Vitamin D: not just the bone. Evidence for beneficial pleiotropic extraskeletal effects

  • Massimiliano CaprioEmail author
  • Marco Infante
  • Matilde Calanchini
  • Caterina Mammi
  • Andrea Fabbri


Vitamin D is a fat-soluble vitamin and a steroid hormone that plays a central role in maintaining calcium-phosphorus and bone homeostasis in close interaction with parathyroid hormone, acting on its classical target tissues, namely, bone, kidney, intestine, and parathyroid glands. However, vitamin D endocrine system regulates several genes (about 3 % of the human genome) involved in cell differentiation, cell-cycle control, and cell function and exerts noncalcemic/pleiotropic effects on extraskeletal target tissues, such as immune and cardiovascular system, pancreatic endocrine cells, muscle, and adipose tissue. Several studies have demonstrated the role of vitamin D supplementation in the prevention/treatment of various autoimmune diseases and improvement of glucose metabolism, muscle, and adipose tissue function. Hence, this review aims to elucidate the effects of vitamin D on extraskeletal target tissues and to investigate the potential therapeutic benefit of vitamin D supplementation among a broad group of pathological conditions, especially with regard to metabolic and autoimmune diseases. In addition, we focused on the best daily intakes and serum levels of vitamin D required for extraskeletal benefits which, even if still controversial, appear to be higher than those widely accepted for skeletal effects.


Autoimmune diseases Hashimoto thyroiditis Multiple sclerosis Glucose metabolism Adipose tissue Obesity Diabetes Skeletal muscle Eating disorders Anorexia nervosa 



Vitamin D3




25-Hydroxyvitamin D3


1,25-Dihydroxyvitamin D3


Vitamin D binding protein


Vitamin D receptor


Parathyroid hormone


Bone mineral density


Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Informed consent

For this type of study Informed consent is not required.


  1. 1.
    Webb AR, Pilbeam C, Hanafin N, Holick MF (1990) An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25-hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr 51:1075–1081CrossRefGoogle Scholar
  2. 2.
    MacLaughlin J, Holick MF (1985) Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 76:1536–1538. doi: 10.1172/JCI112134 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW (2004) Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA 101:7711–7715. doi: 10.1073/pnas.0402490101 CrossRefPubMedGoogle Scholar
  4. 4.
    Foresta C, Strapazzon G, De TL, Perilli L, Di MA, Muciaccia B et al (2011) Bone mineral density and testicular failure: evidence for a role of vitamin D 25-hydroxylase in human testis. J Clin Endocrinol Metab 96:E646–E652. doi: 10.1210/jc.2010-1628 CrossRefPubMedGoogle Scholar
  5. 5.
    Henry HL (2011) Regulation of vitamin D metabolism. Best Pract Res Clin Endocrinol Metab 25:531–541. doi: 10.1016/j.beem.2011.05.003 CrossRefPubMedGoogle Scholar
  6. 6.
    Jones G, Prosser DE, Kaufmann M (2014) Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res 55:13–31. doi: 10.1194/jlr.R031534 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B (2006) Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J. 20:720–722. doi: 10.1096/fj.05-5432fje CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Murayama A, Takeyama K, Kitanaka S, Kodera Y, Hosoya T, Kato S (1998) The promoter of the human 25-hydroxyvitamin D3 1 alpha-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin, and 1 alpha,25(OH)2D3. Biochem Biophys Res Commun 249:11–16CrossRefGoogle Scholar
  9. 9.
    Kato S, Fujiki R, Kim MS, Kitagawa H (2007) Ligand-induced transrepressive function of VDR requires a chromatin remodeling complex. WINAC J Steroid Biochem Mol Biol 103:372–380. doi: 10.1016/j.jsbmb.2006.12.038 CrossRefPubMedGoogle Scholar
  10. 10.
    Fu GK, Lin D, Zhang MY, Bikle DD, Shackleton CH, Miller WL et al (1997) Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol Endocrinol 11:1961–1970. doi: 10.1210/mend.11.13.0035 CrossRefPubMedGoogle Scholar
  11. 11.
    Overbergh L, Decallonne B, Valckx D, Verstuyf A, Depovere J, Laureys J et al (2000) Identification and immune regulation of 25-hydroxyvitamin D-1-alpha-hydroxylase in murine macrophages. Clin Exp Immunol 120:139–146CrossRefGoogle Scholar
  12. 12.
