Aysun GENÇ, Duygu Gülmez SEVİM, Aslı Tok ÖZEN, Gülden YILMAZ

D Vitamininin Çesitli Hastalıklardaki Nadir Kullanım Alanları

D vitamini, serum kalsiyum ve fosfor düzeylerini, emilim ve metabolizma üzerinden etkileyerek düzenler. D vitamini reseptörlerinin vücudun birçok doku ve hücresinde tespit edilmesiyle, klasik olmayan etkileri arastırılmaya baslanmıstır. Hiperkalsemik etkilerinin ortaya çıkmadığı dozlarda verilen vitamin ile diabetes mellitus, multipl skleroz, amyotrofik lateral skleroz, meta- bolik sendrom gibi birçok hastalıkta elde edilen umut veren sonuçlar mevcuttur. Bununla be- raber hangi hastalara ve risk faktörü olanlara hangi dozlarda önerileceği konusu belirsizdir. Bu derlememizde rutin kullanım alanları dısında D vitamini uygulamaları ve elde edilen sonuçları ayrı ayrı ele alınarak derlenmistir.

The Area of Usage of the Vitamin D in Different Diseases and Unknown Benefits

Vitamin D regulates the serum calcium and phosphorus levels by effecting absorption and metabolism of these minerals. Since determining the vitamin D reseptors are expressed in many tissue and cells, non-clasical effects of vitamin D was begun to be investigated. Promising results with non-hypercalcemic doses of vitamin D are available in many diseases such as diabetes mellitus, multiple sclerosis, amyotrophic lateral sclerosis and metabolic syndrome. Additionally the patient selection, risk factors and doses of the vitamin are uncertain. We aimed to review non-routine usages of vitamin D and obtained results.

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1. Wranicz J, Szostak-Wegierek D. Health outcomes of vitamin D. Part I. characteristics and classic role. Roczniki Panstwowego Zakladu Higieny. 2014;65(3):179-84. PubMed PMID: 25247796.
2. Holick MF. Vitamin D deficiency. The New England journal of medicine. 2007;357(3):266-81. PubMed PMID: 17634462.
3. Holick MF, Binkley NC, BischoffFerrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2011;96(7):1911-30. PubMed PMID: 21646368.
4. Prietl B, Treiber G, Mader JK, Hoeller E, Wolf M, Pilz S, et al. High-dose cholecalciferol supplementation significantly increases peripheral CD4(+) Tregs in healthy adults without negatively affecting the frequency of other immune cells. European journal of nutrition. 2014;53(3):751-9. PubMed PMID: 23999998.
5. Malek HA, Shata A. Effect of a high dose of vitamin D on a rabbit model of atherosclerosis. International journal of immunopathology and pharmacology. 2014;27(2):195-201. PubMed PMID: 25004831.
6. Bas A, Lopez I, Perez J, Rodriguez M, Aguilera-Tejero E. Reversibility of calcitriol-induced medial artery calcification in rats with intact renal function. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2006;21(3):484-90. PubMed PMID: 16491297.
7. Haffner D, Hocher B, Muller D, Simon K, Konig K, Richter CM, et al. Systemic cardiovascular disease in uremic rats induced by 1,25(OH)2D3. Journal of hypertension. 2005;23(5):1067-75. PubMed PMID: 15834294.
8. Li F, Liu P, Zhang X, Zhang Q, Tang S, Zhu M, et al. 1,25(OH)2D3-mediated amelioration of aortic injury in streptozotocin-induced diabetic rats. Inflammation. 2013;36(6):1334-43. PubMed PMID: 23813327.
9. Pittas AG, Dawson-Hughes B. Vitamin D and diabetes. The Journal of steroid biochemistry and molecular biology. 2010;121(1-2):425-9. PubMed PMID: 20304061. Pubmed Central PMCID: 2900448.
10. Wu-Wong JR, Nakane M, Ma J, Ruan X, Kroeger PE. Effects of Vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells. Atherosclerosis. 2006;186(1):20- 8. PubMed PMID: 16095599.
11. Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, et al. Synthesis of 1,25- dihydroxyvitamin D(3) by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion. Journal of the American Society of Nephrology : JASN. 2002;13(3):621-9. PubMed PMID: 11856765.
12. Lamawansa MD, Wysocki SJ, House AK, Norman PE. Vitamin D3 exacerbates intimal hyperplasia in balloon-injured arteries. The British journal of surgery. 1996;83(8):1101-3. PubMed PMID: 8869314.
