Vitamin D: Biological Significance and Diagnosis of Mild Deficiency

  • Enrico CarminaEmail author
Reference work entry
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)


Activated vitamin D has a main role in bone metabolism by increasing intestinal calcium absorption and kidney calcium resorption but also by activating both bone formation and resorption. This last effect may be mainly indirect by modulating PTH secretion. In mild forms of vitamin D deficiency, the increase in PTH secretion is probably the main factor determining bone loss.

In diagnosis of vitamin D deficiency, the establishment of a circulating vitamin D (mono or di-hydroxylated vitamin D) cutoff is particularly important but has been difficult because differences in used criteria. Based on PTH circulating levels and femoral neck bone density, a mono-hydroxylated vitamin D cutoff of 25 ng/ml may be the best criterion for distinguishing a mild vitamin D deficiency.

Vitamin D action is not limited to bone metabolism but involves modulation of immune function, stimulation of insulin, and other hormone secretion and inhibition of cell proliferation. Epidemiological studies have correlated low vitamin D levels to increased prevalence of some forms of cancer (mainly colon cancer but also breast and prostate cancer), type II diabetes, some autoimmune disorders, and cardiovascular diseases. However, in all these conditions, with a few exceptions, trials using high doses of vitamin D have been unsuccessful. The possibility that in nonskeletal diseases, different criteria for determining a vitamin D deficiency should be used is discussed.


Vitamin D Bone metabolism Osteoporosis colon cancer Breast cancer Prostate cancer Diabetes Autoimmune diseases Cardiovascular diseases 