    Bouillon R, Carmeliet G, Verlinden L, van EE, Luderer HF, Verstuyf A et al (2008) Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev 29:726–776. doi: 10.1210/er.2008-0004 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Merke J, Milde P, Lewicka S, Hugel U, Klaus G, Mangelsdorf DJ et al (1989) Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Invest 83:1903–1915. doi: 10.1172/JCI114097 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Caprio M, Mammi C, Rosano GM (2012) Vitamin D: a novel player in endothelial function and dysfunction. Arch Med Sci 8:4–5. doi: 10.5114/aoms.2012.27271 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Merke J, Hofmann W, Goldschmidt D, Ritz E (1987) Demonstration of 1,25(OH)2 vitamin D3 receptors and actions in vascular smooth muscle cells in vitro. Calcif Tissue Int 41:112–114CrossRefGoogle Scholar
  16. 16.
    O’Connell TD, Berry JE, Jarvis AK, Somerman MJ, Simpson RU (1997) 1,25-Dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy. Am J Physiol 272:H1751–H1758PubMedGoogle Scholar
  17. 17.
    Jensen SS, Madsen MW, Lukas J, Binderup L, Bartek J (2001) Inhibitory effects of 1alpha,25-dihydroxyvitamin D(3) on the G(1)-S phase-controlling machinery. Mol Endocrinol 15:1370–1380. doi: 10.1210/mend.15.8.0673 CrossRefPubMedGoogle Scholar
  18. 18.
    Santoro D, Sebekova K, Teta D, De NL (2015) Extraskeletal Functions of Vitamin D. Biomed Res Int. doi: 10.1155/2015/294719 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Overbergh L, Stoffels K, Waer M, Verstuyf A, Bouillon R, Mathieu C (2006) Immune regulation of 25-hydroxyvitamin D-1alpha-hydroxylase in human monocytic THP1 cells: mechanisms of interferon-gamma-mediated induction. J Clin Endocrinol Metab 91:3566–3574. doi: 10.1210/jc.2006-0678 CrossRefPubMedGoogle Scholar
  20. 20.
    Amado Diago CA (2016) Garcia-Unzueta MT, Farinas MD, Amado JA. Calcitriol-modulated human antibiotics: new pathophysiological aspects of vitamin D. Endocrinol Nutr 63:87–94. doi: 10.1016/j.endonu.2015.09.005 CrossRefPubMedGoogle Scholar
  21. 21.
    Kankova M, Luini W, Pedrazzoni M, Riganti F, Sironi M, Bottazzi B et al (1991) Impairment of cytokine production in mice fed a vitamin D3-deficient diet. Immunology 73:466–471PubMedPubMedCentralGoogle Scholar
  22. 22.
    Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR et al (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311:1770–1773. doi: 10.1126/science.1123933 CrossRefGoogle Scholar
  23. 23.
    Lucisano S, Arena A, Stassi G, Iannello D, Montalto G, Romeo A et al (2015) Role of Paricalcitol in Modulating the Immune Response in Patients with Renal Disease. Int J Endocrinol 2015:765364. doi: 10.1155/2015/765364 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bouillon R, Lieben L, Mathieu C, Verstuyf A, Carmeliet G (2013) Vitamin D action: lessons from VDR and Cyp27b1 null mice. Pediatr. Endocrinol. Rev. 10(Suppl 2):354–366PubMedGoogle Scholar
  25. 25.
    Armanini D, Andrisani A, Ambrosini G, Dona G, Camozzi V, Bordin L et al (2016) Interrelationship Between Vitamin D Insufficiency, Calcium Homeostasis, Hyperaldosteronism, and Autoimmunity. J Clin Hypertens (Greenwich). doi: 10.1111/jch.12822 CrossRefGoogle Scholar
  26. 26.
    Chang SH, Chung Y, Dong C (2010) Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem 285:38751–38755. doi: 10.1074/jbc.C110.185777 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Herrada AA, Contreras FJ, Marini NP, Amador CA, Gonzalez PA, Cortes CM et al (2010) Aldosterone promotes autoimmune damage by enhancing Th17-mediated immunity. J Immunol 184:191–202. doi: 10.4049/jimmunol.0802886 CrossRefPubMedGoogle Scholar
  28. 28.
    Marzolla V, Armani A, Feraco A, De Martino MU, Fabbri A, Rosano G et al (2014) Mineralocorticoid receptor in adipocytes and macrophages: a promising target to fight metabolic syndrome. Steroids 91:46–53. doi: 10.1016/j.steroids.2014.05.001 CrossRefPubMedGoogle Scholar
  29. 29.
    Takiishi T, Van BT, Gysemans C, Mathieu C (2013) Effects of vitamin D on antigen-specific and non-antigen-specific immune modulation: relevance for type 1 diabetes. Pediatr Diabetes 14:81–89. doi: 10.1111/j.1399-5448.2012.00923.x CrossRefPubMedGoogle Scholar
  30. 30.
