Skip to main content

Advertisement

SpringerLink
Log in

Is vitamin D deficiency a cause of increased morbidity and mortality at older age or simply an indicator of poor health?

  • NUTRITIONAL EPIDEMIOLOGY
  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

To assess whether vitamin D deficiency is a cause of increased morbidity and mortality or simply an indicator of poor health, we assessed (1) the cross-sectional and longitudinal association of vitamin D deficiency with self-rated health (SRH) and frailty and (2) the association of vitamin D deficiency with mortality, with and without control for SRH and frailty. Analyses were performed in 9,579 participants of the German, population-based ESTHER cohort (age-range at baseline: 50–74 years), with follow-ups after 2, 5 and 8 years (mortality: 12 years). During follow-up, 129 subjects newly reported poor SRH, 510 developed frailty and 1,450 died. In cross-sectional analyses, subjects with vitamin D deficiency had higher odds of a poor SRH and frailty but no association with SRH or frailty was observed in longitudinal analyses. The association of vitamin D deficiency with all-cause and several cause-specific mortalities was strong and unaltered by time-dependent adjustment for classic mortality risk factors, SRH and frailty. In conclusion, vitamin D deficiency may not cause frailty or poor general health but may nevertheless be a prognostic marker for mortality, independent of the individual’s morbidity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Murad MH, Elamin KB, Abu Elnour NO, Elamin MB, Alkatib AA, Fatourechi MM, et al. The effect of vitamin D on falls: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011; 96(10):2997–3006.

    Google Scholar 

  2. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293(18):2257–64.

    Article  PubMed  CAS  Google Scholar 

  3. Wang S. Epidemiology of vitamin D in health and disease. Nutr Res Rev. 2009;22:188–203.

    Article  PubMed  CAS  Google Scholar 

  4. Schöttker B, Ball D, Gellert C, Brenner H. Serum 25-hydroxyvitamin D levels and overall mortality. A systematic review and meta-analysis of prospective cohort studies. Ageing Res Rev. 2013;12(2):708–18.

    Article  PubMed  CAS  Google Scholar 

  5. Skaaby T, Husemoen LL, Pisinger C, Jorgensen T, Thuesen BH, Fenger M, et al. Vitamin D status and cause-specific mortality: a general population study. PLoS ONE. 2012;7(12):e52423.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  6. Signorello LB, Han X, Cai Q, Cohen SS, Cope EL, Zheng W, et al. A prospective study of serum 25-hydroxyvitamin d levels and mortality among African Americans and non-African Americans. Am J Epidemiol. 2013;177(2):171–9.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Welsh P, Doolin O, McConnachie A, Boulton E, McNeil G, Macdonald H, et al. Circulating 25OHD, dietary vitamin D, PTH, and calcium associations with incident cardiovascular disease and mortality: the MIDSPAN family study. J Clin Endocrinol Metab. 2012;97(12):4578–87.

    Article  PubMed  CAS  Google Scholar 

  8. Kritchevsky SB, Tooze JA, Neiberg RH, Schwartz GG, Hausman DB, Johnson MA, et al. 25-Hydroxyvitamin D, parathyroid hormone, and mortality in black and white older adults: the health ABC study. J Clin Endocrinol Metab. 2012;97(11):4156–65.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Schöttker B, Haug U, Schomburg L, Köhrle J, Perna L, Müller H, et al. Strong associations of 25-hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study. Am J Clin Nutr. 2013;97(4):782–93.

    Article  PubMed  CAS  Google Scholar 

  10. Durup D, Jorgensen HL, Christensen J, Schwarz P, Heegaard AM, Lind B. A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice: the CopD study. J Clin Endocrinol Metab. 2012;97(8):2644–52.

    Article  PubMed  CAS  Google Scholar 

  11. de Boer IH, Levin G, Robinson-Cohen C, Biggs ML, Hoofnagle AN, Siscovick DS, et al. Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study. Ann Intern Med. 2012;156(9):627–34.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Eaton CB, Young A, Allison MA, Robinson J, Martin LW, Kuller LH, et al. Prospective association of vitamin D concentrations with mortality in postmenopausal women: results from the women’s health initiative (WHI). Am J Clin Nutr. 2011;94:1471–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Johansson H, Oden A, Kanis J, McCloskey E, Lorentzon M, Ljunggren O, et al. Low serum vitamin D is associated with increased mortality in elderly men: MrOS Sweden. Osteoporos Int. 2012;23(3):991–9.

    Article  PubMed  CAS  Google Scholar 

  14. Ensrud KE, Blackwell TL, Cauley JA, Cummings SR, Barrett-Connor E, Dam TT, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc. 2011;59(1):101–6.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010;95(12):5266–73.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Smit E, Crespo CJ, Michael Y, Ramirez-Marrero FA, Brodowicz GR, Bartlett S, et al. The effect of vitamin D and frailty on mortality among non-institutionalized US older adults. Eur J Clin Nutr. 2012;66(9):1024–8.