List of Abbreviations

Activated vitamin D

1,25(OH)2-vitamin D


Parathyroid hormone


Vitamin D receptor




Brush border myosin I




Calcium channel 6


Calcium sensing receptor




Dual-energy X-ray absorptiometry


Dendritic cells

Th cells

T helper cells


  1. Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol. 2008;4:404–12.CrossRefPubMedGoogle Scholar
  2. Avenell A, Cook JA, MacLennan GS, et al. Vitamin D supplementation and type 2 diabetes: a substudy of a randomized placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). Age Ageing. 2009;38:606–9.CrossRefPubMedGoogle Scholar
  3. Biber J, Hernando N, Forster I. Phosphate transporters and their function. Annu Rev Physiol. 2013;75:535–50.CrossRefPubMedGoogle Scholar
  4. Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2014;1:CD007470.Google Scholar
  5. Bikle DD. Regulation of intestinal calcium transport by vitamin D [1, 25(OH)2]: role of membrane structure. In: Aloia RC, Curtain CC, Gordon LM, editors. Membrane transport and information storage. New York: Wiley-Liss; 1990. p. 191–219.Google Scholar
  6. Bikle DD. Vitamin D, and the skin: physiology and pathophysiology. Rev Endocr Metab Disord. 2012;13:3–19.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bojesen SE, Nordestgaard BG. Low 25-hydroxyvitamin D and risk of type 2 diabetes: a prospective cohort study and metaanalysis. Clin Chem. 2013;59:381–91.CrossRefPubMedGoogle Scholar
  8. Carlberg C, Campbell MJ. Vitamin D receptor signaling mechanisms: integrated actions of a well-defined transcription factor. Steroids. 2013;78:127–36.CrossRefPubMedGoogle Scholar
  9. Carmina E, Stanczyk F, Lobo RA. Chapter 34. Laboratory assessment. In: Strauss JF, Barbieri RL, editors. Yen and Jaffe’s reproductive endocrinology: physiology, pathophysiology and clinical management. 7th ed. Philadelphia: Elsevier-Saunders; 2014. p. 822–50.CrossRefGoogle Scholar
  10. Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomized intervention studies. BMJ. 2014;348:g1903.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cipriani C, Piemonte S, Cilli M, et al. Update on vitamin D: pros and cons. Clin Cases Miner Bone Metab. 2015;12:222–3.PubMedPubMedCentralGoogle Scholar
  12. de Boer IH, Tinker LF, Connelly S, et al. Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care. 2008;31:701–7.CrossRefPubMedPubMedCentralGoogle Scholar
  13. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689S–96.PubMedGoogle Scholar
  14. Demay MB, et al. Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci U S A. 1992;89:8097–101.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Eastell R, Hannon RA. Biomarkers of bone health and osteoporosis risk. J Am Diet Assoc. 2011;111:524–7.CrossRefGoogle Scholar
  16. Forman JP, Curhan GC, Taylor EN. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension among young women. Hypertension. 2008;52:828–32.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Forouhi NG, Luan J, Cooper A, et al. 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. 2008;57:2619–25.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Friedman PA, Gesek FA. Cellular calcium transport in renal epithelia: measurement, mechanisms, and regulation. Physiol Rev. 1995;75:429–71.PubMedGoogle Scholar
  19. Froicu M, et al. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol Endocrinol. 2003;17:2386–92.CrossRefPubMedGoogle Scholar
  20. Hawa NS, O’Riordan JL, Farrow SM. Functional analysis of vitamin D response elements in the parathyroid hormone gene and a comparison with the osteocalcin gene. Biochem Biophys Res Commun. 1996;228:352–7.CrossRefPubMedGoogle Scholar
  21. Hoenderop JG, Nilius B, Bindels RJ. Calcium absorption across epithelia. Physiol Rev. 2005;85:373–422.CrossRefPubMedGoogle Scholar
  22. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–30.CrossRefPubMedGoogle Scholar
  23. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. 2011 dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press; 2011.Google Scholar
  24. Jacobs ET, Kohler LN, Kunihiro AG, et al. Vitamin D and colorectal, breast, and prostate cancers: a review of the epidemiological evidence. J Cancer. 2016;7:232–40.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Kadowaki S, Norman AW. Demonstration that the vitamin D metabolite 1,25(OH)2-vitamin D3 and not 24R,25(OH)2-vitamin D3 is essential for normal insulin secretion in the perfused rat pancreas. Diabetes. 1985;34:315–20.CrossRefPubMedGoogle Scholar
  26. Lee S, et al. 1,25-dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors, gene expression, and insulin secretion. Endocrinology. 1994;134:1602–10.CrossRefPubMedGoogle Scholar
  27. Liu SM, et al. Characterization of a response element in the 5′-flanking region of the avian (chicken) PTH gene that mediates negative regulation of gene transcription by 1,25-dihydroxyvitamin D3 and binds the vitamin D3 receptor. Mol Endocrinol. 1996;10:206–15.PubMedGoogle Scholar
  28. Looker AC, Mussolino ME. Serum 25-hydroxyvitamin D and hip fracture risk in older U.S. white adults. J Bone Miner Res. 2008;23:143–50.CrossRefPubMedGoogle Scholar
  29. Maalmi H, Ordonez-Mena JM, Schottker B, et al. Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: systematic review and meta-analysis of prospective cohort studies. Eur J Cancer. 2014;50:1510–21.CrossRefPubMedGoogle Scholar
  30. Nakashima A, Yokoyama K, Yokoo T, et al. Role of vitamin D in diabetes mellitus and chronic kidney disease. World J Diabetes. 2016;7:89–100.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Napoli N, Strollo R, Sprini D, et al. Serum 25-OH Vitamin D in relation to bone mineral density and bone turnover. Int J Endocrinol. 2014;2014:487463.PubMedPubMedCentralGoogle Scholar
  32. Panda DK, et al. Inactivation of the 25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and mineral homeostasis. J Biol Chem. 2004;279:16754–66.CrossRefPubMedGoogle Scholar
  33. Pittas AG, Chung M, Trikalinos T, et al. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med. 2010;152:307–14.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Rabinovitch A, et al. Expression of calbindin-D (28k) in a pancreatic islet beta-cell line protects against cytokine-induced apoptosis and necrosis. Endocrinology. 2001;142(8):3649–55.CrossRefPubMedGoogle Scholar
  35. Rosen CJ, Adams JS, Bikle DD, et al. The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev. 2012;33:456–92.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Ross AC, Manson JE, Abrams SA, 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;96:53–8.CrossRefPubMedGoogle Scholar
  37. Suda T, Takahashi N, Abe E. Role of vitamin D in bone resorption. J Cell Biochem. 1992;49:53–8.CrossRefPubMedGoogle Scholar
  38. Takeda S, et al. Stimulation of osteoclast formation by 1,25-dihydroxyvitamin D requires its binding to vitamin D receptor (VDR) in osteoblastic cells: studies using VDR knockout mice. Endocrinology. 1999;140:1005–8.CrossRefPubMedGoogle Scholar
  39. Touvier M, Chan DS, Lau R, 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;20:1003–16.CrossRefPubMedGoogle Scholar
  40. Tretli S, Schwartz GG, Torjesen PA, et al. Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study. Cancer Causes Control. 2012;23:363–70.CrossRefPubMedGoogle Scholar
  41. Underwood JL, DeLuca HF. Vitamin D is not directly necessary for bone growth and mineralization. Am J Physiol. 1984;246:E493–8.PubMedGoogle Scholar
  42. van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol. 2005;97:93–101.CrossRefPubMedGoogle Scholar
  43. Wang J, Eliassen AH, Spiegelman D, et al. Plasma free 25-hydroxyvitamin D, vitamin D binding protein, and risk of breast cancer in the Nurses’ Health Study II. Cancer Causes Control. 2014;25:819–27.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Wang L, Manson JE, Song Y. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152:315–23.CrossRefPubMedGoogle Scholar
  45. Wasserman RH, Fullmer CS. Vitamin D and intestinal calcium transport: facts, speculations and hypotheses. J Nutr. 1995;125 7 Suppl:1971S–9.Google Scholar
  46. Yin L, Grandi N, Raum E, et al. Meta-analysis: serum vitamin D and breast cancer risk. Eur J Cancer. 2010;46:2196–205.CrossRefPubMedGoogle Scholar
  47. Xu Y, Shao X, Yao Y, et al. Positive association between circulating 25-hydroxyvitamin D levels and prostate cancer risk: new findings from an updated meta-analysis. J Cancer Res Clin Oncol. 2014;140:1465–77.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  1. 1.Department of Health Sciences and Mother and Child CareUniversity of PalermoPalermoItaly

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