    Takiishi T, Ding L, Baeke F, Spagnuolo I, Sebastiani G, Laureys J et al (2014) Dietary supplementation with high doses of regular vitamin D3 safely reduces diabetes incidence in NOD mice when given early and long term. Diabetes 63:2026–2036. doi: 10.2337/db13-1559 CrossRefPubMedGoogle Scholar
  31. 31.
    Treiber G, Prietl B, Frohlich-Reiterer E, Lechner E, Ribitsch A, Fritsch M et al (2015) Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus—a randomized clinical trial. Clin Immunol 161:217–224. doi: 10.1016/j.clim.2015.08.002 CrossRefPubMedGoogle Scholar
  32. 32.
    Giulietti A, Gysemans C, Stoffels K, van EE, Decallonne B, Overbergh L et al (2004) Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice. Diabetologia 47:451–462. doi: 10.1007/s00125-004-1329-3 CrossRefPubMedGoogle Scholar
  33. 33.
    Zella JB, DeLuca HF (2003) Vitamin D and autoimmune diabetes. J Cell Biochem 88:216–222. doi: 10.1002/jcb.10347 CrossRefPubMedGoogle Scholar
  34. 34.
    Cooper JD, Smyth DJ, Walker NM, Stevens H, Burren OS, Wallace C et al (2011) Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes 60:1624–1631. doi: 10.2337/db10-1656 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Guo SW, Magnuson VL, Schiller JJ, Wang X, Wu Y, Ghosh S (2006) Meta-analysis of vitamin D receptor polymorphisms and type 1 diabetes: a HuGE review of genetic association studies. Am J Epidemiol 164:711–724. doi: 10.1093/aje/kwj278 CrossRefPubMedGoogle Scholar
  36. 36.
    Mathieu C, Gysemans C, Giulietti A, Bouillon R (2005) Vitamin D and diabetes. Diabetologia 48:1247–1257. doi: 10.1007/s00125-005-1802-7 CrossRefPubMedGoogle Scholar
  37. 37.
    Karvonen M, Jantti V, Muntoni S, Stabilini M, Stabilini L, Muntoni S et al (1998) Comparison of the seasonal pattern in the clinical onset of IDDM in Finland and Sardinia. Diabetes Care 21:1101–1109CrossRefGoogle Scholar
  38. 38.
    Gabbay MA, Sato MN, Finazzo C, Duarte AJ, Dib SA (2012) Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual beta-cell function in new-onset type 1 diabetes mellitus. Arch Pediatr Adolesc Med 166:601–607. doi: 10.1001/archpediatrics.2012.164 CrossRefPubMedGoogle Scholar
  39. 39.
    Baidal DA, Ricordi C, Garcia-Contreras M, Sonnino A, Fabbri A (2016) Combination high-dose omega-3 fatty acids and high-dose cholecalciferol in new onset type 1 diabetes: a potential role in preservation of beta-cell mass. Eur Rev Med Pharmacol Sci 20:3313–3318PubMedGoogle Scholar
  40. 40.
    Mokry LE, Ross S, Ahmad OS, Forgetta V, Smith GD, Leong A et al (2015) Vitamin D and risk of multiple sclerosis: a mendelian randomization study. PLoS Med 12:e1001866 doi: 10.1371/journal.pmed.1001866
  41. 41.
    Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296:2832–2838. doi: 10.1001/jama.296.23.2832 CrossRefPubMedGoogle Scholar
  42. 42.
    Soilu-Hanninen M, Aivo J, Lindstrom BM, Elovaara I, Sumelahti ML, Farkkila M et al (2012) A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 83:565–571. doi: 10.1136/jnnp-2011-301876 CrossRefPubMedGoogle Scholar
  43. 43.
    Muscogiuri G, Tirabassi G, Bizzaro G, Orio F, Paschou SA, Vryonidou A et al (2015) Vitamin D and thyroid disease: to D or not to D? Eur J Clin Nutr 69:291–296. doi: 10.1038/ejcn.2014.265 CrossRefPubMedGoogle Scholar
  44. 44.
    Vondra K, Starka L, Hampl R (2015) Vitamin D and thyroid diseases. Physiol Res 64(Suppl 2):S95–S100PubMedGoogle Scholar
  45. 45.
    Unal AD, Tarcin O, Parildar H, Cigerli O, Eroglu H, Demirag NG (2014) Vitamin D deficiency is related to thyroid antibodies in autoimmune thyroiditis. Cent Eur J Immunol 39:493–497. doi: 10.5114/ceji.2014.47735 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Evliyaoglu O, Acar M, Ozcabi B, Erginoz E, Bucak F, Ercan O et al (2015) Vitamin D deficiency and hashimoto’s thyroiditis in children and adolescents: a critical vitamin D level for this association? J Clin Res Pediatr Endocrinol 7:128–133. doi: 10.4274/jcrpe.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Mazokopakis EE, Papadomanolaki MG, Tsekouras KC, Evangelopoulos AD, Kotsiris DA, Tzortzinis AA (2015) Is vitamin D related to pathogenesis and treatment of Hashimoto’s thyroiditis? Hell J Nucl Med 18:222–227PubMedGoogle Scholar
  48. 48.
