ER+/PR-) (odds ratio = 0.79, 95% confidence interval: 0.51, 1.22) tumors. This study suggests that vitamin D is associated with a reduced risk of breast cancer regardless of ER/PR status of the tumor. Future studies with a larger number of receptor-negative and mixed tumors are required. PMID: 18756015 [PubMed - indexed for MEDLINE]
(Back) Ann Epidemiol. 2008 Jul 10. [Epub ahead of print] Vitamin D and Intervention Trials in Prostate Cancer: From Theory to Therapy. Schwartz GG. Departments of Cancer Biology and Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC. Studies of vitamin D and prostate cancer have advanced rapidly from the hypothesis that vitamin D deficiency increases the risk of prostate cancer to intervention trials of vitamin D administration in clinical cancer. The hormonal form of vitamin D, 1,25(OH)(2)D, exerts prodifferentiating, antiproliferative, anti-invasive, and antimetastatic effects on prostate cells. Moreover, normal prostate cells synthesize 1,25(OH)(2)D from serum levels of the prohormone, 25-hydroxyvitamin D. The autocrine synthesis of 1,25(OH)(2)D by prostatic cells provides a biochemical mechanism whereby vitamin D may prevent prostate cancer. Many prostate cancer cells have lost the ability to synthesize 1,25(OH)(2)D but still possess 1,25(OH)(2)D receptors. This suggests that whereas vitamin D (e.g., cholecalciferol) might prevent prostate cancer, existing prostate tumors likely would require treatment with 1,25(OH)(2)D and/or its analogs. The major obstacle to the use of 1,25(OH)(2)D in patients therapeutically is the risk of hypercalcemia. Several maneuvers to reduce this risk, including pulse dosing and the use of less calcemic 1,25(OH)(2)D analogs, have been explored in Phase I-III clinical trials. Once merely a promise, vitamin D-based therapies for prostate cancer may soon be medical practice. PMID: 18619854 [PubMed - as supplied by publisher]
(Back) Prog Biophys Mol Biol. 2006 Sep;92(1):39-48. Epub 2006 Feb 28. Vitamin D and disease prevention with special reference to cardiovascular disease. Zittermann A. Department of Cardio-Thoracic Surgery, Heart Center North-Rhine Westfalia, Ruhr University of Bochum, Bad Oeynhausen, Georgstrasse 11, 32545, Germany. azittermann@hdz-nrw.de Circulating 25-hydroxyvitamin D [25(OH)D] is the hallmark for determining vitamin D status. Serum parathyroid hormone [PTH] increases progressively when 25(OH)D falls below 75 nmol/l. Concentrations of 25(OH)D below 50 nmol/l or even below 25 nmol/l are frequently observed in various population groups throughout the world. This paper highlights the relationship of vitamin D insufficiency with cardiovascular disease and non-insulin dependent diabetes mellitus, two diseases that account for up to 50% of all deaths in western countries. There is evidence from patients with end-stage renal disease that high PTH concentrations are causally related to cardiovascular morbidity and mortality. Activated vitamin D is able to increase survival in this patient group significantly. Moreover, already slightly enhanced PTH concentrations are associated with ventricular hypertrophy and coronary heart disease in the general population. Experimental studies have demonstrated that a lack of vitamin D action leads to hypertension in mice. Some intervention trials have also shown that vitamin D can reduce blood pressure in hypertensive patients. In young and elderly adults, serum 25(OH)D is inversely correlated with blood glucose concentrations and insulin resistance. Sun-deprived lifestyle, resulting in low cutaneous vitamin D synthesis, is the major factor for an insufficient vitamin D status. Unfortunately, vitamin D content of most foods is negligible. Moreover, fortified foods and over-the-counter supplements usually contain inadequate amounts of vitamin D to increase serum 25(OH)D to 75 nmol/l. As a consequence, legislation has to be changed to allow higher amounts of vitamin D in fortified foods and supplements. PMID: 16600341 [PubMed - indexed for MEDLINE]
(Back) J Am Coll Cardiol. 2008 Dec 9;52(24):1949-56. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? Lee JH, O'Keefe JH, Bell D, Hensrud DD, Holick MF. Mid America Heart Institute and University of Missouri, Kansas City, Missouri, USA. Vitamin D deficiency is a highly prevalent condition, present in approximately 30% to 50% of the general population. A growing body of data suggests that low 25-hydroxyvitamin D levels may adversely affect cardiovascular health. Vitamin D deficiency activates the renin-angiotensin-aldosterone system and can predispose to hypertension and left ventricular hypertrophy. Additionally, vitamin D deficiency causes an increase in parathyroid hormone, which increases insulin resistance and is associated with diabetes, hypertension, inflammation, and increased cardiovascular risk. Epidemiologic studies have associated low 25-hydroxyvitamin D levels with coronary risk factors and adverse cardiovascular outcomes. Vitamin D supplementation is simple, safe, and inexpensive. Large randomized controlled trials are needed to firmly establish the relevance of vitamin D status to cardiovascular health. In the meanwhile, monitoring serum 25-hydroxyvitamin D levels and correction of vitamin D deficiency is indicated for optimization of musculoskeletal and general health. PMID: 19055985 [PubMed - in process]