13. Mathieu C, Badenhoop K. Vitamin D and type 1 diabetes mellitus: state of the art. Trends in endocrinology and metabolism: TEM. 2005;16(6):261-6. PubMed PMID: 15996876.
14. Wang G, Hu C, Hu C, Ruan L, Bo Q, Li L. [Impact of oral vitamin D supplementation in early life on diabetic mice induced by streptozotocin]. Wei sheng yan jiu = Journal of hygiene research. 2013;42(3):455-9. PubMed PMID: 23805526.
15. Takiishi T, Ding L, Baeke F, Spagnuolo I, Sebastiani G, Laureys J, et al. Dietary supplementation with high doses of regular vitamin D3 safely reduces diabetes incidence in NOD mice when given early and long term. Diabetes. 2014 Jun;63(6):2026-36. PubMed PMID: 24550187.
16. Sergeev IN, Song Q. High vitamin D and calcium intakes reduce diet-induced obesity in mice by increasing adipose tissue apoptosis. Molecular nutrition & food research. 2014;58(6):1342-8. PubMed PMID: 24449427.
17. Barengolts E, Manickam B, Eisenberg Y, Akbar A, Kukreja S, Ciubotaru I. Effect of High-Dose Vitamin D Repletion on Glycemic Control in African American Men with Prediabetes and Hypovitaminosis D. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2015;25:1- 30. PubMed PMID: 25716637.
18. Cantorna MT, Hayes CE, DeLuca HF. 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(15):7861-4. PubMed PMID: 8755567. Pubmed Central PMCID: 38839.
19. Cantorna MT, Humpal-Winter J, DeLuca HF. Dietary calcium is a major factor in 1,25-dihydroxycholecalciferol suppression of experimental autoimmune encephalomyelitis in mice. The Journal of nutrition. 1999;129(11):1966-71. PubMed PMID: 10539770.
20. Wergeland S, Torkildsen O, Myhr KM, Aksnes L, Mork SJ, Bo L. Dietary vitamin D3 supplements reduce demyelination in the cuprizone model. PloS one. 2011;6(10):e26262. PubMed PMID: 22028844.
21. Chabas JF, Stephan D, Marqueste T, Garcia S, Lavaut MN, Nguyen C, et al. Cholecalciferol (vitamin D(3)) improves myelination and recovery after nerve injury. PloS one. 2013;8(5):e65034. PubMed PMID: 23741446.
22. Gianforcaro A, Hamadeh MJ. Vitamin D as a potential therapy in amyotrophic lateral sclerosis. CNS neuroscience & therapeutics. 2014;20(2):101-11. PubMed PMID: 24428861.
23. Peterlik M, Cross HS. Vitamin D and calcium deficits predispose for multiple chronic diseases. European journal of clinical investigation. 2005;35(5):290- 304. PubMed PMID: 15860041.
24. Wei MY, Garland CF, Gorham ED, Mohr SB, Giovannucci E. Vitamin D and prevention of colorectal adenoma: a meta-analysis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2008;17(11):2958-69. PubMed PMID: 18990737.
25. Leyssens C, Marien E, Verlinden L, Derua R, Waelkens E, Swinnen JV, et al. Remodeling of phospholipid composition in colon cancer cells by 1alpha,25(OH)D and its analogs. The Journal of steroid biochemistry and molecular biology. 2015;148:172-8. PubMed PMID: 25625664.
26. Chen TC, Holick MF. Vitamin D and prostate cancer prevention and treatment. Trends in endocrinology and metabolism: TEM. 2003;14(9):423-30. PubMed PMID: 14580762.
27. Kristal AR, Till C, Song X, Tangen CM, Goodman PJ, Neuhauser ML, et al. Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2014;23(8):1494-504. PubMed PMID: 24732629. Pubmed Central PMCID: 4119495.
28. Verstappen A, Parmentier M, Chirnoaga M, Lawson DE, Pasteels JL, Pochet R. Vitamin D-dependent calcium binding protein immunoreactivity in human retina. Ophthalmic research. 1986;18(4):209-14. PubMed PMID: 3534678.
29. Johnson JA, Grande JP, Roche PC, Campbell RJ, Kumar R. Immunolocalization of the calcitriol receptor, calbindin-D28k and the plasma membrane calcium pump in the human eye. Current eye research. 1995;14(2):101-8. PubMed PMID: 7539352.
