Multipe Sclerosis - Treatment

Vitamin D - updated: 19 November 2009

Revolutionary advances in the prevention of demyelinating diseases

J Environ Pathol Toxicol Oncol. 2009;28(2):143-52

Edlich R, Mason SS, Chase ME, Fisher AL, Gubler K, Long WB 3rd, Newkirk AT.

This collective review focuses on three major factors that influence the incidences of multiple sclerosis (MS) to include ultraviolet radiation (UVR), vitamin D3 supplementation, and vitamin D receptor gene (VDRG) polymorphisms. In general, the rate of MS increases with latitude. Individuals tend to carry their original risk with them if they migrate to a different latitude after adolescence. It is important to emphasize that UVR increases the synthesis of vitamin D3, which has a known immune suppressant action via the VDRG. Clinical studies have pointed out that vitamin D deficiency may exacerbate the development of MS. Because vitamin D3 is an inhibitor of MS, providing supplemental D3 for individuals at risk for MS should be mandatory. There is unanimous agreement that exposure to UVR and vitamin D3 supplementation can reduce the incidence of MS. Although there is debate regarding the association of MS with the use of silver mercury fillings, there is general agreement throughout the world that there is a need for dental-patient informed-consent brochures for all dentists who use dental restoration materials. For the dentists who remove silver mercury amalgam from their patients, there is a uniform international agreement that all dental offices should use reliable debris collection devices that prevent pollution of our environment.

Publication Types:

• Review

Naar een toereikende inname van vitamine D

Gezondheidsraad, 2008; publicatienr. 2008/15.

ISBN-13: 978-90-5549-729-4

Bepaalde groepen in de bevolking blijken niet voldoende vitamine D binnen te krijgen via de voeding. Ook komen ze niet voldoende buiten om genoeg aan te maken in de huid. Vooral ouderen lopen de kans op een tekort, omdat de productie in de huid terugloopt met de leeftijd. Maar ook mensen met een donkere huid – die minder vitamine D produceert – hebben geregeld een tekort. Verder zijn er speciale groepen die risico lopen, zoals zwangere vrouwen, gesluierde vrouwen, kinderen en ouderen in verpleeg- en verzorgingstehuizen. Voor al deze risicogroepen is het gebruik van supplementen aan te bevelen. Voor alle anderen is het advies: eet gezond, gebruik genoeg margarine, halvarine en bak- en braadproducten (want daar is extra vitamine D aan toegevoegd), en ga dagelijks minstens een kwartier naar buiten. Deze boodschap moet door eenduidige voorlichting onder de aandacht worden gebracht. Anders dan de vitamine D-inname blijkt de jodiuminname van de Nederlandse bevolking wel goed. Daar is consolideren dus voldoende. Dit schrijft de Gezondheidsraad in twee adviezen die vandaag worden aangeboden aan de minister van Volksgezondheid, Welzijn en Sport.

Publication Types:

• Government Guideline

Online - Abstract

Online - Press Release

Online - Article

Clinical implications of a possible role of vitamin D in multiple sclerosis

J Neurol. 2009 Sep;256(9):1468-79. Epub 2009 Apr 28.

Pierrot-Deseilligny C.

Hypovitaminosis D is currently one of the most studied environmental risk factors for multiple sclerosis (MS) and is potentially the most promising in terms of new clinical implications. These practical consequences, which could be applied to MS patients without further delay, constitute the main purpose of this review. Vitamin D is involved in a number of important general actions, which were not even suspected until quite recently. In particular, this vitamin could play an immunomodulatory role in the central nervous system. Many and varied arguments support a significant role for vitamin D in MS. In animal studies, vitamin D prevents and improves experimental autoimmune encephalomyelitis. Epidemiologically, latitude, past exposure to sun and the serum level of vitamin D influence the risk of MS, with, furthermore, significant links existing between these different factors. Clinically, most MS patients have low serum levels of vitamin D and are in a state of insufficiency or even deficiency compared to the international norm, which has been established on a metabolic basis. Large therapeutic trials using vitamin D are still lacking but the first results of phase I/II studies are promising. In the meantime, while awaiting the results of future therapeutic trials, it can no longer be ignored that many MS patients have a lack of vitamin D, which could be detected by a serum titration and corrected using an appropriate vitamin D supplementation in order to restore their serum level to within the normal range. From a purely medical point of view, vitamin D supplementation appears in this light to be unavoidable in order to improve the general state of these patients. Furthermore, it cannot currently be ruled out that this supplementation could also be neurologically beneficial.

