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Use of vitamin D in clinical practice. Cannell JJ, Hollis BW. Altern Med Rev. 2008 Mar;13(1):6-20. PMID: 18377099 The recent discovery--from a meta-analysis of 18 randomized controlled trials--that supplemental cholecalciferol (vitamin D) significantly reduces all-cause mortality emphasizes the medical, ethical, and legal implications of promptly diagnosing and adequately treating vitamin D deficiency. Not only are such deficiencies common, and probably the rule, vitamin D deficiency is implicated in most of the diseases of civilization. Vitamin D's final metabolic product is a potent, pleiotropic, repair and maintenance, seco-steroid hormone that targets more than 200 human genes in a wide variety of tissues, meaning it has as many mechanisms of action as genes it targets. One of the most important genes vitamin D up-regulates is for cathelicidin, a naturally occurring broad-spectrum antibiotic. Natural vitamin D levels, those found in humans living in a sun-rich environment, are between 40-70 ng per ml, levels obtained by few modern humans. Assessing serum 25-hydroxy-vitamin D (25(OH)D) is the only way to make the diagnosis and to assure treatment is adequate and safe. Three treatment modalities exist for vitamin D deficiency: sunlight, artificial ultraviolet B (UVB) radiation, and vitamin D3 supplementation. Treatment of vitamin D deficiency in otherwise healthy patients with 2,000-7,000 IU vitamin D per day should be sufficient to maintain year-round 25(OH)D levels between 40-70 ng per mL. In those with serious illnesses associated with vitamin D deficiency, such as cancer, heart disease, multiple sclerosis, diabetes, autism, and a host of other illnesses, doses should be sufficient to maintain year-round 25(OH)D levels between 55 -70 ng per mL. Vitamin D-deficient patients with serious illness should not only be supplemented more aggressively than the well, they should have more frequent monitoring of serum 25(OH)D and serum calcium. Vitamin D should always be

Diagnosis and treatment of vitamin D deficiency. Cannell JJ, Hollis BW, Zasloff M, Heaney RP. Expert Opin Pharmacother. 2008 Jan;9(1):107-18. PMID: 18076342 The recent discovery - in a randomised, controlled trial - that daily ingestion of 1100 IU of colecalciferol (vitamin D) over a 4-year period dramatically reduced the incidence of non-skin cancers makes it difficult to overstate the potential medical, social and economic implications of treating vitamin D deficiency. Not only are such deficiencies common, probably the rule, vitamin D deficiency stands implicated in a host of diseases other than cancer. The metabolic product of vitamin D is a potent, pleiotropic, repair and maintenance, secosteroid hormone that targets > 200 human genes in a wide variety of tissues, meaning it has as many mechanisms of action as genes it targets. A common misconception is that government agencies designed present intake recommendations to prevent or treat vitamin D deficiency. They did not. Instead, they are guidelines to prevent particular metabolic bone diseases. Official recommendations were never designed and are not effective in preventing or treating vitamin D deficiency and in no way limit the freedom of the physician - or responsibility - to do so. At this time, assessing serum 25-hydroxy-vitamin D is the only way to make the diagnosis and to assure that treatment is adequate and safe. The authors believe that treatment should be sufficient to maintain levels found in humans living naturally in a sun-rich environment, that is, > 40 ng/ml, year around. Three treatment modalities exist: sunlight, artificial ultraviolet B radiation or supplementation. All treatment modalities have their potential risks and benefits. Benefits of all treatment modalities outweigh potential risks and greatly outweigh the risk of no treatment. As a prolonged 'vitamin D winter', centred on the winter solstice, occurs at many temperate latitudes, ≤ 5000 IU (125 μg) of vitamin D/d

"Let's shine some sunlight on these knowledge deficiencies: * Serum vitamin D levels have been dropping (as chronic inflammation has been increasing) over the last three decades -- has something changed in our diets? * Vitamin D deficiencies occur globally (not restricted to Northern latitudes or winter) -- related to diet? * Women are more vulnerable, because of cultural modesty in some countries, but males are still D-deficient. * A subset of people exposed to ample sunshine are still D-deficient. * Vitamin D deficient individuals also have elevated TNF. * Vitamin D deficiency and inflammation are risk factors in the same diseases. It seems that the simplest conclusion is that chronic inflammation leads to vitamin D deficiency, even though vitamin D deficiency may also contribute to inflammation."

