Vitamin D and Major Chronic Illness
Sadeq A Quraishi
Carlos A Camargo
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Keywords

25(OH)D
25-hydroxyvitamin
Vitamin D
chronic illness
general health
restorative medicine
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Abstract

OBJECTIVE: To review the current literature regarding vitamin D insufficiency and supplementation in major illnesses.

DESIGN AND METHODS: We reviewed Pubmed-indexed, English language manuscripts from January, 2003 to June, 2012 using search terms related to vitamin D, all-cause mortality, cardiovascular disease, pulmonary disease, diabetes mellitus, and cancer.

OUTCOME MEASURES: Incidence of disease, risk ratios associated with 25-hydroxyvitamin D [25(OH)D] levels, and/or vitamin D supplementation schedules were documented.

RESULTS: Although 25(OH)D levels ≥20 ng/mL were often associated with improved health outcomes, evidence suggests that 25(OH)D levels ≥30 ng/mL may confer additional health benefits.

CONCLUSIONS: Based on the available evidence, vitamin D supplementation to restore 25(OH)D levels within a range of 30-50 ng/mL is reasonable in order to optimize potential benefits and minimize potential risks. This, of course, should be considered in the context of individual patient needs and co-morbidities.

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References

Adams JS, Hewison M. Update in vitamin D. J. Clin. Endocrinol. Metab. 2010; 95(2):471–8.
Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch. Intern. Med. 2009; 169(6):626–32.
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J. Clin. Endocrinol. Metab. 2011; 96(1):53–8.
Heaney RP, Holick MF. Why the IOM recommendations for vitamin D are deficient. J. Bone Miner. Res. 2011; 26(3):455–7.
Moreno LA, Valtueña J, Pérez-López F, González-Gross M. Health effects related to low vitamin d concentrations: beyond bone metabolism.Ann. Nutr. Metab. 2011; 59(1):22–7.
Kulie T, Groff A, Redmer J, Hounshell J, Schrager S. Vitamin D: an evidence-based review. J. Am. Board Fam. Med. 2009; 22(6):698–706.
Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vitamin d deficiency and supplementation and relation to cardiovascular health. Am. J. Cardiol. 2012; 109(3):359–63.
Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am. J. Clin. Nutr. 2007; 85(6):1586–91.
Laaksi I, Ruohola JP, Mattila V, Auvinen A, Ylikomi T, Pihlajamäki H. Vitamin D supplementation for the prevention of acute respiratory tract infection: a randomized, double-blinded trial among young Finnish men. J. Infect. Dis. 2010; 202(5):809–14.
Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch. Intern. Med. 2007; 167(16):1730–7.
Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2011;(7):CD007470.
de Paula FJA, Rosen CJ. Vitamin D safety and requirements. Arch. Biochem. Biophys. 2011 Dec. 9.
Lai JKC, Lucas RM, Clements MS, Harrison SL, Banks E. Assessing vitamin D status: pitfalls for the unwary. Mol. Nutr. Food Res. 2010 Aug.; 54(8):1062–71.
Heaney RP, Recker RR, Grote J, Horst RL, Armas LAG. Vitamin D(3) is more potent than vitamin D(2) in humans. J. Clin. Endocrinol. Metab. 2011 Mar.; 96(3):E447–52.
Glendenning P, Inderjeeth CA. Screening for vitamin D deficiency: defining vitamin D deficiency, target thresholds of treatment and estimating the benefits of treatment. Pathology. 2012 Feb.; 44(2):160–5.
Henry HL. Regulation of vitamin D metabolism. Best Pract. Res. Clin. Endocrinol. Metab. 2011 Aug.; 25(4):531–41.
Amrein K, Venkatesh B. Vitamin D and the critically ill patient. Curr Opin Clin Nutr Metab Care. 2012 Mar.; 15(2):188–93.
Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br. J. Nutr. 2003 May; 89(5):552–72.