    Article  PubMed  CAS  Google Scholar 

  17. Wong YY, McCaul KA, Yeap BB, Hankey GJ, Flicker L. Low vitamin D status is an independent predictor of increased frailty and all-cause mortality in older men: the health in men study. J Clin Endocrinol Metab 2013; (epub ahead of print).

  18. Ordóñez-Mena JM, Schöttker B, Haug U, Müller H, Köhrle J, Schomburg L, et al. Serum 25-hydroxyvitamin D and cancer risk in older adults. Results Large Ger Prospect Cohort Study. 2013;22:905–16.

    Google Scholar 

  19. Perna L, Schöttker B, Holleczek B, Brenner H. Serum 25-hydroxyvitamin d and incidence of fatal and nonfatal cardiovascular events: a prospective study with repeated measurements. J Clin Endocrinol Metab. 2013 Dec;98(12):4908–15.

    Article  PubMed  CAS  Google Scholar 

  20. Walston J, Hadley EC, Ferrucci L, Guralnik JM, Newman AB, Studenski SA, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc. 2006;54(6):991–1001.

    Google Scholar 

  21. Shamliyan T, Talley KM, Ramakrishnan R, Kane RL. Association of frailty with survival: a systematic literature review. Ageing Res Rev. 2013;12:719–36.

    Article  PubMed  Google Scholar 

  22. Idler EL, Benyamini Y. Self-rated health and mortality: a review of twenty-seven community studies. J Health Soc Behav. 1997;38(1):21–37.

    Article  PubMed  CAS  Google Scholar 

  23. Raum E, Rothenbacher D, Löw M, Stegmaier C, Ziegler H, Brenner H. Changes of cardiovascular risk factors and their implications in subsequent birth cohorts of older adults in Germany: a life course approach. Eur J Cardiovasc Prev Rehabil. 2007;14(6):809–14.

    Article  PubMed  Google Scholar 

  24. Löw M, Stegmaier C, Ziegler H, Rothenbacher D. Brenner H.[Epidemiological investigations of the chances of preventing, recognizing early and optimally treating chronic diseases in an elderly population (ESTHER study)]. Dtsch Med Wochenschr. 2004;129(49):2643–7.

    Article  PubMed  Google Scholar 

  25. Schöttker B, Jansen EH, Haug U, Schomburg L, Köhrle J, Brenner H. Standardization of misleading immunoassay based 25-hydroxyvitamin D levels with liquid chromatography tandem-mass spectrometry in a large cohort study. PLoS ONE. 2012;7(11):e48774.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Food and Nutrition Board, Institute of Medicine Dietary reference intakes for calcium and vitamin D. In: Catharine R, Taylor CL, Yaktine AL et al., eds. National Academies Press, Washington, DC, USA, 2011.

  27. Slomski A. IOM endorses vitamin D, calcium only for bone health, dispels deficiency claims. JAMA. 2011;305:453–4.

    Article  PubMed  CAS  Google Scholar 

  28. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy measure of aging. Sci World J. 2001;1:323–36.

    Article  CAS  Google Scholar 

  29. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A standard procedure for creating a frailty index. BMC Geriatr. 2008;8:24.

    Article  PubMed Central  PubMed  Google Scholar 

  30. Saum KU, Müller H, Stegmaier C, Hauer K, Raum E, Brenner H. Development and evaluation of a modification of the Fried frailty criteria using population-independent cutpoints. J Am Geriatr Soc. 2012;60(11):2110–5.

    PubMed  Google Scholar 

  31. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146–56.

    Article  PubMed  CAS  Google Scholar 

  32. Desquilbet L, Mariotti F. Dose–response analyses using restricted cubic spline functions in public health research. Stat Med. 2010;29(9):1037–57.

    PubMed  Google Scholar 

  33. Perna L, Haug U, Schottker B, Muller H, Raum E, Jansen EH, et al. Public health implications of standardized 25-hydroxyvitamin D levels: a decrease in the prevalence of vitamin D deficiency among older women in Germany. Prev Med. 2012;55(3):228–32.

    Article  PubMed  CAS  Google Scholar 

  34. Hirani V, Naganathan V, Cumming RG, Blyth F, Le Couteur DG, Handelsman DJ, et al. Associations Between Frailty and Serum 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Concentrations in Older Australian Men: The Concord Health and Ageing in Men Project. J Gerontol A Biol Sci Med Sci. 2013 (epub ahead of print).

  35. Tajar A, Lee DM, Pye SR, O’Connell MD, Ravindrarajah R, Gielen E, et al. The association of frailty with serum 25-hydroxyvitamin D and parathyroid hormone levels in older European men. Age Ageing. 2013;42(3):352–9.

    Article  PubMed  Google Scholar 

  36. Wilhelm-Leen ER, Hall YN, Deboer IH, Chertow GM. Vitamin D deficiency and frailty in older Americans. J Intern Med. 2010;268(2):171–80.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. Puts MT, Visser M, Twisk JW, Deeg DJ, Lips P. Endocrine and inflammatory markers as predictors of frailty. Clin Endocrinol (Oxf). 2005;63(4):403–11.