Publication Types:

• Review

The relevance of vitamin D receptor gene polymorphisms for vitamin D research in multiple sclerosis

Autoimmun Rev. 2009 Jun;8(7):621-6

Smolders J, Peelen E, Thewissen M, Menheere P, Cohen Tervaert JW, Hupperts R, Damoiseaux J.

A poor vitamin D status has been associated with several autoimmune diseases, including multiple sclerosis (MS). The receptor for the biologically active metabolite of vitamin D appears to be a key player in these associations, not only as a mediator of the biological effects of vitamin D, but also as a mediator of the regulation of vitamin D metabolism itself. In this concise review, we will discuss the mostly investigated genetic polymorphisms of the vitamin D receptor (VDR), and their consequences for VDR functionality and immune regulation. Next, we will discuss the association of these polymorphisms with MS, and their relation with vitamin D metabolism. We conclude that polymorphisms of the VDR have major effects on vitamin D function and metabolism, and should therefore be assessed in studies on vitamin D and MS.

Publication Types:

• Review

A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis

J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):152-7.

Soilu-Hänninen M, Laaksonen M, Laitinen I, Erälinna JP, Lilius EM, Mononen I.

BACKGROUND: Past sun exposure and vitamin D3 supplementation have been associated with a reduced risk of multiple sclerosis (MS). There are no previous longitudinal studies of vitamin D in MS. OBJECTIVES: To compare regulation of vitamin D and calcium homeostasis between patients with MS and healthy controls. To study the correlation of parameters of vitamin D metabolism with MS activity. METHODS: We measured 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), calcium, phosphate, magnesium, chloride, alkaline phosphatase, albumin and thyroid stimulating hormone in serum every 3 months and at the time of relapse over 1 year in 23 patients with MS and in 23 healthy controls. MRI burden of disease and T2 activity were assessed every 6 months. RESULTS: Vitamin D deficiency (S-25(OH)D < or = 37 nmol/l) was common, affecting half of the patients and controls at some time in the year. Seasonal variation of 25(OH)D was similar in patients and controls, but 25(OH)D serum levels were lower and intact PTH (iPTH) serum levels were higher during MS relapses than in remission. All 21 relapses during the study occurred at serum iPTH levels > 20 ng/l (2.2 pmol/l), whereas 38% of patients in remission had iPTH levels < or = 20 ng/l. Patients with MS had a relative hypocalcaemia and a blunted PTH response in the winter. There was no correlation between serum 25(OH)D and MRI parameters. CONCLUSIONS: The endocrine circuitry regulating serum calcium may be altered in MS. There is an inverse relationship between serum vitamin D level and MS clinical activity. The role of vitamin D in MS must be explored further.

Publication Types:

• Study

Therapeutic potential of vitamin D for multiple sclerosis

Curr Med Chem. 2008;15(5):499-505

Niino M, Fukazawa T, Kikuchi S, Sasaki H.

Multiple sclerosis (MS) is a major inflammatory and demyelinating disease of the central nervous system and has an increasing prevalence in populations residing at higher latitudes. This observation may indicate a protective effect of sunlight exposure, which is reduced at higher latitudes and may contribute to insufficient levels of vitamin D in the MS population. The vitamin D hormone is important for bone metabolism and can regulate cell proliferation and differentiation as well as apoptosis and immune regulation in immune cells such as T helper cells and dendritic cells. Evidence from experimental autoimmune encephalomyelitis and prospective studies on MS suggests an important role of vitamin D as a modifiable environmental factor in MS. These provide guidance for future studies with regard to the potential role of vitamin D in the prevention and/or treatment of MS. Here, we first review the metabolism and immune functions of vitamin D. Then, we describe the current thinking on the etiology of vitamin D in MS and the accumulating evidence pointing to a link between vitamin D and MS. Further, we describe how genetic susceptibility interacts with environmental risk factors at the population level, MS-associated risk factors, and genetic studies related to the vitamin D receptor. This review also discusses the therapeutic potential of vitamin D for treating MS.