(Back) Curr Opin Clin Nutr Metab Care. 2008 Nov;11(6):752-7. Vitamin D in the prevention and treatment of coronary heart disease. Zittermann A, Koerfer R. Department of Thoracic and Cardiovascular Surgery, Heart and Diabetes Center North-Rhine Westfalia, Ruhr University Bochum, Bad Oeynhausen, Germany. azittermann@hdz-nrw.de PURPOSE OF REVIEW: The pathogenesis of coronary heart disease is of multifactorial origin. Probably, not all risk factors are satisfactorily understood. This article outlines beneficial vitamin D effects on cardiac function and the vasculature. In addition, human data associating serum vitamin D metabolite levels or oral vitamin D dosages or both with coronary heart disease outcome parameters are reviewed. RECENT FINDINGS: There is accumulating evidence that the vitamin D hormone calcitriol exerts important physiological effects in cardiomyocytes, vascular smooth muscle cells, and the vascular endothelium. Low levels of the calcitriol precursor 25-hydoxyvitamin D are associated with myocardial infarction, congestive heart failure, and calcific aortic stenosis. Deficient calcitriol concentrations probably contribute to the massive vascular calcification seen in chronic kidney disease. In patients with end-stage renal disease and end-stage heart failure, very low-circulating calcitriol levels or nonuse of active vitamin D or both are independently associated with high mortality rates. SUMMARY: Despite these exciting data, it is still too early to recommend exact dosages for the prevention or therapy of coronary heart disease. Prospective, randomized controlled trials with different amounts of vitamin D and probably with its active form calcitriol are needed to determine whether vitamin D can prevent coronary heart disease events and mortality. PMID: 18827580 [PubMed - in process
(Back) NHypertension. 2008 Nov;52(5):847-55. Epub 2008 Sep 29 Effect of calcium and vitamin D supplementation on blood pressure: the Women's Health Initiative Randomized Trial. Margolis KL, Ray RM, Van Horn L, Manson JE, Allison MA, Black HR, Beresford SA, Connelly SA, Curb JD, Grimm RH Jr, Kotchen TA, Kuller LH, Wassertheil-Smoller S, Thomson CA, Torner JC; Women's Health Initiative Investigators. HealthPartners Research Foundation, Box 1524, Mailstop 21111R, Minneapolis, Minnesota 55440-1524, USA. Karen.L.Margolis@HealthPartners.com Experimental and epidemiological studies suggest that calcium and vitamin D supplements may lower blood pressure. We examined the effect of calcium plus vitamin D supplementation on blood pressure and the incidence of hypertension in postmenopausal women. The Women's Health Initiative Calcium/Vitamin D Trial randomly assigned 36 282 postmenopausal women to receive 1000 mg of elemental calcium plus 400 IU of vitamin D3 daily or placebo in a double-blind fashion. Change in blood pressure and the incidence of hypertension were ascertained. Over a median follow-up time of 7 years, there was no significant difference in the mean change over time in systolic blood pressure (0.22 mm Hg; 95% CI: -0.05 to 0.49 mm Hg) and diastolic blood pressure (0.11 mm Hg; 95% CI: -0.04 to 0.27 mm Hg) between the active and placebo treatment groups. This null result was robust in analyses accounting for nonadherence to study pills and in baseline subgroups of interest, including black subjects and women with hypertension or high levels of blood pressure, with low intakes of calcium and vitamin D or low serum levels of vitamin D. In 17 122 nonhypertensive participants at baseline, the hazard ratio for incident hypertension associated with calcium/vitamin D treatment was 1.01 (95% CI: 0.96 to 1.06.) In postmenopausal women, calcium plus vitamin D3 supplementation did not reduce either blood pressure or the risk of developing hypertension over 7 years of follow-up. PMID: 18824662 [PubMed - indexed for MEDLINE]
(Back) Pediatr Diabetes. 2008 Nov 24. [Epub ahead of print] Long-term trends in the incidence of type 1 diabetes in Denmark: the seasonal variation changes over time. Svensson J, Lyngaae-Jørgensen A, Carstensen B, Simonsen LB, Mortensen HB; Danish Childhood Diabetes Registry. Paediatric Department, Glostrup University Hospital, Glostrup, Denmark. There is a worldwide increase of type 1 diabetes mellitus (T1DM). In 1996, the Danish population-based registry was initiated including all newly diagnosed children aged 0-15 yr. This is the report of incidence and seasonal variation for the first 10 yr of the registry. The data was analyzed using Poisson's regression analysis. A total of 2166 children with diabetes were diagnosed before the age of 15 yr between 1996 and 2005. In this period, the annual increase in childhood T1DM was 3.43% (95% confidence interval: 1.91-4.97), which was unaffected by age and gender. Seasonal variation in incidence rates varied by year but not by age and gender. In conclusion, there is a steep increase in incidence of childhood T1DM in Denmark; the increase is comparable with the increase seen in other European countries. There is a significant seasonal variation that changes on a year-to-year basis. The observed variations in cadence rates may be associated with viral epidemics, sunshine exposure, or vitamin D levels and suggest further exploration of these relations. PMID: 19067889 [PubMed - as supplied by publisher]
(Back) Endocrine. 2008 Nov 1. [Epub ahead of print] Vitamin D and diabetes mellitus. Danescu LG, Levy S, Levy J. Department of Internal Medicine, St. Joseph Mercy Oakland Hospital, Pontiac, MI, USA. Better understanding of the physiological role of the vitamin-D system, in particular its potential effects on inflammatory and autoimmune conditions as well as on insulin secretion and possibly also on insulin resistance, increased the interest in its potential role in prevention and control of the diabetic condition, both type-1 and -2 diabetes. Both these conditions are associated with inflammation and type-1 diabetes also with an autoimmune pathology. Indeed, animal and human studies support the notion that adequate vitamin-D supplementation may decrease the incidence of type-1 and possibly also of type-2 diabetes mellitus and may improve the metabolic control in the diabetes state. However, the exact mechanisms by which vitamin-D and calcium supplementation exert their beneficial effects are not clear and need further investigation. PMID: 18979202 [PubMed - as supplied by publisher]