    Article  CAS  Google Scholar 

  38. Shardell M, Hicks GE, Miller RR, Kritchevsky S, Andersen D, Bandinelli S, et al. Association of low vitamin D levels with the frailty syndrome in men and women. J Gerontol A Biol Sci Med Sci. 2009;64(1):69–75.

    Article  PubMed  CAS  Google Scholar 

  39. Chang CI, Chan DC, Kuo KN, Hsiung CA, Chen CY. Vitamin D insufficiency and frailty syndrome in older adults living in a Northern Taiwan community. Arch Gerontol Geriatr. 2010;50(Suppl 1):S17–21.

    Article  PubMed  CAS  Google Scholar 

  40. Engelsen O. The relationship between ultraviolet radiation exposure and vitamin D status. Nutrients. 2010;2(5):482–95.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  41. MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985;76(4):1536–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.

    PubMed Central  PubMed  CAS  Google Scholar 

  43. Lin SW, Chen W, Fan JH, Dawsey SM, Taylor PR, Qiao YL, et al. Prospective study of serum 25-hydroxyvitamin D concentration and mortality in a Chinese population. Am J Epidemiol. 2012;176(11):1043–50.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266–81.

    Article  PubMed  CAS  Google Scholar 

  45. Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys. 2000;374(2):334–8.

    Article  PubMed  CAS  Google Scholar 

  46. Brewer LC, Michos ED, Reis JP. Vitamin D in atherosclerosis, vascular disease, and endothelial function. Curr Drug Targets. 2011;12(1):54–60.

    Article  PubMed  CAS  Google Scholar 

  47. Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension. 2010;55(5):1283–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  48. Krishnan AV, Trump DL, Johnson CS, Feldman D. The role of vitamin D in cancer prevention and treatment. Endocrinol Metab Clin N Am. 2010;39(2):401–18.

    Article  CAS  Google Scholar 

  49. Wolden-Kirk H, Overbergh L, Christesen HT, Brusgaard K, Mathieu C. Vitamin D and diabetes: its importance for beta cell and immune function. Mol Cell Endocrinol. 2011;347(1–2):106–20.

    Article  PubMed  CAS  Google Scholar 

  50. Herr C, Greulich T, Koczulla RA, Meyer S, Zakharkina T, Branscheidt M, et al. The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer. Respir Res. 2011;12:31.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  51. Di RM, Malaguarnera M, Nicoletti F, Malaguarnera L. Vitamin D3: a helpful immuno-modulator. Immunology. 2011;134(2):123–39.

    Google Scholar 

  52. Schöttker B, Herder C, Rothenbacher D, Perna L, Müller H, Brenner H. Serum 25-hydroxyvitamin D levels and incident diabetes mellitus type 2: a competing risk analysis in a large population-based cohort of older adults. Eur J Epidemiol. 2013;28(3):267–75.

    Article  PubMed  CAS  Google Scholar 

  53. Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Endocrinol Metab Clin N Am. 2010;39(2):365–79.

    Article  CAS  Google Scholar 

  54. White JH. Vitamin D metabolism and signaling in the immune system. Rev Endocr Metab Disord. 2012;13(1):21–9.

    Article  PubMed  CAS  Google Scholar 

  55. Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013;5(7):2502–21.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  56. Bird A. The epistemological function of Hill’s criteria. Prev Med. 2011;53(4–5):242–5.

    Article  PubMed  Google Scholar 

  57. 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.

  58. Rejnmark L, Avenell A, Masud T, Anderson F, Meyer HE, Sanders KM, et al. Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials. J Clin Endocrinol Metab. 2012;97(8):2670–81.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  59. 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 D(3) and/or calcium (RECORD trial). J Clin Endocrinol Metab. 2012;97(2):614–22.

    Article  PubMed  CAS  Google Scholar 

  60. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012;3:CD007176.

Download references

Acknowledgments

This work was supported by the CHANCES project funded in the FP7 framework programme of DG-RESEARCH in the European Commission (Grant 242244) and the German Cancer Aid (Grants 108250, 108426). The ESTHER study was funded by the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany) and the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany). We thank Prudence Carr for linguistic revision of the article.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany

    Ben Schöttker, Kai-Uwe Saum, Laura Perna, José Manuèl Ordóñez-Mena & Hermann Brenner

  2. Saarland Cancer Registry, Präsident Baltz-Straße 5, 66119, Saarbrücken, Germany

    Bernd Holleczek

Authors
  1. Ben Schöttker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai-Uwe Saum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura Perna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José Manuèl Ordóñez-Mena
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernd Holleczek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hermann Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ben Schöttker.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 659 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schöttker, B., Saum, KU., Perna, L. et al. Is vitamin D deficiency a cause of increased morbidity and mortality at older age or simply an indicator of poor health?. Eur J Epidemiol 29, 199–210 (2014). https://doi.org/10.1007/s10654-014-9894-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-014-9894-3

Keywords

Search

Navigation