Publication Types:

• Review

Vitamin D: a natural inhibitor of multiple sclerosis

Proc Nutr Soc. 2000 Nov;59(4):531-5

Hayes CE.

Inheriting genetic risk factors for multiple sclerosis (MS) is not sufficient to cause this demyelinating disease of the central nervous system; exposure to environmental risk factors is also required. MS may be preventable if these unidentified environmental factors can be avoided. MS prevalence increases with decreasing solar radiation, suggesting that sunlight may be protective in MS. Since the vitamin D endocrine system is exquisitely responsive to sunlight, and MS prevalence is highest where environmental supplies of vitamin D are lowest, we have proposed that the hormone, 1, 25-dihydroxycholecalciferol (1,25-(OH)2D3), may protect genetically-susceptible individuals from developing MS. Evidence consistent with this hypothesis comes not only from geographic studies, but also genetic and biological studies. Over-representation of the vitamin D receptor gene b allele was found in Japanese MS patients, suggesting it may confer MS susceptibility. Fish oil is an excellent vitamin D source, and diets rich in fish may lower MS prevalence or severity. Vitamin D deficiency afflicts most MS patients, as demonstrated by their low bone mass and high fracture rates. However, the clearest evidence that vitamin D may be a natural inhibitor of MS comes from experiments with experimental autoimmune encephalomyelitis (EAE), a model of MS. Treatment of mice with 1,25-(OH)2D3 completely inhibited EAE induction and progression. The hormone stimulated the synthesis of two anti-encephalitogenic cytokines, interleukin 4 and transforming growth factor beta-1, and influenced inflammatory cell trafficking or apoptosis. If vitamin D is a natural inhibitor of MS, providing supplemental vitamin D to individuals who are at risk for MS would be advisable.

Publication Types:

• Review

Vitamin D and multiple sclerosis

Proc Soc Exp Biol Med. 1997 Oct;216(1):21-7

Hayes CE, Cantorna MT, DeLuca HF.

Recently, it has been clearly demonstrated that exogenous 1,25-dihydroxyvitamin D3, the hormonal form of vitamin D3, can completely prevent experimental autoimmune encephalomyelitis (EAE), a widely accepted mouse model of human multiple sclerosis (MS). This finding has focused attention on the possible relationship of this disease to vitamin D. Although genetic traits certainly contribute to MS susceptibility, an environmental factor is also clearly involved. It is our hypothesis that one crucial environmental factor is the degree of sunlight exposure catalyzing the production of vitamin D3 in skin, and, further, that the hormonal form of vitamin D3 is a selective immune system regulator inhibiting this autoimmune disease. Thus, under low-sunlight conditions, insufficient vitamin D3 is produced, limiting production of 1,25-dihydroxyvitamin D3, providing a risk for MS. Although the evidence that vitamin D3 is a protective environmental factor against MS is circumstantial, it is compelling. This theory can explain the striking geographic distribution of MS, which is nearly zero in equatorial regions and increases dramatically with latitude in both hemispheres. It can also explain two peculiar geographic anomalies, one in Switzerland with high MS rates at low altitudes and low MS rates at high altitudes, and one in Norway with a high MS prevalence inland and a lower MS prevalence along the coast. Ultraviolet (UV) light intensity is higher at high altitudes, resulting in a greater vitamin D3 synthetic rate, thereby accounting for low MS rates at higher altitudes. On the Norwegian coast, fish is consumed at high rates and fish oils are rich in vitamin D3. Further, experimental work on EAE provides strong support for the importance of vitamin D3 in reducing the risk and susceptibility for MS. If this hypothesis is correct, then 1,25-dihydroxyvitamin D3 or its analogs may have great therapeutic potential in patients with MS. More importantly, current research together with data from migration studies opens the possibility that MS may be preventable in genetically susceptible individuals with early intervention strategies that provide adequate levels of hormonally active 1,25-dihydroxyvitamin D3 or its analogs.