30. Alsalem JA, Patel D, Susarla R, CocaPrados M, Bland R, Walker EA, et al. Characterization of vitamin D production by human ocular barrier cells. Investigative ophthalmology & visual science. 2014;55(4):2140-7. PubMed PMID: 24576880.
31. Lin Y, Ubels JL, Schotanus MP, Yin Z, Pintea V, Hammock BD, et al. Enhancement of vitamin D metabolites in the eye following vitamin D3 supplementation and UV-B irradiation. Current eye research. 2012 Oct;37(10):871-8. PubMed PMID: 22632164.
32. Annamaneni S, Bindu CH, Reddy KP, Vishnupriya S. Association of vitamin D receptor gene start codon (Fok1) polymorphism with high myopia. Oman journal of ophthalmology. 2011;4(2):57-62. PubMed PMID: 21897619.
33. Dulhunty AF, Beard NA, Pouliquin P, Kimura T. Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically-linked myopathies. Journal of muscle research and cell motility. 2006;27(5-7):351-65. PubMed PMID: 16909197.
34. Verhoeff FH. Retinoblastoma undergoing spontaneous regression. Calcifying agent suggested in treatment of retinoblastoma. American journal of ophthalmology. 1966;62(3):573-4. PubMed PMID: 5922000.
35. Albert DM, Marcus DM, Gallo JP, O'Brien JM. The antineoplastic effect of vitamin D in transgenic mice with retinoblastoma. Investigative ophthalmology & visual science. 1992;33(8):2354-64. PubMed PMID: 1634333.
36. Sabet SJ, Darjatmoko SR, Lindstrom MJ, Albert DM. Antineoplastic effect and toxicity of 1,25-dihydroxy-16-ene- 23-yne-vitamin D3 in athymic mice with Y-79 human retinoblastoma tumors. Archives of ophthalmology. 1999;117(3):365-70. PubMed PMID: 10088815.
37. Suarez F, Jockovich ME, Hernandez E, Feuer W, Parel JM, Murray TG. Paclitaxel in the treatment of retinal tumors of LH beta-Tag murine transgenic model of retinoblastoma. Investigative ophthalmology & visual science. 2007;48(8):3437-40. PubMed PMID: 17652710.
38. Wagner N, Wagner KD, Schley G, Badiali L, Theres H, Scholz H. 1,25- dihydroxyvitamin D3-induced apoptosis of retinoblastoma cells is associated with reciprocal changes of Bcl-2 and bax. Experimental eye research. 2003;77(1):1-9. PubMed PMID: 12823982.
39. Audo I, Darjatmoko SR, Schlamp CL, Lokken JM, Lindstrom MJ, Albert DM, et al. Vitamin D analogues increase p53, p21, and apoptosis in a xenograft model of human retinoblastoma. Investigative ophthalmology & visual science. 2003;44(10):4192-9. PubMed PMID: 14507860.
40. Kulkarni AD, van Ginkel PR, Darjatmoko SR, Lindstrom MJ, Albert DM. Use of combination therapy with cisplatin and calcitriol in the treatment of Y-79 human retinoblastoma xenograft model. The British journal of ophthalmology. 2009;93(8):1105-8. PubMed PMID: 19336429.
41. Graffe A, Beauchet O, Fantino B, Milea D, Annweiler C. Vitamin D and macular thickness in the elderly: an optical coherence tomography study. Investigative ophthalmology & visual science. 2014;55(8):5298-303. PubMed PMID: 25028353.
42. Singh A, Falk MK, Subhi Y, Sorensen TL. The association between plasma 25- hydroxyvitamin D and subgroups in age-related macular degeneration: a cross-sectional study. PloS one. 2013;8(7):e70948. PubMed PMID: 23923033.
43. Tong Y, Liao J, Zhang Y, Zhou J, Zhang H, Mao M. LOC387715/HTRA1 gene polymorphisms and susceptibility to age-related macular degeneration: A HuGE review and meta-analysis. Molecular vision. 2010;16:1958-81. PubMed PMID: 21031019. Pubmed Central PMCID: 2956667.
44. Lee V, Rekhi E, Hoh Kam J, Jeffery G. Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function. Neurobiology of aging. 2012;33(10):2382-9. PubMed PMID: 22217419.
45. Albert DM, Scheef EA, Wang S, Mehraein F, Darjatmoko SR, Sorenson CM, et al. Calcitriol is a potent inhibitor of retinal neovascularization. Investigative ophthalmology & visual science. 2007;48(5):2327-34. PubMed PMID: 17460298.