Passeri G, Pini G, Troiano L, Vescovini R, Sansoni P, Passeri M, et al. Low vitamin D status, high bone turnover, and bone fractures in centenarians. Journal of Clinical Endocrinology & Metabolism. Endocrine Soc; 2003; 88(11):5109.
Cashman KD, Kiely M. Towards prevention of vitamin D deficiency and beyond: knowledge gaps and research needs in vitamin D nutrition and public health. BJN. 2011 Dec.; 106(11):1617–27.
Biesalski HK. Vitamin D recommendations: beyond deficiency. Ann Nutr Metab. 2011; 59(1):10–6.
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2011. p. 1911–30.
Durazo-Arvizu RA, Dawson-Hughes B, Sempos CT, Yetley EA, Looker AC, Cao G, et al. Three-phase model harmonizes estimates of the maximal suppression of parathyroid hormone by 25-hydroxyvitamin D in persons 65 years of age and older. J. Nutr. 2010 Mar.; 140(3):595–9.
Holick MF. Vitamin D: A millenium perspective. J. Cell. Biochem. 2003 Feb. 1; 88(2):296–307.
White JH. Vitamin D metabolism and signaling in the immune system. Rev Endocr Metab Disord. 2011 Aug. 16.
Schwalfenberg GK. A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol. Nutr. Food Res. 2011 Jan.; 55(1):96–108.
Aranow C. Vitamin D and the immune system. J. Investig. Med. 2011 Aug.; 59(6):881–6.
Sigmundsdottir H. From the bench to the clinic: New aspects on immunoregulation by vitamin D analogs. Dermatoendocrinol. 2011 Jul.; 3(3):187–92.
Clendenen TV, Koenig KL, Arslan AA, Lukanova A, Berrino F, Gu Y, et al. Factors associated with inflammation markers, a cross-sectional analysis. Cytokine. 2011 Dec.; 56(3):769–78.
White JH. Regulation of intracrine production of 1,25-dihydroxyvitamin D and its role in innate immune defense against infection. ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS. 2011Nov. 15.
Wu S, Sun J. Vitamin D, vitamin D receptor, and macroautophagy in inflammation and infection. Discov Med. 2011 Apr.; 11(59):325–35.
Méndez-Samperio P. The human cathelicidin hCAP18/LL-37: a multifunctional peptide involved in mycobacterial infections. Peptides. 2010 Sep.; 31(9):1791–8.
Bhan I, Camargo CA Jr, Wenger J, Ricciardi C, Ye J, Borregaard N, et al. Circulating levels of 25-hydroxyvitamin D and human cathelicidin in healthy adults. J. Allergy Clin. Immunol. 2011 May; 127(5):1302–4.e1.
Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch. Intern. Med. 2008 Jun. 23; 168(12):1340–9.
Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch. Intern. Med. 2008 Aug. 11; 168(15):1629–37.
Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older US. adults. J Am Geriatr Soc. 2009 Sep.; 57(9):1595–603.
Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. European Journal of Clinical Nutrition. 2011 Sep.; 65(9):1016–26.
Akin F, Ayça B, Köse N, Duran M, Sar M, Uysal OK, et al. Serum Vitamin D Levels Are Independently Associated With Severity of Coronary Artery Disease. J. Investig. Med. 2012 Apr. 24.
Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, et al. Vitamin D deficiency and risk of cardiovascular disease.Circulation. 2008 Jan. 29; 117(4):503–11.
Khalili H, Talasaz AH, Salarifar M. Serum vitamin D concentration status and its correlation with early biomarkers of remodeling following acute myocardial infarction. Clin Res Cardiol. 2011 Dec. 11.
Kestenbaum B, Katz R, de Boer I, Hoofnagle A, Sarnak MJ, Shlipak MG, et al. Vitamin D, parathyroid hormone, and cardiovascular events among older adults. J. Am. Coll. Cardiol. 2011 Sep. 27; 58(14):1433–41.
Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet. Med. 2008 Mar.; 25(3):320–5.