Vitamin D in preventive medicine: are we ignoring the evidence? Zittermann A. Br J Nutr. 2003 May;89(5):552-72. Review. PMID: 12720576 Vitamin D is metabolised by a hepatic 25-hydroxylase into 25-hydroxyvitamin D (25(OH)D) and by a renal 1alpha-hydroxylase into the vitamin D hormone calcitriol. Calcitriol receptors are present in more than thirty different tissues. Apart from the kidney, several tissues also possess the enzyme 1alpha-hydroxylase, which is able to use circulating 25(OH)D as a substrate. Serum levels of 25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis, adequacy, and toxicity. European children and young adults often have circulating 25(OH)D levels in the insufficiency range during wintertime. Elderly subjects have mean 25(OH)D levels in the insufficiency range throughout the year. In institutionalized subjects 25(OH)D levels are often in the deficiency range. There is now general agreement that a low vitamin D status is involved in the pathogenesis of osteoporosis. Moreover, vitamin D insufficiency can lead to a disturbed muscle function. Epidemiological data also indicate a low vitamin D status in tuberculosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, hypertension, and specific types of cancer. Some intervention trials have demonstrated that supplementation with vitamin D or its metabolites is able: (i) to reduce blood pressure in hypertensive patients; (ii) to improve blood glucose levels in diabetics; (iii) to improve symptoms of rheumatoid arthritis and multiple sclerosis. The oral dose necessary to achieve adequate serum 25(OH)D levels is probably much higher than the current recommendations of 5-15 microg/d.

Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic. Cannell JJ, Vieth R, Willett W, Zasloff M, Hathcock JN, White JH, Tanumihardjo SA, Larson-Meyer DE, Bischoff-Ferrari HA, Lamberg-Allardt CJ, Lappe JM, Norman AW, Zittermann A, Whiting SJ, Grant WB, Hollis BW, Giovannucci E. Ann Otol Rhinol Laryngol. 2008 Nov;117(11):864-70. Review. PMID: 19102134 Until we have better information on doses of vitamin D that will reliably provide adequate blood levels of 25(OH)D without toxicity, treatment of vitamin D deficiency in otherwise healthy children should be individualized according to the numerous factors that affect 25(OH)D levels, such as body weight, percent body fat, skin melanin, latitude, season of the year, and sun exposure.2 The doses of sunshine or oral vitamin D3 used in healthy children should be designed to maintain 25(OH)D levels above 50 ng/mL. As a rule, in the absence of significant sun exposure, we believe that most healthy children need about 1,000 IU of vitamin D3 daily per 11 kg (25 lb) of body weight to obtain levels greater than 50 ng/mL. Some will need more, and others less. In our opinion, children with chronic illnesses such as autism, diabetes, and/or frequent infections should be supplemented with higher doses of sunshine or vitamin D3, doses adequate to maintain their 25(OH)D levels in the mid-normal of the reference range (65 ng/mL) - and should be so supplemented year round. Otolaryngologists treating children are in a good position to both diagnose and treat vitamin D deficiency.

Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. Hollis BW, Wagner CL, Drezner MK, Binkley NC. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):631-4. Epub 2007 Jan 10. PMID: 17218096 In the present study, we sought to investigate what circulating 25(OH)D levels would result in populations exhibiting no substrate limitations to the vitamin D-25-hydroxylase. To perform this, we chose two distinct populations. The first were individuals from a year-found sunny environment who spent a good deal of time outdoors. The second were a group of lactating women receiving a substantial daily oral dose of vitamin D3. Surprisingly, a study such as this previously had not been undertaken. There are several reasons for this. First, finding a group of sun-exposed individuals is not an easy task; in fact, we had to go to Hawaii to find them. Secondly, very few studies have been performed where subjects actually received adequate vitamin D3 supplementation to make them replete. Finally, it is very difficult and costly to measure circulating vitamin D3 and relate it to circulating 25(OH)D. The results of our study are far-reaching. This study also demonstrates that individuals can be vitamin D deficient with significant sun exposure if the skin area exposed is limited as was suggested several years ago (19). Finally, whether one receives their vitamin D3 orally or through UV exposure, the vitamin D-25-hydroxylase appears to handle it in an equivalent fashion with respect to maintaining circulating 25(OH)D levels. Thus, we believe that the relationship between circulating vitamin D and 25(OH)D may define adequate nutritional vitamin D status.