    Raman M, Milestone AN, Walters JR, Hart AL, Ghosh S (2011) Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancer. Therap Adv Gastroenterol 4:49–62. doi: 10.1177/1756283X10377820 CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Hypponen E, Boucher BJ, Berry DJ, Power C (2008) 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort. Diabetes 57:298–305. doi: 10.2337/db07-1122 CrossRefPubMedGoogle Scholar
  50. 50.
    Stokic E, Kupusinac A, Tomic-Naglic D, Smiljenic D, Kovacev-Zavisic B, Srdic-Galic B et al (2015) Vitamin D and dysfunctional adipose tissue in obesity. Angiology 66:613–618. doi: 10.1177/0003319714543512 CrossRefPubMedGoogle Scholar
  51. 51.
    Bellia A, Garcovich C, D’Adamo M, Lombardo M, Tesauro M, Donadel G et al (2013) Serum 25-hydroxyvitamin D levels are inversely associated with systemic inflammation in severe obese subjects. Intern Emerg Med 8:33–40. doi: 10.1007/s11739-011-0559-x CrossRefPubMedGoogle Scholar
  52. 52.
    Marcotorchino J, Tourniaire F, Astier J, Karkeni E, Canault M, Amiot MJ et al (2014) Vitamin D protects against diet-induced obesity by enhancing fatty acid oxidation. J Nutr Biochem 25:1077–1083. doi: 10.1016/j.jnutbio.2014.05.010 CrossRefPubMedGoogle Scholar
  53. 53.
    Sergeev IN, Song Q (2014) High vitamin D and calcium intakes reduce diet-induced obesity in mice by increasing adipose tissue apoptosis. Mol Nutr Food Res 58:1342–1348. doi: 10.1002/mnfr.201300503 CrossRefPubMedGoogle Scholar
  54. 54.
    Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Hiraki LT et al (2013) Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med 10:e1001383 doi: 10.1371/journal.pmed.1001383
  55. 55.
    Davidson MB, Duran P, Lee ML, Friedman TC (2013) High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. Diabetes Care 36:260–266. doi: 10.2337/dc12-1204 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Yin X, Yan L, Lu Y, Jiang Q, Pu Y, Sun Q (2016) Correction of hypovitaminosis D does not improve the metabolic syndrome risk profile in a Chinese population: a randomized controlled trial for 1 year. Asia Pac J Clin Nutr 25:71–77. doi: 10.6133/apjcn.2016.25.1.06 CrossRefPubMedGoogle Scholar
  57. 57.
    Wood AD, Secombes KR, Thies F, Aucott L, Black AJ, Mavroeidi A et al (2012) Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT. J Clin Endocrinol Metab 97:3557–3568. doi: 10.1210/jc.2012-2126 CrossRefPubMedGoogle Scholar
  58. 58.
    Mammi C, Calanchini M, Antelmi A, Feraco A, Gnessi L, Falcone S, Quintarelli F, Rosano GM, Fabbri A, Caprio M (2013) Bisphosphonates and adipogenesis: evidence for alendronate inhibition of adipocyte differentiation in 3T3-L1 preadipocytes through a vitamin D receptor mediated effect. Nat Sci 5(8) doi: 10.4236/ns.2013.58116
  59. 59.
    Armani A, Mammi C, Marzolla V, Calanchini M, Antelmi A, Rosano GM et al (2010) Cellular models for understanding adipogenesis, adipose dysfunction, and obesity. J Cell Biochem 110:564–572. doi: 10.1002/jcb.22598 CrossRefPubMedGoogle Scholar
  60. 60.
    Milner RD, Hales CN (1967) The role of calcium and magnesium in insulin secretion from rabbit pancreas studied in vitro. Diabetologia 3:47–49CrossRefGoogle Scholar
  61. 61.
    Sergeev IN, Rhoten WB (1995) 1,25-Dihydroxyvitamin D3 evokes oscillations of intracellular calcium in a pancreatic beta-cell line. Endocrinology 136:2852–2861. doi: 10.1210/endo.136.7.7789310 CrossRefPubMedGoogle Scholar
  62. 62.
    Johnson JA, Grande JP, Roche PC, Kumar R (1994) Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28 k in human and rat pancreas. Am J Physiol 267:E356–E360PubMedGoogle Scholar
  63. 63.
    Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, Erben RG (2003) Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. FASEB J. 17:509–511. doi: 10.1096/fj.02-0424fje CrossRefPubMedGoogle Scholar
  64. 64.