Salehpour A, Shidfar F, Hosseinpanah F, Vafa M, Razaghi M, Hoshiarrad A, et al. Vitamin D3 and the risk of CVD in overweight and obese women: a randomised controlled trial. BJN. 2012 Feb. 9;1–8.
Vaidya A, Sun B, Forman JP, Hopkins PN, Brown NJ, Kolatkar NS, et al. The Fok1 vitamin D receptor gene polymorphism is associated with plasma renin activity in Caucasians. Clin. Endocrinol. (Oxf) . 2011 Jun. 74(6):783–90.
Shirts BH, Howard MT, Hasstedt SJ, Nanjee MN, Knight S, Carlquist JF, et al. Vitamin D dependent effects of APOA5 polymorphisms on HDL cholesterol. Atherosclerosis. 2012 May; 222(1):167–74.
Ortlepp JR, Korff von A, Hanrath P, Zerres K, Hoffmann R. Vitamin D receptor gene polymorphism BsmI is not associated with the prevalence and severity of CAD in a large-scale angiographic cohort of 3441 patients. Eur. J. Clin. Invest. 2003 Feb.; 33(2):106–9.
Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol. 2008 Feb.; 37(1):113–9.
Martineau AR, Wilkinson RJ, Wilkinson KA, Newton SM, Kampmann B, Hall BM, et al. A single dose of vitamin D enhances immunity to mycobacteria. Am. J. Respir. Crit. Care Med. 2007 Jul.; 15; 176(2):208–13.
Nursyam EW, Amin Z, Rumende CM. The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med Indones. 2006 Jan.; 38(1):3–5.
Martineau AR, Timms PM, Bothamley GH, Hanifa Y, Islam K, Claxton AP, et al. High-dose vitamin D3 during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet. Elsevier; 2011.
Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung DYM. Vitamin D levels, lung function, and steroid response in adult asthma. Am. J. Respir. Crit. Care Med. 2010 Apr. 1; 181(7):699–704.
Devereux G, Wilson A, Avenell A, McNeill G, Fraser WD. A case-control study of vitamin D status and asthma in adults. Allergy. 2010 May; 65(5):666–7.
Hughes AM, Lucas RM, Ponsonby AL, Chapman C, Coulthard A, Dear K, et al. The role of latitude, ultraviolet radiation exposure and vitamin D in childhood asthma and hayfever: an Australian multicenter study. Pediatr Allergy Immunol. 2011 May; 22(3):327–33.
Searing DA, Zhang Y, Murphy JR, Hauk PJ, Goleva E, Leung DYM. Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use. J. Allergy Clin. Immunol. 2010 May; 125(5):995–1000.
Goleva E, Searing DA, Jackson LP, Richers BN, Leung DYM. Steroid requirements and immune associations with vitamin D are stronger in children than adults with asthma. J. Allergy Clin. Immunol. 2012 May; 129(5):1243–51.
Poon AH, Laprise C, Lemire M, Montpetit A, Sinnett D, Schurr E, et al. Association of vitamin D receptor genetic variants with susceptibility to asthma and atopy. Am. J. Respir. Crit. Care Med. Am Thoracic Soc ; 2004; 170(9):967–73.
Raby BA, Lazarus R, Silverman EK, Lake S, Lange C, Wjst M, et al. Association of vitamin D receptor gene polymorphisms with childhood and adult asthma. Am. J. Respir. Crit. Care Med. Am Thoracic Soc ; 2004; 170(10):1057–65.
Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, et al. Epidemic influenza and vitamin D. Epidemiol. Infect. 2006 Dec.; 134(6):1129–40.
White ANJ, Ng V, Spain CV, Johnson CC, Kinlin LM, Fisman DN. Let the sun shine in: effects of ultraviolet radiation on invasive pneumococcal disease risk in Philadelphia, Pennsylvania. BMC Infect Dis. 2009; 9:196.
Leow L, Simpson T, Cursons R, Karalus N, Hancox RJ. Vitamin D, innate immunity and outcomes in community acquired pneumonia.Respirology. 2011 May; 16(4):611–6.
Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS ONE. 2010; 5(6):e11088.
Laaksi I, Ruohola JP, Tuohimaa P, Auvinen A, Haataja R, Pihlajamäki H, et al. An association of serum vitamin D concentrations. Am. J. Clin. Nutr. Am Soc Nutrition ; 2007; 86(3):714.
Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch. Intern. Med. 2009 Feb. 23; 169(4):384–90.
Berry DJ, Hesketh K, Power C, Hyppönen E. Vitamin D status has a linear association with seasonal infections and lung function in British adults. BJN. 2011 Nov.; 106(9):1433–40.
Aloia JF, LI-NG M. Re: epidemic influenza and vitamin D. Epidemiol. Infect. 2007 Oct.; 135(7): 1095–6–author-reply–1097–8. .
Wolfenden LL, Judd SE, Shah R, Sanyal R, Ziegler TR, Tangpricha V. Vitamin D and bone health in adults with cystic fibrosis. Clin. Endocrinol. (Oxf) . 2008 Sep.; 69(3):374–81.
Stephenson A, Brotherwood M, Robert R, Atenafu E, Corey M, Tullis E. Cholecalciferol significantly increases 25-hydroxyvitamin D concentrations in adults with cystic fibrosis. Am. J. Clin. Nutr. Am Soc Nutrition ; 2007; 85(5):1307–11.
Pincikova T, Nilsson K, Moen IE, Karpati F, Fluge G, Hollsing A, et al. Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study. European Journal of Clinical Nutrition. 2011 Jan.; 65(1):102–9.
Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest. 2005 Dec.; 128(6):3792–8.
Ferrari M, Schenk K, Papadopoulou C, Ferrari P, Dalle Carbonare L, Bertoldo F. Serum 25-hydroxy vitamin D and exercise capacity in COPD.Thorax. BMJ Publishing Group Ltd and British Thoracic Society ; 2011; 66(6):544–5.
Janssens W, Bouillon R, Claes B, Carremans C, Lehouck A, Buysschaert I, et al. Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax. 2010 Mar.; 65(3):215–20.
Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van Eldere J, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann. Intern. Med. 2012 Jan. 17; 156(2):105–14.
Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. Elsevier ; 2001; 358(9292):1500–3.
Zipitis CS, Akobeng AK. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis.Arch. Dis. Child. 2008 Jun.; 93(6):512–7.
Mohr SB, Garland FC, Garland CF, Gorham ED, Ricordi C. Is there a role of vitamin D deficiency in type 1 diabetes of children? Am J Prev Med. 2010 Aug.; 39(2):189–90.
Zhang J, Li W, Liu J, Wu W, Ouyang H, Zhang Q, et al. Polymorphisms in the vitamin D receptor gene and type 1 diabetes mellitus risk: an update by meta-analysis. Molecular and Cellular Endocrinology. 2012 May 15; 355(1):135–42.
Chiu KC, Chu A, Go VLW, Saad MF. Hypovitaminosis D is associated with insulin resistance and ß cell dysfunction. Am. J. Clin. Nutr. Am Soc Nutrition ; 2004; 79(5):820–5.
Karnchanasorn R, Ou H. Plasma 25-Hydroxyvitamin D Levels Are Favorably Associated With [beta]-Cell Function. Pancreas. 2012.
Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care. 2007 Apr.; 30(4):980–6.
Forouhi NG, Ye Z, Rickard AP, Khaw KT, Luben R, Langenberg C, et al. Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia. 2012 Apr. 15.
González-Molero I, Rojo-Martínez G, Morcillo S, Gutiérrez-Repiso C, Rubio-Martín E, Almaraz MC, et al. Vitamin D and incidence of diabetes: A prospective cohort study. Clin Nutr. 2011 Dec. 26.
Bid HK, Konwar R, Aggarwal CG, Gautam S, Saxena M, Nayak VL, et al. Vitamin D receptor (FokI, BsmI and TaqI) gene polymorphisms and type 2 diabetes mellitus: a North Indian study. Indian J Med Sci. 2009 May; 63(5):187–94.