(VIDEO) Shedding light on the vitamin D deficiency 'crisis' By GrassRootsHealth.com Oct 11, 2009 - 4:49:39 PM San Diego, CA - Can vitamin D prevent 80% of the incidence of breast cancer? What is its affect on colon cancer and other major illnesses? These questions and more will be addressed when some of the most prominent vitamin D researchers in North America participate in the " Diagnosis & Treatment of Vitamin D Deficiency" seminar presented by GrassrootsHealth at the University of Toronto on Tuesday, November 3 from 8 a.m. - 5 p.m. GrassrootsHealth is the founder of D*action, an international public health project whose goal is to solve the vitamin D deficiency epidemic. GrassrootsHealth and D*action work with over 30 scientists, institutions and individuals committed to educate, test, and study vitamin D levels worldwide. At the conference, a group of physicians and researchers in the vitamin D field will discuss vitamin D's role in the potential prevention of many diseases, including breast cancer, colon cancer, type 1 diabetes and multiple sclerosis, the ultimate reduction in the incidence of infectious diseases and the economic impact of such action

Vitamin D: a D-Lightful health perspective. Holick MF. Nutr Rev. 2008 Oct;66(10 Suppl 2):S182-94. Review. PMID: 18844847 DOI: 10.1111/j.1753-4887.2008.00104.x Sunlight provides most humans with their vitamin D requirement. Adequate vitamin D(3) by synthesis in the skin or from dietary and supplemental sources is essential for bone health throughout life. Vitamin D deficiency is defined as a 25(OH)D concentration 30 ng/mL (75 nmol/L), and insufficiency as 21-29 ng/mL. Vitamin D deficiency and insufficiency has been linked to a wide variety of chronic diseases including common cancers, autoimmune, cardiovascular, and infectious diseases. Healthcare professionals need to be aware of the vitamin D deficiency pandemic. Guidelines for sensible sun exposure and supplemental vitamin D of 800-1000 IU/day are needed.

"For more than 80 years, scientists have known that vitamin D is important for building bones. And for most of those 80 years, people thought this was the only thing it was good for. In the past decade, however, we've learned two important things about vitamin D: it appears to have many other important health effects, and many Americans don't get enough of it. In 2008, new research pointed to a vitamin D deficiency as a possible contributing factor in heart disease. And the suspected link between vitamin D deficiency and cancer grew even stronger. This surely will spur much new research in 2009. Why is vitamin D deficiency so common? The vitamin is made in our skin when sunlight strikes it. Many Americans-especially those who live in the northern part of the country, are elderly or have dark skin-don't soak up enough sun. And the vitamin isn't found in many foods. The main sources are fatty fish (such as salmon, mackerel, herring and sardines) and milk, cereal and juices that have been fortified with it. Vitamin D deficiency often is unsuspected because it causes no direct symptoms; like high blood pressure, it does its damage silently."

The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Gombart AF. Future Microbiol. 2009 Nov;4:1151-65. PMID: 19895218 Vitamin D deficiency has been correlated with increased rates of infection. Since the early 19th century, both environmental (i.e., sunlight) and dietary sources (cod liver) of vitamin D have been identified as treatments for TB. The recent discovery that vitamin D induces antimicrobial peptide gene expression explains, in part, the 'antibiotic' effect of vitamin D and has greatly renewed interest in the ability of vitamin D to improve immune function. Subsequent work indicates that this regulation is biologically important for the response of the innate immune system to wounds and infection and that deficiency may lead to suboptimal responses toward bacterial and viral infections. The regulation of the cathelicidin antimicrobial peptide gene is a human/primate-specific adaptation and is not conserved in other mammals. The capacity of the vitamin D receptor to act as a high-affinity receptor for vitamin D and a low-affinity receptor for secondary bile acids and potentially other novel nutritional compounds suggests that the evolutionary selection to place the cathelicidin gene under control of the vitamin D receptor allows for its regulation under both endocrine and xenobiotic response systems. Future studies in both humans and humanized mouse models will elucidate the importance of this regulation and lead to the development of potential therapeutic applications