Publication Types:

• Review

Vitamin D as an immune modulator in multiple sclerosis, a review

J Neuroimmunol. 2008 Feb;194(1-2):7-17

Smolders J, Damoiseaux J, Menheere P, Hupperts R.

The role of vitamin D in calcium homeostasis is well known. More recently vitamin D has become a topic of interest in immune regulation and multiple sclerosis. The main reason for this is the observed geographical distribution of multiple sclerosis. Areas with high sunlight exposure, the principal inducer of vitamin D synthesis, have a relatively low prevalence of multiple sclerosis and vice versa. Furthermore, low levels of the principal vitamin D metabolite (25-hydroxy vitamin D) in the circulation are associated with a high incidence of multiple sclerosis. Other epidemiological evidence also supports the view that vitamin D metabolites have an immune and disease modulating effect in multiple sclerosis. Experimental research in vitro and in animal models has further clarified the interaction of vitamin D metabolites with the immune system. The evidence obtained from these studies strongly supports a model in which vitamin D mediates a shift to a more anti-inflammatory immune response, and in particular to enhanced regulatory T cell functionality. In the current review we link the basic knowledge on vitamin D and immune regulation with the vitamin D related observations in multiple sclerosis. We conclude that there is a sound basis on which to initiate double-blind placebo-controlled trials that not only address the effect of vitamin D on the clinical outcome of multiple sclerosis, but also on the regulatory T cell compartment.

Publication Types:

• Review

Multiple sclerosis and vitamin D: an update.

Eur J Clin Nutr. 2004 Aug;58(8):1095-109

VanAmerongen BM, Dijkstra CD, Lips P, Polman CH.

MS is a chronic, immune-mediated inflammatory and neurodegenerative disease of the central nervous system (CNS), with an etiology that is not yet fully understood. The prevalence of MS is highest where environmental supplies of vitamin D are lowest. It is well recognized that the active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH)(2)D), is a natural immunoregulator with anti-inflammatory action. The mechanism by which vitamin D nutrition is thought to influence MS involves paracrine or autocrine metabolism of 25OHD by cells expressing the enzyme 1 alpha-OHase in peripheral tissues involved in immune and neural function. Administration of the active metabolite 1,25-(OH)(2)D in mice and rats with experimental allergic encephalomyelitis (EAE, an animal model of MS) not only prevented, but also reduced disease activity. 1,25-(OH)(2)D alters dendritic cell and T-cell function and regulates macrophages in EAE. Interestingly, 1,25-(OH)(2)D is thought to be operating on CNS constituent cells as well. Vitamin D deficiency is caused by insufficient sunlight exposure or low dietary vitamin D(3) intake. Subtle defects in vitamin D metabolism, including genetic polymorphisms related to vitamin D, might possibly be involved as well. Optimal 25OHD serum concentrations, throughout the year, may be beneficial for patients with MS, both to obtain immune-mediated suppression of disease activity, and also to decrease disease-related complications, including increased bone resorption, fractures, and muscle weakness.

Publication Types:

• Review

Vitamin D and autoimmune disease--implications for practice from the multiple sclerosis literature

J Am Diet Assoc. 2006 Mar;106(3):418-24

Mark BL, Carson JA.

Recent studies and commentaries link vitamin D with several autoimmune diseases, including multiple sclerosis (MS). Adequate vitamin D intake reduces inflammatory cytokines through control of gene expression, thus inadequate vitamin D intake is suggested as a mechanism that could contribute to inflammation and, consequently, development of MS. Poor vitamin D status has been associated with increased risk for development of MS, and patients with MS may suffer consequences of vitamin D deficiency, such as bone loss. Animal studies and very limited human data suggest possible benefit from vitamin D supplementation in patients with MS. Based on the current state of research, a key principle for practicing dietetics professionals is to include vitamin D status in nutritional assessment. For those at risk for poor vitamin D status, intake can be enhanced by food-based advice and, when indicated, vitamin D supplementation.