    Maestro B, Davila N, Carranza MC, Calle C (2003) Identification of a Vitamin D response element in the human insulin receptor gene promoter. J Steroid Biochem Mol Biol 84:223–230CrossRefGoogle Scholar
  65. 65.
    Dunlop TW, Vaisanen S, Frank C, Molnar F, Sinkkonen L, Carlberg C (2005) The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. J Mol Biol 349:248–260. doi: 10.1016/j.jmb.2005.03.060 CrossRefPubMedGoogle Scholar
  66. 66.
    Wright DC, Hucker KA, Holloszy JO, Han DH (2004) Ca2+ and AMPK both mediate stimulation of glucose transport by muscle contractions. Diabetes 53:330–335CrossRefGoogle Scholar
  67. 67.
    Gilsanz V, Kremer A, Mo AO, Wren TA, Kremer R (2010) Vitamin D status and its relation to muscle mass and muscle fat in young women. J Clin Endocrinol Metab 95:1595–1600. doi: 10.1210/jc.2009-2309 CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Chiu KC, Chuang LM, Lee NP, Ryu JM, McGullam JL, Tsai GP et al (2000) Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level. Metabolism 49:1501–1505. doi: 10.1053/meta.2000.17708 CrossRefPubMedGoogle Scholar
  69. 69.
    Pittas AG, Lau J, Hu FB, Dawson-Hughes B (2007) The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 92:2017–2029. doi: 10.1210/jc.2007-0298 CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    George PS, Pearson ER, Witham MD (2012) Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis. Diabet Med 29:e142–e150. doi: 10.1111/j.1464-5491.2012.03672.x CrossRefPubMedGoogle Scholar
  71. 71.
    Chandler PD, Giovannucci EL, Scott JB, Bennett GG, Ng K, Chan AT et al (2015) Effects of vitamin D supplementation on C-peptide and 25-hydroxyvitamin D concentrations at 3 and 6 months. Sci. Rep 5:10411. doi: 10.1038/srep10411 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Calvo-Romero JM, Ramiro-Lozano JM (2016) Metabolic effects of supplementation with vitamin D in type 2 diabetic patients with vitamin D deficiency. Diabetes Metab Syndr 10:72–74. doi: 10.1016/j.dsx.2015.09.008 CrossRefPubMedGoogle Scholar
  73. 73.
    Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ (2008) Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990–2000. Diabetes 57:2619–2625. doi: 10.2337/db08-0593 CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Salekzamani S, Mehralizadeh H, Ghezel A, Salekzamani Y, Jafarabadi MA, Bavil AS et al (2016) Effect of high-dose vitamin D supplementation on cardiometabolic risk factors in subjects with metabolic syndrome: a randomized controlled double-blind clinical trial. J Endocrinol Invest. doi: 10.1007/s40618-016-0507-8 CrossRefPubMedGoogle Scholar
  75. 75.
    Jafari T, Fallah AA, Barani A (2016) Effects of vitamin D on serum lipid profile in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Clin Nutr. doi: 10.1016/j.clnu.2016.03.001 CrossRefPubMedGoogle Scholar
  76. 76.
    Boland R (1986) Role of vitamin D in skeletal muscle function. Endocr Rev 7:434–448. doi: 10.1210/edrv-7-4-434 CrossRefPubMedGoogle Scholar
  77. 77.
    Houston DK, Cesari M, Ferrucci L, Cherubini A, Maggio D, Bartali B et al (2007) Association between vitamin D status and physical performance: the InCHIANTI study. J Gerontol A Biol Sci Med Sci 62:440–446CrossRefGoogle Scholar
  78. 78.
    Yoshikawa S, Nakamura T, Tanabe H, Imamura T (1979) Osteomalacic myopathy. Endocrinol. Jpn. 26:65–72CrossRefGoogle Scholar
  79. 79.
    Bouillon R, Van Schoor NM, Gielen E, Boonen S, Mathieu C, Vanderschueren D et al (2013) Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. J Clin Endocrinol Metab 98:E1283–E1304. doi: 10.1210/jc.2013-1195 CrossRefPubMedGoogle Scholar
  80. 80.
    Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA, Burckhardt P, Li R, Spiegelman D et al (2007) Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. Am J Clin Nutr 86:1780–1790CrossRefGoogle Scholar
  81. 81.
    Bischoff-Ferrari HA (2012) Relevance of vitamin D in muscle health. Rev Endocr Metab Disord 13:71–77. doi: 10.1007/s11154-011-9200-6 CrossRefPubMedGoogle Scholar
  82. 82.
    Fornari R, Francomano D, Greco EA, Marocco C, Lubrano C, Wannenes F et al (2015) Lean mass in obese adult subjects correlates with higher levels of vitamin D, insulin sensitivity and lower inflammation. J Endocrinol Invest 38:367–372. doi: 10.1007/s40618-014-0189-z CrossRefPubMedGoogle Scholar
  83. 83.