Severe vitamin D deficiency in Swiss hip fracture patients. Bischoff-Ferrari HA, Can U, Staehelin HB, Platz A, Henschkowski J, Michel BA, Dawson-Hughes B, Theiler R. Bone. 2008 Mar;42(3):597-602. Epub 2007 Nov 28. PMID: 18180211 BACKGROUND: Most clinical guidelines for the prevention of hip fractures recommend 800 IU vitamin D per day. This dose shifted serum 25-hydroxyvitamin D levels (25(OH)D) in previous studies to between 60 and 100 nmol/l. AIM: To measure 25(OH)D levels and prevalence of vitamin D supplementation in individuals age 65+ with acute hip fracture. METHODS: 222 consecutive hip fracture patients were investigated over a 12 month period. Mean age of patients was 86 years and 77% were women. RESULTS: Mean serum 25(OH)D levels were low among hip fracture patients admitted from home (34.6 nmol/l), from assisted living (27.7 nmol/l), and from nursing homes (24 nmol/l). Severe vitamin D deficiency below 30 nmol/l was present in 60%, 80% were below 50 nmol/l, and less than 4% reached desirable levels of at least 75 nmol/l. Consistently, only 10% of hip fracture patients had any vitamin D supplementation on admission to acute care with significantly higher 25(OH)D levels among individuals supplemented with 800-880 IU/day (63.5 nmol/l). Controlling for age and gender, vitamin D supplementation, type of dwelling, and season were independently and significantly associated with 25(OH)D levels. CONCLUSION: These data provide evidence that current guidelines for the prevention of hip fractures need further effort to be translated into clinical practice.

Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited. Glerup H, Mikkelsen K, Poulsen L, Hass E, Overbeck S, Thomsen J, Charles P, Eriksen EF. J Intern Med. 2000 Feb;247(2):260-8. PMID: 10692090 Conclusions. Severe vitamin D deficiency is prevalent amongst sunlight-deprived individuals living in Denmark. In veiled Arab women, vitamin D deficiency is the result of a combination of limitations in sunlight exposure and a low oral intake of vitamin D. The oral intake of vitamin D amongst veiled ethnic Danish Moslems was, however, very high, at 13.53 µg (approximately 600 IU), but they were still vitamin D-deficient. Our results suggest that the daily oral intake of vitamin D in sunlight-deprived individuals should exceed 600 IU; most probably it should be 1000 IU day-1 to secure a normal level of 25-hydroxyvitamin D. This finding is in contrast with the commonly used RDA (recommended daily allowance) for adults in Europe: 200 IU day-1.

Vitamin D and skin physiology: a D-lightful story. Holick MF, Chen TC, Lu Z, Sauter E. J Bone Miner Res. 2007 Dec;22 Suppl 2:V28-33. PMID: 18290718 doi: 10.1359/jbmr.07s211 Very few foods naturally contain vitamin D, and those that do have a very variable vitamin D content. Recently it was observed that wild caught salmon had between 75% and 90% more vitamin D(3) compared with farmed salmon. The associations regarding increased risk of common deadly cancers, autoimmune diseases, infectious diseases, and cardiovascular disease with living at higher latitudes and being prone to vitamin D deficiency should alert all health care professionals about the importance of vitamin D for overall health and well being. Humans have depended on sunlight for their vitamin D requirement. The impact of season, time of day, and latitude on vitamin D synthesis is well documented.(2,3) We now report that altitude also has a dramatic influence on vitamin D3 production and that living at altitudes above 3500 m permits previtamin D3 production at a time when very little is produced at latitudes below 3400 m. It was surprising that, at 27° N in Agra (169 M), little previtamin D3 production was observed. However, there was significant air pollution that caused a haze over the city. It is likely the ozone and other UVB-absorbing pollutants in the air prevented the solar UVB photons from reaching the earth's surface to produce previtamin D3.