Publication Types:

• Review

Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis

Mult Scler. 2008 Nov;14(9):1220-4.

Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R.

BACKGROUND: Multiple 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-DESIGN: Cross-sectional study. PATIENTS AND METHODS: Serum 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 < or = 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. CONCLUSION: Serum 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.

Publication Types:

• Cross-sectional study

Immunomodulatory effects of Vitamin D in multiple sclerosis

Brain. 2009 May;132(Pt 5):1146-60

Correale J, Ysrraelit MC, Gaitįn MI.

Although Vitamin D is best known as a modulator of calcium homeostasis, it also has immune modulating potential. A protective effect of Vitamin D on multiple sclerosis is supported by the reduced risk associated with sun exposure and use of Vitamin D supplements. Moreover, high circulating levels of Vitamin D have been associated with lower risk of multiple sclerosis. In this study, we measured 1,25 (OH)(2) Vitamin D and 25 (OH) Vitamin D levels in multiple sclerosis patients separated into different clinical subgroups according to disease status. In addition, direct effects of 1,25 (OH)(2) Vitamin D on ex vivo CD4+ T cells and myelin-peptide specific T cell lines were investigated to gain more insight into putative regulatory mechanisms in the disease pathogenesis. One hundred and thirty-two Hispanic patients with clinically definite multiple sclerosis were studied, 58 with relapsing remitting multiple sclerosis during remission, 34 during relapse and 40 primary progressive multiple sclerosis cases. Sixty healthy individuals matched with respect to place of residence, race/ethnicity, age and gender served as controls. Levels of 25(OH)D(3) and 1,25(OH)(2)D(3), measured by ELISA were significantly lower in relapsing-remitting patients than in controls. In addition, levels in patients suffering relapse were lower than during remissions. In contrast, primary progressive patients showed similar values to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specific T cells was significantly inhibited by 1,25(OH)(2)D(3). Moreover, activated Vitamin D enhanced the development of IL-10 producing cells, and reduced the number of IL-6 and IL-17 secreting cells. Notably, Vitamin D receptor expression was induced by 1,25(OH)(2)D(3) in both activated and resting cells. Interestingly, T cells were able to metabolize 25(OH)D(3) into biologically active 1,25(OH)(2)D(3), since T cells express alpha1-hydroxylase constitutively. Finally, 1,25(OH)(2)D(3) also increased the expression and biological activity of indoleamine 2,3-dioxygenase, mediating significant increase in the number of CD4+CD25+ T regulatory cells. Collectively, these data suggest that 1,25(OH)(2)D(3) plays an important role in T cell homeostasis during the course of multiple sclerosis, thus making correction of its deficiency may be useful during treatment of the disease.

Publication Types:

• Study

Vitamin D toxicity, policy, and science

J Bone Miner Res. 2007 Dec;22 Suppl 2:V64-8

Vieth R.

The serum 25-hydroxyvitamin D [25(OH)D] concentration that is the threshold for vitamin D toxicity has not been established. Hypercalcemia is the hazard criterion for vitamin D. Past policy of the Institute of Medicine has set the tolerable upper intake level (UL) for vitamin D at 50 mug (2000 IU)/d, defining this as "the highest level of daily nutrient intake that is likely to pose no risks of adverse health effects to almost all individuals in the general population." However, because sunshine can provide an adult with vitamin D in an amount equivalent to daily oral consumption of 250 mug (10,000 IU)/d, this is intuitively a safe dose. The incremental consumption of 1 mug (40 IU)/day of vitamin D(3) raises serum 25(OH)D by approximately 1 nM (0.4 ng/ml). Therefore, if sun-deprived adults are to maintain serum 25(OH)D concentrations >75 nM (30 ng/ml), they will require an intake of more than the UL for vitamin D. The mechanisms that limit vitamin D safety are the capacity of circulating vitamin D-binding protein and the ability to suppress 25(OH)D-1-alpha-hydroxylase. Vitamin D causes hypercalcemia when the "free" concentration of 1,25-dihydroxyvitamin D is inappropriately high. This displacement of 1,25(OH)(2)D becomes excessive as plasma 25(OH)D concentrations become higher than at least 600 nM (240 ng/ml). Plasma concentrations of unmetabolized vitamin D during the first days after an acute, large dose of vitamin D can reach the micromolar range and cause acute symptoms. The clinical trial evidence shows that a prolonged intake of 250 mug (10,000 IU)/d of vitamin D(3) is likely to pose no risk of adverse effects in almost all individuals in the general population; this meets the criteria for a tolerable upper intake level.

