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Should vitamin D supplements be recommended to prevent chronic diseases?

BMJ 2015; 350 doi: (Published 29 January 2015) Cite this as: BMJ 2015;350:h321

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There is strong evidence from observational studies that 25-hydroxyvitamin D [25(OH)D] concentrations above 75 nmol/L (30 ng/mL) are associated with better outcomes for chronic diseases [1-3]. In addition, for African-Americans, there is evidence that the poor survival rates after diagnosis of cancer in this community is linked to lower 25(OH)D concentrations independent of socioeconomic status, stage at diagnosis and treatment [4].

Unfortunately, most vitamin D randomized controlled trials (RCTs) conducted to date, as well as the major ones currently underway that are listed in Meyer et al [5], have not been designed to answer the question of the relationship of serum25(OH)D to intended health outcomes. Therefore, if studies are not conducted in vitamin D deficient or insufficient populations, one would not expect a positive outcome [6].

In fact, most published vitamin D RCTs were based on the guidelines for pharmaceutical agents, assuming that the trial agent is the only source of intervention and there is a linear dose-response relation; however, this is not the case. Neither assumption is satisfied for vitamin D. Heaney recently outline guidelines that are applicable for RCTs designed to assess the impact of nutrient supplementation [6]. The main steps for conducting vitamin D RCTs should include, (A) start with an understanding of the 25(OH)D concentration-health outcome relation; (B) measure 25(OH)D concentrations prior to the clinical study in all prospective participants and only include those with concentrations below the optimal threshold; (C) supplement with adequate vitamin D3 to raise (and titrate) serum 25(OH)D concentrations to near the upper end of the expected relation; (D) measure 25(OH)D concentrations following enrollment to the trial to assure the right serum concentrations have been achieved; and (E) optimize co-nutrients in all participants.

In this regard, we refer to the recent paper by Meyer and colleagues who concluded that vitamin D supplementation for preventing chronic diseases is not recommended due to ‘lack’ of supporting evidence [5]. However, their paper overlooked a large body of evidence that supports higher 25(OH)D concentrations in reducing risk of chronic diseases [7, 8]. There are only three ways that 25(OH)D concentrations can be raised: by UVB exposure, diet, and supplements. This commentary intended to presents some of that missing and important evidence that supports why supplementing with vitamin D is imperative in reducing the escalating incidence of chronic disease, worldwide.

First, inflammation is a risk factor for many types of chronic disease [9] and adequate levels of vitamin D have the potential to reduce inflammation [10]. A meta-analysis of vitamin D RCTs found that those studies using vitamin D3 in subjects with mean baseline 25(OH)D concentrations below 48 nmol/L had a 49% chance of finding reduced biomarkers of inflammation but only 27% of those with higher 25(OH)D concentrations did [11]. Raising 25(OH)D concentrations to the range 35-82 nmol/L resulted in 55% beneficial reduction in inflammation. This study and many other studies, support a value of 75 nmol/L as more protective against chronic disease than 50 nmol/L.

Another approach is to use sensible and adequate exposure to solar UVB radiation to improve the human’s well-being. There are many new findings in the recent literature supporting exposure to solar UVB radiation B reducing risk for many chronic diseases including multiple sclerosis, type 1 diabetes and many types of cancer [12]. Moreover, solar UVB, UVA and visible light exposure has beneficial effects independent of vitamin D production [13-15].

A mouse model of UVB exposure found that UVB exposure raising 25(OH)D concentrations the same amount as oral vitamin D intake decreased the progression of intestinal tumors more than oral vitamin D [16]. This finding could further explain why geographical and ecological studies reporting strong evidence of inverse correlation of solar UVB doses with the incidence and mortality rates of many types of cancers [17]. In addition, outdoor occupation has been shown to inversely correlate with incidence rates of many types of cancer in Nordic countries [18].

There are many other benefits of appropriate exposure to solar and artificial UVB and UVA, including lowering blood pressure, increasing beta endorphin concentrations, improving wound healing and many other benefits [19]. However, incidental short exposures are inadequate to generate appreciable amounts of vitamin D in the skin, especially during non-summer months. A study found an increased risk of MS for young people who spent less time in the sun in summer in Norway and during the wintertime in Italy [15]. Another study in Sweden found that those who avoided sun exposure had significantly higher all-cause mortality rates [19].

It should be noted that the understanding of the mechanisms whereby solar UVB exposure reduces risk of chronic diseases independent of vitamin D production is limited at present [13]. In addition, some people are concerned about the risk of skin cancer and melanoma from UV exposure, but data suggest that sun-exposure is only applicable and specific to squamous cell carcinoma of the skin [20]. In fact most melanomas occur on the least sun exposed areas, and occupational sun exposure in fact, reduces risk for this deadly skin cancer [21].

It is well documented not only in the United States but worldwide that it is not possible to obtain even the minimum 600 IUs daily of vitamin D that is recommended by the Institute of Medicine for most children and adults from dietary sources.