Dilmec F, Uzer E, Akkafa F, Kose E, van Kuilenburg ABP. Detection of VDR gene ApaI and TaqI polymorphisms in patients with type 2 diabetes mellitus using PCR-RFLP method in a Turkish population. J. Diabetes Complicat. 2010 May; 24(3):186–91.
Malecki M, Klupa T, Wolkow P, Bochenski J, Wanic K, Sieradzki J. Association study of the vitamin D: 1alpha-hydroxylase (CYP1alpha) gene and type 2 diabetes mellitus in a Polish population. Diabetes Metab. Elsevier ; 2003; 29(2):119–24.
Malecki M, Frey J, Moczulski D, Klupa T, Kozek E, Sieradzki J. Vitamin D receptor gene polymorphisms and association with type 2 diabetes mellitus in a Polish population. Experimental and Clinical Endocrinology and Diabetes. Heidelberg: Johann Ambrosius Barth, 1995 ; 2003; 111(8):505.
Valdivielso JM, Fernandez E. Vitamin D receptor polymorphisms and diseases. Clin. Chim. Acta. 2006 Sep.; 371(1-2):1–12.
Avenell A, Maclennan GS, Jenkinson DJ, McPherson GC, McDonald AM, Pant PR, et al. Long-Term Follow-Up for Mortality and Cancer in a Randomized Placebo-Controlled Trial of Vitamin D3 and/or Calcium (RECORD Trial). J. Clin. Endocrinol. Metab. 2012 Feb.; 97(2):614–22.
Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J. Natl. Cancer Inst. 2006 Apr. 5; 98(7):451–9.
Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. J. Natl. Cancer Inst. 2007 Nov. 7; 99(21):1594–602.
Lee JE. Circulating levels of vitamin D, vitamin D receptor polymorphisms, and colorectal adenoma: a meta-analysis. Nutr Res Pract. 2011 Oct.; 5(5):464–70.
Gorham ED, Garland CF, Garland FC, Grant WB, Mohr SB, Lipkin M, et al. Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am J Prev Med. 2007 Mar.; 32(3):210–6.
Touvier M, Chan DSM, Lau R, Aune D, Vieira R, Greenwood DC, et al. Meta-analyses of vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms, and colorectal cancer risk. Cancer Epidemiol. Biomarkers Prev. 2011 May; 20(5):1003–16.
Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM. Intakes of calcium and vitamin D and breast cancer risk in women. Arch. Intern. Med. 2007 May 28; 167(10):1050–9.
Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: serum vitamin D and breast cancer risk. Eur. J. Cancer. 2010 Aug.; 46(12):2196–205.
Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int. J. Cancer. 2011 Mar. 15; 128(6):1414–24.
Köstner K, Denzer N, Müller CSL, Klein R, Tilgen W, Reichrath J. The relevance of vitamin D receptor (VDR) gene polymorphisms for cancer: a review of the literature. Anticancer Res. 2009 Sep.; 29(9):3511–36.
Dorjgochoo T, Delahanty R, Lu W, Long J, Cai Q, Zheng Y, et al. Common genetic variants in the vitamin D pathway including genome-wide associated variants are not associated with breast cancer risk among Chinese women. Cancer Epidemiol. Biomarkers Prev. 2011 Oct.; 20(10):2313–6.
McKay JD, McCullough ML, Ziegler RG, Kraft P, Saltzman BS, Riboli E, et al. Vitamin D receptor polymorphisms and breast cancer risk: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. Cancer Epidemiol. Biomarkers Prev. 2009 Jan.; 18(1):297–305.
Tang C, Chen N, Wu M, Yuan H, Du Y. Fok1 polymorphism of vitamin D receptor gene contributes to breast cancer susceptibility: a meta-analysis. Breast Cancer Res. Treat. 2009 Sep.; 117(2):391–9.