Publication Types:

• Review

Risk assessment for vitamin D

American Journal of Clinical Nutrition, Vol. 85, No. 1, 6-18, January 2007 © 2007

John N Hathcock, Andrew Shao, Reinhold Vieth and Robert Heaney

The objective of this review was to apply the risk assessment methodology used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D. New data continue to emerge regarding the health benefits of vitamin D beyond its role in bone. The intakes associated with those benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing concern exists, however, regarding the potential for toxicity related to excessive vitamin D intakes. The UL established by the FNB for vitamin D (50 µg, or 2000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL. We present a risk assessment based on relevant, well-designed human clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose 250 µg/d (10 000 IU vitamin D3) supports the confident selection of this value as the UL.

Publication Types:

• Review

Safety of vitamin D3 in adults with multiple sclerosis

American Journal of Clinical Nutrition, Vol. 86, No. 3, 645-651, September 2007 © 2007

Samantha M Kimball, Melanie R Ursell, Paul O'Connor and Reinhold Vieth

Background: Vitamin D3 may have therapeutic potential in several diseases, including multiple sclerosis. High doses of vitamin D3 may be required for therapeutic efficacy, and yet tolerability—in the present context, defined as the serum concentration of 25-hydroxyvitamin D [25(OH)D] that does not cause hypercalcemia—remains poorly characterized. Objective: The objective of the study was to characterize the calcemic response to specific serum 25(OH)D concentrations. Design: In a 28-wk protocol, 12 patients in an active phase of multiple sclerosis were given 1200 mg elemental Ca/d along with progressively increasing doses of vitamin D3: from 700 to 7000 µg/wk (from 28 000 to 280 000 IU/wk). Results: Mean (± SD) serum concentrations of 25(OH)D initially were 78 ± 35 nmol/L and rose to 386 ± 157 nmol/L (P < 0.001). Serum calcium concentrations and the urinary ratio of calcium to creatinine neither increased in mean values nor exceeded reference values for any participant (2.1–2.6 mmol/L and <1.0, respectively). Liver enzymes, serum creatinine, electrolytes, serum protein, and parathyroid hormone did not change according to Bonferroni repeated-measures statistics, although parathyroid hormone did decline significantly according to the paired t test. Disease progression and activity were not affected, but the number of gadolinium-enhancing lesions per patient (assessed with a nuclear magnetic brain scan) decreased from the initial mean of 1.75 to the end-of-study mean of 0.83 (P = 0.03). Conclusions: Patients' serum 25(OH)D concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalciuria. The data support the feasibility of pharmacologic doses of vitamin D3 for clinical research, and they provide objective evidence that vitamin D intake beyond the current upper limit is safe by a large margin.

Publication Types:

• Clinical Study

Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety

Am J Clin Nutr. 1999 May;69(5):842-56

Vieth R.