    Rondanelli M, Klersy C, Terracol G, Talluri J, Maugeri R, Guido D et al (2016) Whey protein, amino acids, and vitamin D supplementation with physical activity increases fat-free mass and strength, functionality, and quality of life and decreases inflammation in sarcopenic elderly. Am J Clin Nutr 103:830–840. doi: 10.3945/ajcn.115.113357 CrossRefPubMedGoogle Scholar
  84. 84.
    Stockton KA, Mengersen K, Paratz JD, Kandiah D, Bennell KL (2011) Effect of vitamin D supplementation on muscle strength: a systematic review and meta-analysis. Osteoporos Int 22:859–871. doi: 10.1007/s00198-010-1407-y CrossRefPubMedGoogle Scholar
  85. 85.
    Wang Y, DeLuca HF (2011) Is the vitamin d receptor found in muscle? Endocrinology 152:354–363. doi: 10.1210/en.2010-1109 CrossRefPubMedGoogle Scholar
  86. 86.
    Chen S, Law CS, Grigsby CL, Olsen K, Hong TT, Zhang Y et al (2011) Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Circulation 124:1838–1847. doi: 10.1161/CIRCULATIONAHA.111.032680 CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Endo I, Inoue D, Mitsui T, Umaki Y, Akaike M, Yoshizawa T et al (2003) Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors. Endocrinology 144:5138–5144. doi: 10.1210/en.2003-0502 CrossRefPubMedGoogle Scholar
  88. 88.
    Szulc P, Schoppet M, Goettsch C, Rauner M, Dschietzig T, Chapurlat R et al (2012) Endocrine and clinical correlates of myostatin serum concentration in men–the STRAMBO study. J Clin Endocrinol Metab 97:3700–3708. doi: 10.1210/jc.2012-1273 CrossRefPubMedGoogle Scholar
  89. 89.
    Pike JW (2016) Closing in on vitamin D action in skeletal muscle: early activity in muscle stem cells? Endocrinology 157:48–51. doi: 10.1210/en.2015-2009 CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Teng K (2011) Premenopausal osteoporosis, an overlooked consequence of anorexia nervosa. Cleve Clin J Med 78:50–58. doi: 10.3949/ccjm.78a.10023 CrossRefPubMedGoogle Scholar
  91. 91.
    Umhau JC, George DT, Heaney RP, Lewis MD, Ursano RJ, Heilig M et al (2013) Low vitamin D status and suicide: a case-control study of active duty military service members. PLoS One 8:e51543 doi: 10.1371/journal.pone.0051543
  92. 92.
    Favaro A, Ferrara S, Santonastaso P (2007) Self-injurious behavior in a community sample of young women: relationship with childhood abuse and other types of self-damaging behaviors. J Clin Psychiatry 68:122–131CrossRefGoogle Scholar
  93. 93.
    Divasta AD, Feldman HA, Brown JN, Giancaterino C, Holick MF, Gordon CM (2011) Bioavailability of vitamin D in malnourished adolescents with anorexia nervosa. J Clin Endocrinol Metab 96:2575–2580. doi: 10.1210/jc.2011-0243 CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Turner JM, Bulsara MK, McDermott BM, Byrne GC, Prince RL, Forbes DA (2001) Predictors of low bone density in young adolescent females with anorexia nervosa and other dieting disorders. Int J Eat Disord 30:245–251CrossRefGoogle Scholar
  95. 95.
    Trombetti A, Richert L, Herrmann FR, Chevalley T, Graf JD, Rizzoli R (2013) Selective determinants of low bone mineral mass in adult women with anorexia nervosa. Int J Endocrinol 2013:897193. doi: 10.1155/2013/897193 CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Veronese N, Solmi M, Rizza W, Manzato E, Sergi G, Santonastaso P et al (2015) Vitamin D status in anorexia nervosa: a meta-analysis. Int J Eat Disord 48:803–813. doi: 10.1002/eat.22370 CrossRefPubMedGoogle Scholar
  97. 97.
    Giel KE, Kullmann S, Preissl H, Bischoff SC, Thiel A, Schmidt U et al (2013) Understanding the reward system functioning in anorexia nervosa: crucial role of physical activity. Biol Psychol 94:575–581. doi: 10.1016/j.biopsycho.2013.10.004 CrossRefPubMedGoogle Scholar
  98. 98.
    Haagensen AL, Feldman HA, Ringelheim J, Gordon CM (2008) Low prevalence of vitamin D deficiency among adolescents with anorexia nervosa. Osteoporos Int 19:289–294. doi: 10.1007/s00198-007-0476-z CrossRefPubMedGoogle Scholar
  99. 99.
    Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF (2000) Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 72:690–693CrossRefGoogle Scholar
  100. 100.
    Schebendach JE, Porter KJ, Wolper C, Walsh BT, Mayer LE (2012) Accuracy of self-reported energy intake in weight-restored patients with anorexia nervosa compared with obese and normal weight individuals. Int J Eat Disord 45:570–574. doi: 10.1002/eat.20973 CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    De RM, Toffanello ED, Veronese N, Zambon S, Bolzetta F, Sartori L et al (2014) Vitamin D deficiency and leisure time activities in the elderly: are all pastimes the same? PLoS One 9:e94805 doi: 10.1371/journal.pone.0094805
  102. 102.
    Goss K, Allan S (2009) Shame, pride and eating disorders. Clin Psychol Psychother 16:303–316. doi: 10.1016/j.clnu.2016.03.001 CrossRefPubMedGoogle Scholar
  103. 103.
    Helou M, Ning Y, Yang S, Irvine P, Bachmann LM, Godder K et al (2014) Vitamin d deficiency in children with cancer. J Pediatr Hematol Oncol 36:212–217. doi: 10.1097/MPH.0b013e31829f3754 CrossRefPubMedGoogle Scholar
  104. 104.
    Gatti D, El GM, Viapiana O, Ruocco A, Chignola E, Rossini M et al (2015) Strong relationship between vitamin D status and bone mineral density in anorexia nervosa. Bone 78:212–215. doi: 10.1016/j.bone.2015.05.014 CrossRefPubMedGoogle Scholar
  105. 105.
    Tasegian A, Curcio F, Dalla RL, Rossetti F, Cataldi S, Codini M et al (2016) Hypovitaminosis D3, leukopenia, and human serotonin transporter polymorphism in anorexia nervosa and bulimia nervosa. Mediators Inflamm 2016:8046479. doi: 10.1155/2016/8046479 CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Amaya-Mejia AS, O’Farrill-Romanillos PM, Galindo-Pacheco LV, Vargas-Ortega G, Mendoza-Zubieta V, Del Rivero-Hernandez LG et al (2013) Vitamin D deficiency in patients with common variable immunodeficiency, with autoimmune diseases and bronchiectasis. Rev Alerg Mex 60:110–116PubMedGoogle Scholar
  107. 107.
    Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP et al (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 96:1911–1930. doi: 10.1210/jc.2011-0385 CrossRefGoogle Scholar
  108. 108.
    Adami S, Romagnoli E, Carnevale V, Scillitani A, Giusti A, Rossini M (2011) [Guidelines on prevention and treatment of vitamin D deficiency. Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS)]. Reumatismo 63:129–147 doi: 10.4081/reumatismo.2011.129
  109. 109.
    Mitri J, Pittas AG (2014) Vitamin D and diabetes. Endocrinol Metab Clin North Am 43:205–232. doi: 10.1016/j.ecl.2013.09.010 CrossRefPubMedGoogle Scholar
  110. 110.
    Institute of Medicine Dietary. Dietary Reference Intakes for Calcium and Vitamin D. 2011. (GENERIC)Google Scholar
  111. 111.
    Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA et al (2012) IOM committee members respond to Endocrine Society vitamin D guideline. J Clin Endocrinol Metab 97:1146–1152. doi: 10.1210/jc.2011-2218 CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Rosen CJ, Adams JS, Bikle DD, Black DM, Demay MB, Manson JE et al (2012) The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev 33:456–492. doi: 10.1210/er.2012-1000 CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Alvarez JA, Law J, Coakley KE, Zughaier SM, Hao L, Shahid SK et al (2012) High-dose cholecalciferol reduces parathyroid hormone in patients with early chronic kidney disease: a pilot, randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 96:672–679. doi: 10.3945/ajcn.112.040642 CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Kearns MD, Alvarez JA, Seidel N, Tangpricha V (2015) Impact of vitamin D on infectious disease. Am J Med Sci 349:245–262. doi: 10.1097/MAJ.0000000000000360 CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Masood MQ, Khan A, Awan S, Dar F, Naz S, Naureen G et al (2015) Comparison of vitamin D replacement strategies with high-dose intramuscular or oral cholecalciferol: a prospective intervention study. Endocr Pract 21:1125–1133. doi: 10.4158/EP15680.OR CrossRefPubMedGoogle Scholar
  116. 116.
    Bacchetta J, Zaritsky JJ, Sea JL, Chun RF, Lisse TS, Zavala K et al (2014) Suppression of iron-regulatory hepcidin by vitamin D. J Am Soc Nephrol 25:564–572. doi: 10.1681/ASN.2013040355 CrossRefPubMedGoogle Scholar
  117. 117.