Vitamin D deficiency is the cause of common obesity. Foss YJ. Med Hypotheses. 2009 Mar;72(3):314-21. Epub 2008 Dec 2. PMID: 19054627 doi:10.1016/j.mehy.2008.10.005 Common obesity and the metabolic syndrome may therefore result from an anomalous adaptive winter response. The stimulus for the winter response is proposed to be a fall in vitamin D. The synthesis of vitamin D is dependent upon the absorption of radiation in the ultraviolet-B range of sunlight. At ground level at mid-latitudes, UV-B radiation falls in the autumn and becomes negligible in winter. It has previously been proposed that vitamin D evolved in primitive organisms as a UV-B sensitive photoreceptor with the function of signaling changes in sunlight intensity. It is here proposed that a fall in vitamin D in the form of circulating calcidiol is the stimulus for the winter response, which consists of an accumulation of fat mass (obesity) and the induction of a winter metabolism (the metabolic syndrome). Vitamin D deficiency can account for the secular trends in the prevalence of obesity and for individual differences in its onset and severity. It may be possible to reverse the increasing prevalence of obesity by improving vitamin D status.

Table of Contents Ch. I Is calcidiol an active hormone? 1 Ch. II Vitamin D as a neurosteroid hormone : from neurobiological effects to behavior 29 Ch. III Inhibitors of vitamin D hydroxylases : mechanistic tools and therapeutic aspects 67 Ch. IV Vitamin D analogues as anti-cancer therapies 145 Ch. V Paricalcitol : a vitamin D2 analog with anticancer effects with low calcemic activity 169 Ch. VI Vitamin D use among older adults in U.S. : results form national surveys 1997 to 2002 181 Ch VII Vitamin D deficiency in migrants 199 Vitamin D is a fat-soluble steroid hormone precursor that contributes to the maintenance of normal levels of calcium and phosphorus in the bloodstream. Strictly speaking, it is not a vitamin since human skin can manufacture it, but it is referred to as one for historical reasons. It is often known as calciferol. The major biologic function of vitamin D is to maintain normal blood levels of calcium and phosphorus. Vitamin D aids in the absorption of calcium, helping to form and maintain strong bones. It promotes bone mineralisation in concert with a number of other vitamins, minerals and hormones. Without vitamin D, bones can become thin, brittle, soft or misshapen. Vitamin D prevents rickets in children and osteomalacia in adults -- skeletal diseases that result in defects that weaken bones. This book gathers international research on the leading-edge of the scientific front.

Strong correlations have been noted between cardiovascular diseases and low bone density / osteoporosis-connections so strong that the presence of one type of pathology is considered a likely predictor of the other. This potentially causal relationship has led to the hypothesis that these conditions share core mechanisms. Recent advances in our understanding of the complimentary roles played by vitamin D3 and vitamin K2 in vascular and bone health provide support for this hypothesis, along with insight into key metabolic dysfunctions underlying cardiovascular disease and osteoporosis. Part I of this review summarizes current research linking vitamin D deficiency to cardiovascular disease, the physiological mechanisms underlying vitamin D's cardiovascular effects, and leading vitamin D researchers' recommendations for significantly higher supplemental doses of the pro-hormone. Part II reviews the vitamin K connection to cardiovascular disease; the ways in which vitamin D and vitamin K pair up to prevent inflammation, vascular calcification and osteoporosis; and the necessity of providing vitamin K along with vitamin D to preclude adverse effects associated with hypervitaminosis D, which include vascular and other soft tissue calcification.