For adults, the 5-microg (200 IU) vitamin D recommended dietary allowance may prevent osteomalacia in the absence of sunlight, but more is needed to help prevent osteoporosis and secondary hyperparathyroidism. Other benefits of vitamin D supplementation are implicated epidemiologically: prevention of some cancers, osteoarthritis progression, multiple sclerosis, and hypertension. Total-body sun exposure easily provides the equivalent of 250 microg (10000 IU) vitamin D/d, suggesting that this is a physiologic limit. Sailors in US submarines are deprived of environmentally acquired vitamin D equivalent to 20-50 microg (800-2000 IU)/d. The assembled data from many vitamin D supplementation studies reveal a curve for vitamin D dose versus serum 25-hydroxyvitamin D [25(OH)D] response that is surprisingly flat up to 250 microg (10000 IU) vitamin D/d. To ensure that serum 25(OH)D concentrations exceed 100 nmol/L, a total vitamin D supply of 100 microg (4000 IU)/d is required. Except in those with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations <140 nmol/L, which require a total vitamin D supply of 250 microg (10000 IU)/d to attain. Published cases of vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intake of > or = 1000 microg (40000 IU)/d. Because vitamin D is potentially toxic, intake of >25 microg (1000 IU)/d has been avoided even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 50 microg (2000 IU)/d is too low by at least 5-fold.

Publication Types:

• Review

Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards

Nutr. 2006 Apr;136(4):1117-22

Vieth R.

The tolerable upper intake level (UL) for vitamin D is 50 mcg/d (2000 iu/d) in North America and in Europe. In the United Kingdom a guidance level exists for vitamin D, 25 mcg/d (1000 iu/d), defined as the dose "of vitamins and minerals that potentially susceptible individuals could take daily on a life-long basis, without medical supervision in reasonable safety." Exposure of skin to sunshine can safely provide an adult with vitamin D in an amount equivalent to an oral dose of 250 mcg/d. The incremental consumption of 1 mcg/d of vitamin D3 raises serum 25-hydroxyvitamin D [25(OH)D ] by approximately 1 nmol/L (0.4 microg/L). Published reports suggest toxicity may occur with 25(OH)D concentrations beyond 500 nmol/L (200 microg/L). Older adults are advised to maintain serum 25(OH)D concentrations >75 nmol/L. The preceding numbers indicate that vitamin D3 intake at the UL raises 25(OH)D by approximately 50 nmol/L and that this may be more desirable than harmful. The past decade has produced separate North American, European, and U.K. reports that address UL or guidance-level values for vitamin D. Despite similar well-defined models for risk assessment, each report has failed to adapt its message to new evidence of no adverse effects at higher doses. Inappropriately low UL values, or guidance values, for vitamin D have hindered objective clinical research on vitamin D nutrition, they have hindered our understanding of its role in disease prevention, and restricted the amount of vitamin D in multivitamins and foods to doses too low to benefit public health.

Publication Types:

• Review

What is the optimal vitamin D status for health?

Prog Biophys Mol Biol. 2006 Sep;92(1):26-32.

Vieth R.

The most objectively substantiated health-related reason for tanning is that it improves vitamin D status. The serum 25-hydroxyvitamin D concentration (25(OH)D) is the measure of vitamin D nutrition status. Human biology was probably optimized through natural selection for a sun-rich environment that maintained serum 25(OH)D higher than 100 nmol/L. These levels are now only prevalent in people who spend an above-average amount of time outdoors, with the sun high in the sky. The best-characterized criteria for vitamin D adequacy are based on randomized clinical trials that show fracture prevention and preservation of bone mineral density. Based upon these studies, 25(OH)D concentrations should exceed 75 nmol/L. This concentration is near the upper end of the 25(OH)D reference ("normal") range for populations living in temperate climates, or for people who practice sun-avoidance, or who wear head coverings. Officially mandated nutrition guidelines restrict vitamin D intake from fortified food and supplements to less than 25 mcg/day, a dose objectively shown to raise serum 25(OH)D in adults by about 25 nmol/L. The combined effect of current nutrition guidelines and current sun-avoidance advice is to ensure that adults who follow these recommendations will have 25(OH)D concentrations lower than 75 nmol/L. Therefore, advice to avoid UVB light should be accompanied by encouragement to supplement with vitamin D in an amount that will correct for the nutrient deficit that sun-avoidance will cause.

Publication Types:

• Review

Publication Types:

• Review