    Adams JS, Ren S, Liu PT, Chun RF, Lagishetty V, Gombart AF et al (2009) Vitamin d-directed rheostatic regulation of monocyte antibacterial responses. J. Immunol. 182:4289–4295. doi: 10.4049/jimmunol.0803736 CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Murad MH, Elamin KB, Abu Elnour NO, Elamin MB, Alkatib AA, Fatourechi MM et al (2011) Clinical review: the effect of vitamin D on falls: a systematic review and meta-analysis. J Clin Endocrinol Metab 96:2997–3006. doi: 10.1210/jc.2011-1193 CrossRefPubMedGoogle Scholar
  119. 119.
    Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R et al (2009) Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ 339:b3692. doi: 10.1136/bmj.b3692 CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    American Geriatrics Society (2014) Recommendations abstracted from the American Geriatrics Society Consensus Statement on vitamin D for Prevention of Falls and Their Consequences. J Am Geriatr Soc 62:147–152. doi: 10.1111/jgs.12631 CrossRefGoogle Scholar
  121. 121.
    Kearns MD, Alvarez JA, Tangpricha V (2014) Large, single-dose, oral vitamin d supplementation in adult populations: a systematic review. Endocr Pract 20:341–351. doi: 10.4158/EP13265.RA CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D et al (2010) Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 303:1815–1822. doi: 10.1001/jama.2010.594 CrossRefPubMedGoogle Scholar
  123. 123.
    Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, Staehelin HB, Meyer OW, Theiler R et al (2016) Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med 176:175–183. doi: 10.1001/jamainternmed.2015.7148 CrossRefPubMedGoogle Scholar
  124. 124.
    Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281. doi: 10.1056/NEJMra070553 CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Heaney RP (2007) The case for improving vitamin D status. J Steroid Biochem Mol Biol 103:635–641. doi: 10.1016/j.jsbmb.2006.12.006 CrossRefPubMedGoogle Scholar
  126. 126.
    Sotirchos ES, Bhargava P, Eckstein C, Van HK, Baynes M, Ntranos A et al (2016) Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology 86:382–390. doi: 10.1212/WNL.0000000000002316 CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Bhargava P, Cassard S, Steele SU, Azevedo C, Pelletier D, Sugar EA et al (2014) The vitamin D to ameliorate multiple sclerosis (VIDAMS) trial: study design for a multicenter, randomized, double-blind controlled trial of vitamin D in multiple sclerosis. Contemp Clin Trials 39:288–293. doi: 10.1016/j.cct.2014.10.004 CrossRefPubMedGoogle Scholar
  128. 128.
    Dorr J, Ohlraun S, Skarabis H, Paul F (2012) Efficacy of vitamin D supplementation in multiple sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial. Trials 13:15. doi: 10.1186/1745-6215-13-15 CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Kimball S, Vieth R, Dosch HM, Bar-Or A, Cheung R, Gagne D et al (2011) Cholecalciferol plus calcium suppresses abnormal PBMC reactivity in patients with multiple sclerosis. J Clin Endocrinol Metab 96:2826–2834. doi: 10.1210/jc.2011-0325 CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Konijeti GG, Arora P, Boylan MR, Song Y, Huang S, Harrell F et al (2016) Vitamin D Supplementation Modulates T Cell-Mediated Immunity in Humans: results from a Randomized Control Trial. J Clin Endocrinol Metab 101:533–538. doi: 10.1210/jc.2015-3599 CrossRefPubMedGoogle Scholar
  131. 131.
    Finamor DC, Sinigaglia-Coimbra R, Neves LC, Gutierrez M, Silva JJ, Torres LD et al (2013) A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. Dermatoendocrinology 5:222–234. doi: 10.4161/derm.24808 CrossRefGoogle Scholar
  132. 132.
    Rosen CJ (2011) Clinical practice. Vitamin D insufficiency. N Engl J Med 364:248–254. doi: 10.1056/NEJMcp1009570 CrossRefPubMedGoogle Scholar
  133. 133.
    Pepper KJ, Judd SE, Nanes MS, Tangpricha V (2009) Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. Endocr Pract 15:95–103. doi: 10.4158/EP.15.2.95 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Massimiliano Caprio
    • 1
    • 2
    Email author
  • Marco Infante
    • 3
  • Matilde Calanchini
    • 3
  • Caterina Mammi
    • 1
  • Andrea Fabbri
    • 3
  1. 1.Laboratory of Cardiovascular EndocrinologyIRCCS San Raffaele PisanaRomeItaly
  2. 2.Department of Human Sciences and Promotion of the Quality of LifeSan Raffaele Roma Open UniversityRomeItaly
  3. 3.Unit of Endocrinology and Metabolic DiseasesDepartment of Systems Medicine, CTO A. Alesini Hospital, ASL Roma 2, University Tor VergataRomeItaly

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