46. Ren Z, Li W, Zhao Q, Ma L, Zhu J. The impact of 1,25-dihydroxy vitamin D3 on the expressions of vascular endothelial growth factor and transforming growth factor-beta(1) in the retinas of rats with diabetes. Diabetes research and clinical practice. 2012;98(3):474-80. PubMed PMID: 23089551.
47. Tang J, Zhou R, Luger D, Zhu W, Silver PB, Grajewski RS, et al. Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. Journal of immunology. 2009;182(8):4624-32. PubMed PMID: 19342637.
48. Tian Y, Wang C, Ye Z, Xiao X, Kijlstra A, Yang P. Effect of 1,25- dihydroxyvitamin D3 on Th17 and Th1 response in patients with Behcet's disease. Investigative ophthalmology & visual science. 2012 Sep;53(10):6434- 41. PubMed PMID: 22918640.
49. Kutuzova GD, Gabelt BT, Kiland JA, Hennes-Beann EA, Kaufman PL, DeLuca HF. 1alpha,25- Dihydroxyvitamin D(3) and its analog, 2-methylene-19-nor-(20S)-1alpha,25- dihydroxyvitamin D(3) (2MD), suppress intraocular pressure in nonhuman primates. Archives of biochemistry and biophysics. 2012;518(1):53-60. PubMed PMID: 22198282.
50. Alexandra V. Yamshchikov, Nirali S. Desai, Henry M. Blumberg, Thomas R. Ziegler and Vin Tangpricha. Vitamin D for treatment and prevention of infectious diseases: A systematic review of randomized controlled trials. National Institute of Health , 2009 ; 15(5): 438- 449.
51. Von Essen MR, Kongsback M, Schjerling P, Olgaard K. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol 2010;11: 344-349.
52. Adorini L, Penna G. Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists. Human immunology. 2009 May;70(5):345-52. PubMed PMID: 19405173.
53. Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, et al. 1,25- Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. Journal of immunology. 2009;183(9):5458-67. PubMed PMID: 19843932.
54. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR. Tool-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311: 1770-1773.
55. Haan K, Groeneveld AB J, Geus H RH, Egal M, Strujs A. Vitamin D deficiency as arisk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis. Critical Care 2014; 18: 660.
56. Walker VP, Modlin RL. The vitamin D connection to pediatric infections and immune function. Pediatr Res 2009; 5: 106R-113R
57. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006;134:1129-1140. PubMed PMID: 16959053
58. Kawaura A. Inhibitory effect of long term 1alpha-hydroxyvitamin D3 administration on Helicobacter pylori infection. J Clin Biochem Nutr 2006;38: 103- 106.
59. Wong KK, Lee R, Watkins RR, Haller NH. Prolonged Clostridium difficile infection may be associated with Vitamin D deficiency. Original Communication 2015 (doi: 10.1177/0148607114568121. 60. Lachmann R, Bevan MA, Kim S, Patel N, Hawrylowicz C, Vyakarnam A, et al. A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection. AIDS. 2015 Apr 13. [Epub ahead of print]
61. Holick MF, Binkley NC, BischoffFerrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D de- ficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930.
62. Mosekilde L. Vitamin D and the elderly. Clin Endocrinol. 2005;62(3):265- 281.
63. Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the third national and nutrition examination survey. Atherosclerosis. 2009;205(1):255- 260.
64. Cigolini M, Jagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2006;29: 722-724.
65. Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens. 2009;27(10):1948-54.
66. Soysal P, Yay A, Işık AT. Does vitamin d deficiency increase orthostatic hypotension risk in the elderyl patients? Archives of Gerontology and Geriatrics. 2014;59:74-77.
67. Talaei A, Mohamadi M, Adgi Z. The effect of vitamin D on insulin resistance in patients with type 2 diabetes. Diabetol Metab Syndr. 2013;26;5(1):5-8.
68. Lapid MI, Cha SS, Takahashi PY. Vitamin D and depression in geriatric primary care patients. Clinical Interventions in Aging 2013;8: 509-514.
69. Gronli O, Kvamme JM, Jorde R, Wynn R. Vitamin D deficiency is common in psychogeriatric patients, independent of diagnosis. BMC Psychiatry. 2014;14:134.