Improved cholecalciferol nutrition in rats is noncalcemic, suppresses parathyroid hormone and increases responsiveness to 1, 25-dihydroxycholecalciferol. Vieth R, Milojevic S, Peltekova V. J Nutr. 2000 Mar;130(3):578-84. PMID: 10702588 We conclude suppression of 1,25(OH)(2)D and PTH, and higher renal VDR mRNA and 24-hydroxylase did not involve higher free 1,25(OH)(2)D concentration or a first pass effect at the gut. Thus, 25(OH)D or a metabolite other than 1,25(OH)(2)D is a physiological, transcriptionally and biochemically active, noncalcemic vitamin D metabolite. When viewed from a perspective that starts with higher vitamin D nutrition, the results indicate that low vitamin D nutrition may bring about a form of resistance to 1,25(OH)2D. This situation would explain why, in humans, nutritional rickets and osteomalacia are commonly associated with normal or increased levels of 1,25(OH)2D (Chesney et al. 1981Citation , Eastwood et al. 1979Citation , Garabedian et al. 1983Citation ,Rasmussen et al. 1980Citation )-these are not like the low hormone levels associated with any other endocrine-deficiency disorder. A connection between lower vitamin D nutrition and vitamin D resistance helps to explain why the supposedly inactive compound 25(OH)D is more relevant in diagnosing nutritional rickets than is the active hormone 1,25(OH)2D. If the features of improved vitamin D nutrition shown here were demonstrated for any newly synthesized compound, the compound would be classified as a noncalcemic 1,25(OH)2D analogue (Brown et al. 1989Citation , Finch et al. 1999Citation , Goff et al. 1993Citation , Koshizuka et al. 1999Citation ). Thus, we contend that 25(OH)D or a metabolite of it other than 1,25(OH)2D exists as a physiological and biologically-active noncalcemic vitamin D metabolite whose effects require further examination, particularly in relationship to studies involving the synthetic analogs of 1,25(OH)2D.

Why is it that vitamin D deficiency can manifest in so many different ways in different people? One big reason is something called vitamin D receptor (VDR) genotypes, the variation in the receptor for vitamin D. Why is it that the dose of vitamin D necessary to reach a specific level differs so widely from one person to the next? VDR genotype, again. Variation in blood levels of 25-hydroxy vitamin D from a specific dose of vitamin D can vary three-fold, as shown by a University of Toronto study. In other words, a dose of 4000 units per day may yield a 25-hydroxy vitamin D blood level of 30 ng/ml in Mary, 60 ng/ml in Paul, and 90 ng/ml in Pete--same dose, different blood levels

Vitamin D and living in northern latitudes--an endemic risk area for vitamin D deficiency. Huotari A, Herzig KH. Int J Circumpolar Health. 2008 Jun;67(2-3):164-78. Review. PMID: 18767337 CONCLUSIONS: Vitamin D plays a fundamental role in calcium and phosphate homeostasis. A deficiency of vitamin D has been attributed to several diseases. Since its production in the skin depends on exposure to UVB-radiation via the sunlight, the level of vitamin D is of crucial importance for the health of inhabitants who live in the Nordic latitudes where there is diminished exposure to sunlight during the winter season. Therefore, fortification or supplementation of vitamin D is necessary for most of the people living in the northern latitudes during the winter season to maintain adequate levels of circulating 25(OH)D3 to maintain optimal body function and prevent diseases.

"June 29, 2009 | Shelley Wood Boston, MA - A massive, National Institutes of Health-sponsored study looking at whether vitamin-D and/or omega-3 fatty-acid supplementation can reduce the risk of developing heart disease, stroke, or cancer will get under way in January 2010, according to a website for the study. Drs JoAnn Manson and Julie Buring (Harvard Medical School/ Brigham and Women's Hospital, Boston, MA) will head up the Vitamin D and Omega-3 Trial (VITAL). The study is aiming to enroll 20 000 men and women, one-quarter of whom will be black. According to a Brigham and Women's Hospital press release, the study is intentionally aiming to illuminate a potential racial and ethnic disparity hypothesized to be linked to vitamin D [1]. "African Americans have a higher risk of vitamin-D deficiency as well as a greater frequency of diabetes, hypertension, and certain types of cancer," a press release notes. For VITAL, women need to be over age 65 to enter the study; men need to be over age 60. Study participants will be randomized to one of four groups: daily vitamin D (2000 IU) and fish oil (1 g); daily vitamin D and fish-oil placebo; daily vitamin-D placebo and fish oil; or daily vitamin-D placebo and fish-oil placebo. The trial will run for five years and is expected to cost US $20 million."