Anderson LN, Cotterchio M, Cole DEC, Knight JA. Vitamin D-related genetic variants, interactions with vitamin D exposure, and breast cancer risk among Caucasian women in Ontario. Cancer Epidemiol. Biomarkers Prev. 2011 Aug.; 20(8):1708–17.
Yin L, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis of longitudinal studies: Serum vitamin D and prostate cancer risk. Cancer Epidemiol. 2009 Dec.; 33(6):435–45.
Gilbert R, Martin RM, Beynon R, Harris R, Savovic J, Zuccolo L, et al. Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control. 2011 Mar.; 22(3):319–40.
Travis RC, Crowe FL, Allen NE, Appleby PN, Roddam AW, Tjønneland A, et al. Serum vitamin D and risk of prostate cancer in a case-control analysis nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Am. J. Epidemiol. 2009 May 15; 169(10):1223–32.
Luxwolda MF, Kuipers RS, Kema IP, Janneke Dijck-Brouwer DA, Muskiet FAJ. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. BJN. 2012 Jan. 23;1–5.
Barker T, Martins TB, Hill HR, Kjeldsberg CR, Henriksen VT, Dixon BM, et al. Different doses of supplemental vitamin D maintain interleukin-5 without altering skeletal muscle strength: a randomized, double-blind, placebo-controlled study in vitamin D sufficient adults. Nutr Metab (Lond). 2012; 9(1):16.
Vieth R, Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am. J. Clin. Nutr. 2001 Feb.; 73(2):288–94.
Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J. 2004 Jul. 19; 3:8.
Diamond T, Wong YK, Golombick T. Effect of oral cholecalciferol 2,000 versus 5,000 IU on serum vitamin D, PTH, bone and muscle strength in patients with vitamin D deficiency. Osteoporos Int. 2012 Mar. 16.
Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am. J. Clin. Nutr. Am Soc Nutrition ; 2003; 77(1):204–10.
Ilahi M, Armas LAG, Heaney RP. Pharmacokinetics of a single, large dose of cholecalciferol. American Journal of Clinical Nutrition. 2008 Mar.; 87(3):688–91.
Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003 Mar. 1; 326(7387):469.
Peppone LJ, Huston AJ, Reid ME, Rosier RN, Zakharia Y, Trump DL, et al. The effect of various vitamin D supplementation regimens in breast cancer patients. Breast Cancer Res. Treat. 2011 May; 127(1):171–7.
Sanders KM, Stuart AL, Williamson EJ, Jacka FN, Dodd S, Nicholson G, et al. Annual high-dose vitamin D3 and mental well-being: randomised controlled trial. Br J Psychiatry. 2011 May; 198(5):357–64.
Rossini M, Gatti D, Viapiana O, Fracassi E, Idolazzi L, Zanoni S, et al. Short-Term Effects on Bone Turnover Markers of a Single High Dose of Oral Vitamin D3. J. Clin. Endocrinol. Metab. 2012 Feb. 1.
Vieth R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J. Nutr. 2006Apr.; 136(4):1117–22.
Vieth R. Vitamin D toxicity, policy, and science. J. Bone Miner. Res. 2007 Dec.; 22 Suppl 2:V64–8.
Jones G. Pharmacokinetics of vitamin D toxicity. American Journal of Clinical Nutrition. 2008 Aug.; 88(2):582S–586S.
Heaney RP. Vitamin D: criteria for safety and efficacy. Nutr. Rev. 2008 Oct.; 66(10Suppl 2):S178–81.
Glade MJ. A 21st century evaluation of the safety of oral vitamin D. Nutrition. 2012 Apr.; 28(4):344–56.
Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am. J. Clin. Nutr. 1999 May; 69(5):842–56.
Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int. 1998; 8(3):222–30.
Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am. J. Clin. Nutr. 2007 Jan.; 85(1):6–18.
Holick MF. Sunlight “D”ilemma: risk of skin cancer or bone disease and muscle weakness. Lancet. 2001 Jan. 6; 357(9249):4–6.

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