70. Cavalcante IGM, Silva AS, Costa MJC, Persuhn DC, Issa CTMI, Freire TLL, Gonçalves MCR. Effect of vitamin D3 supplementation and influence of BsmI polymorphism of the VDR gene of the inflammatory profile and oxidative stress in elderyl women with vitamin d insufficiency vitamin D3 megadose reduces inflammatory markers. Experimental Gerontology. 2015;66:10-16.
71. Krishnan AV, Peehl DM, Feldman D. Inhibition of prostate cancer growth by vitamin D: regulationof targed gene expression. Journal of Cellular Biochemistry. 2003;88: 363-371.
72. Cavalcante I, Silva AS, Costa MJC, Persuhn DC, Issa C, Freire T, et al. Effect of vitamin D3 supplementation and influence of BsmI polymorphism of the VDR gene of the inflammatory profile and oxidative stress in elderly women with vitamin D insufficiency Vitamin D3 megadose reduces inflammatory markers.Experimental Gerontology 2015;66:10-16.
73. Prasad P, Kochhar A. Interplay of vitamin D and metabolic syndrome: A review Diabetes & Metabolic Syndrome: Clinical Research & Reviews xxx (2015) xxx-xxx. http://dx.doi.org/ 10.1016/j.dsx.2015.02.014
74. Kunutsor SK, Apekey TA, Steur M. Vitamin D and risk of future hypertension: meta-analysis of 283,537 participants. Eur J Epidemiol 2013;28:205-21.
75. Forman JP, Giovannucci E, Holmes MD. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension 2007;49:1063-9.
76. Hypponen E, Boucher BJ, Berry DJ. 25- Hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a crosssectional study in the 1958 British Birth Cohort. Diabetes 2008;57:298-305.
77. Forman JP, Scott JB, Drake BF, Suarez EG, Hayden DL, Bennett GG, et al. Effect of vitamin D supplementation on blood pressure in blacks. Hypertension 2013;61:779-85.
78. Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Hiraki LT, et al. Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med 2013;10:e1001383.
79. Grineva EN, Karonova T, Micheeva E, Belyaeva O, Nikitina IL. Vitamin D deficiency is a risk factor for obesity and diabetes type 2 in women at late reproductive age. Aging 2013;5:575-81.
80. Guasch A, Bullo M, Rabassa A, Bonada A, Castillo D, Sabench F, et al. Plasma vitamin D and parathormone are associated with obesity and atherogenic dyslipidemia: a cross-sectional study. Cardiovasc Diabetol 2012;11: 149-60.
81. Salehpour A, Hosseinpanah F, Shidfar F, Vafa M, Razaghi M, Dehghani S, et al. A 12-week double-blind randomized clinical trial of vitamin D3 supplementation on body fat mass in healthy overweight and obese women. Nutr J 2012;11:78.
82. Carrillo A, Flynn M, Pinkston C, Markofski M, Jiang Y, Donkin S, et al. Impact of vitamin D supplementation during a resistance training intervention on body composition, muscle function, and glucose tolerance in overweight and obese adults. Clin Nutr 2013;32:375-81
83. Mathieu C, Gysemans C, Giulietti A. Vitamin D and diabetes. Diabetologia 2005;48:1247-57.
84. Liu E, Meigs JB, Pittas AG. Plasma 25- hydroxyvitamin D is associated with markers of the insulin resistant phenotype in nondiabetic adults. J Nutr 2009;139:329-34.
85. Pittas AG, Harris SS, Stark PC. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 2007;30:980-6.
86. Harris SS, Pittas GA, Palermo JN. A randomized, placebo-controlled trial of vitamin D supplementation to improve glycaemia in overweight and obese African Americans. Diabetes Obes Metab 2012;14:789-94.
87. Jorde R, Grimnes G. Vitamin D and metabolic health with special reference to the effect of vitamin D on serum lipids. Prog Lipid Res 2011;50:303-12.
88. Jaimungal S, Wehmeier K, Mooradian AD, Haas MJ. The emerging evidence for vitamin D-mediated regulation of apolipoprotein AI synthesis. Nutr Res 2011;31:805-12.
89. Chai W, Cooney RV, Franke AA, Bostick RM. Effects of calcium and vitamin D supplementation on blood pressure and serum lipids and carotenoids: a randomized, double-blind, placebocontrolled, clinical trial. Ann Epidemiol 2013;23:564-70.
90. Pilz S, Tomaschitz A, Marz W, Drechsler C, Ritz E, Zittermann A, et al. Vitamin D, cardiovascular disease and mortality. Clin Endocrinol (Oxf) 2011;75:575-84.