Thus, without adequate sun exposure most of the world population is vitamin D deficient. The only way to guarantee sufficiency is to recommend a three-part strategy to improve everyone’s vitamin D status. This includes (A): Encouraging consuming more foods that naturally contain vitamin D including oily fish such as salmon and foods fortified with vitamin D. There needs to be an evaluation by health regulatory agencies for regulations to promote vitamin D fortification of local foods. (B): The World Health Organization and local health regulatory agencies should provide guidelines for sensible sun exposure which would improve the world’s vitamin D status while minimizing risk for skin cancer. And (C): Because vitamin D deficiency is pandemic all children and adults who were unable to obtain adequate vitamin D from dietary, food fortification, and solar sources should be encouraged to take a vitamin D supplement to satisfy their vitamin D requirement.

Based on the evidence to date from ecological and observational studies and RCTs, serum 25(OH)D concentrations should be above 75 nmol/L (30 ng/mL) for optimal health through a combination of UVB exposure, diet, and supplements. Available results to date support that this would cost-effectively decrease the escalating incidences of chronic non-communicable disease worldwide.

Disclosure and conflicts of interests:

WBG receives funding from Bio-Tech Pharmacal (Fayetteville, AR),MediSun Technology (Highland Park, IL), and the Vitamin D Council (San Luis Obispo, CA). MFH and SJW have no conflicts of interests.

1. Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: A meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5(6):819-29.
2. Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence. Autoimmun Rev. 2013;12(10):976-89.
3. Garland CF, Kim JJ, Mohr SB, Gorham ED, Grant WB, Giovannucci EL, et al. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Pub Health. 2014;104(8):e43-50.
4. Grant WB, Peiris AN. Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and White Americans. Dermatoendocrinol. 2012;4(2):85-94.
5. Meyer HE, Holvik K, Lips P. Should vitamin D supplements be recommended toprevent chronic diseases? BMJ. BMJ 2015;350:h321doi: 10.1136/bmj.h321
6. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48-54.
7. Gröber U, Spitz J, Reichrath J, Kisters K, Holick MF. Vitamin D: Update 2013: From rickets prophylaxis to general preventive healthcare. Dermatoendocrinol. 2013;5(3):331-47.
8. Hossein-Nezhad A, Holick MF. Vitamin D for health: A global perspective. Mayo Clin Proc. 2013;88(7):720-55.
9. Vendramini-Costa DB, Carvalho JE. Molecular link mechanisms between inflammation and cancer.Curr Pharm Des. 2012;18(26):3831-52.
10. Yin K, Agrawal DK. Vitamin D and inflammatory diseases.J Inflamm Res. 2014;7:69-87.
11. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermatoendocrinol. 2014;6(1): e983401-1-10.
12. Wacker M, Holick MF. Sunlight and vitamin D: A global perspective for health. Dermatoendocrinol. 2013;5(1) :51-108.
13. Juzeniene A, Moan J. Beneficial effects of UV radiation other than via vitamin D production. Dermatoendocrinol. 2012;4(2):109-17.
14. Liu D, Fernandez BO, Hamilton A, Lang NN, Gallagher JM, Newby DE, et al. UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxidesynthase. J Invest Dermatol. 2014;134(7):1839-46.
15. Bjørnevik K, Riise T, Casetta I, Drulovic J, Granieri E, Holmøy T, et al. Sun exposure and multiple sclerosis risk in Norway and Italy: The EnvIMSstudy. MultScler. 2014;20(8):1042-1049.
16. Rebel H, der Spek CD, Salvatori D, van Leeuwen JP, Robanus-Maandag EC, de Gruijl FR.UV exposure inhibits intestinal tumour growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet.Int J Cancer. 2015;136(2):271-7.
17. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5(10):3993-4023.
18. Grant WB. Role of solar UV irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol. 2012;4(2):203-11.
19. Lindqvist PG, Epstein E, Landin-Olsson M, Ingvar C, Nielsen K, Stenbeck M, et al. Avoidance of sun exposure is a risk factor for all-cause mortality: results from the MISS cohort. J Intern Med. 2014;276(1):77-86.
20. English DR, Armstrong BK, Kricker A, Fleming C. Sunlight and cancer.Cancer Causes Control. 1997;8(3):271-83.
21. Chang YM, Barrett JH, Bishop DT, Armstrong BK, Bataille V, Bergman W, et al. Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls. Int J Epidemiol. 2009;38(3):814-30.

Competing interests: WBG receives funding from Bio-Tech Pharmacal (Fayetteville, AR),MediSun Technology (Highland Park, IL), and the Vitamin D Council (San Luis Obispo, CA). MFH and SJW have no conflicts of interests.

04 February 2015
William B. Grant
Health researcher
Michael F. Holick, Sunil J Wimalawansa
Sunlight, Nutrition and Health Research Center
PO Box 641603, San Francisco, CA 94164-1603, USA