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Original article

Vol. 148 No. 0304 (2018)

Vitamin D levels in Swiss breast cancer survivors

  • Michael Baumann
  • Sergio U. Dani
  • Daniel Dietrich
  • Andreas Hochstrasser
  • Dirk Klingbiel
  • Michael T. Mark
  • Walter F. Riesen
  • Thomas Ruhstaller
  • Arnoud J. Templeton
  • Beat Thürlimann
DOI
https://doi.org/10.4414/smw.2018.14576
Cite this as:
Swiss Med Wkly. 2018;148:w14576
Published
16.01.2018

Summary

BACKGROUND

Cholecalciferol (vitamin D3) is widely supplemented in breast cancer survivors because of the role of vitamin D in multiple health outcomes.

METHODS

We conducted an observational study in 332 women in Eastern Switzerland with early, i.e., nonmetastatic breast cancer. Tumour-, patient-related and sociodemographic variables were recorded. Cholecalciferol intake and serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were measured at the first visit (baseline) and during a follow-up visit in a median of 210 days (range 87–857) after the first visit. Patients presenting 25(OH)D deficiency were advised to take cholecalciferol supplementation.

RESULTS

At baseline, 60 (18%) patients had 25(OH)D deficiency (≤50 nmol/l, ≤20 ng/l), and 70 (21%) had insufficiency (50–74 nmol/l, 20–29 ng/l). Out of 121 patients with ongoing cholecalciferol supplementation at baseline, 25(OH)D deficiency and insufficiency was observed in 9 (7%) and 16 (13%) patients, respectively, whereas out of 52 patients with no supplementation, 15 (29%) had deficiency and 19 (37%) had insufficiency. Only 85 (26%) patients had optimal 25(OH)D levels (75–100 nmol/l, 30–40 ng/l) at baseline. Seasonal variation was significant for 25(OH)D (p = 0.042) and 1,25(OH)2D (p = 0.001) levels. Living in a rural area was associated with a higher median 25(OH)D concentration as compared with living in an urban area (87 nmol/l, range 16–216 vs 72 nmol/l, range 17–162; p = 0.001). Regular sporting activity was positively associated with 25(OH)D (p = 0.045). Body mass index was inversely related to both 25(OH)D and 1,25(OH)2D (Spearman’s rho = −0.24, p <0.001; rho = −0.23, p <0.001, respectively). The levels of 25(OH)D and 1,25(OH)2D were correlated (rho = 0.21, p <0.001). Age and bone mineral density had no significant correlation with the levels of 25(OH)D. Follow-up 25(OH)D was available for 230 patients, 44 (19%) of whom had 25(OH)D deficiency and 47 (21%) had insufficiency; 25 (41.6%) initially 25(OH)D-deficient patients attained sufficient 25(OH)D levels, whereas 33 (16.5%) patients with sufficient baseline 25(OH)D levels became deficient. Only 67 (30%) patients presented optimal 25(OH)D at the follow-up.

CONCLUSION

A remarkable fraction of the patients had serum 25(OH)D below (40%) or above (30%) optimal levels, and only around 30% of patients had optimal levels. Levels of 25(OH)D and 1,25(OH)2D increased on cholecalciferol supplementation, but the usual supplementation regimens were not adequate to bring 25(OH)D to the optimal range for a large proportion of patients.

Trial registration number

EKSG 08/082/2B.

References

  1. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84(1):18–28. Correction in: Am J Clin Nutr. 2006;84(5):1253.
  2. Hossein-nezhad A, Holick MF. Vitamin D for health: a global perspective. Mayo Clin Proc. 2013;88(7):720–55. doi:.https://doi.org/10.1016/j.mayocp.2013.05.011
  3. 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 from a large German prospective cohort study. Cancer Epidemiol Biomarkers Prev. 2013;22(5):905–16. doi:.https://doi.org/10.1158/1055-9965.EPI-12-1332
  4. Durup D, Jørgensen HL, Christensen J, Tjønneland A, Olsen A, Halkjær J, et al. A Reverse J-Shaped Association Between serum 25-hydroxyvitamin D and cardiovascular disease mortality: The CopD study. J Clin Endocrinol Metab. 2015;100(6):2339–46. doi:.https://doi.org/10.1210/jc.2014-4551
  5. Pant S, Shapiro CL. Aromatase inhibitor-associated bone loss: clinical considerations. Drugs. 2008;68(18):2591–600. doi:.https://doi.org/10.2165/0003495-200868180-00005
  6. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2(1):76–89. doi:.https://doi.org/10.1016/S2213-8587(13)70165-7
  7. Wimalawansa SJ. Non-musculoskeletal benefits of vitamin D. J Steroid Biochem Mol Biol. 2018;175:60–81. doi:.https://doi.org/10.1016/j.jsbmb.2016.09.016
  8. Sakaki T, Yasuda K, Kittaka A, Yamamoto K, Chen TC. CYP24A1 as a potential target for cancer therapy. Anticancer Agents Med Chem. 2014;14(1):97–108. doi:.https://doi.org/10.2174/18715206113139990307
  9. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control. 2005;16(2):83–95. doi:.https://doi.org/10.1007/s10552-004-1661-4
  10. Lazzeroni M, Serrano D, Pilz S, Gandini S. Vitamin D supplementation and cancer: review of randomized controlled trials. Anticancer Agents Med Chem. 2013;13(1):118–25. doi:.https://doi.org/10.2174/187152013804487281
  11. Scarmo S, Afanasyeva Y, Lenner P, Koenig KL, Horst RL, Clendenen TV, et al. Circulating levels of 25-hydroxyvitamin D and risk of breast cancer: a nested case-control study. Breast Cancer Res. 2013;15(1):R15. doi:.https://doi.org/10.1186/bcr3390
  12. 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.
  13. Mohr SB, Gorham ED, Kim J, Hofflich H, Garland CF. Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer. Anticancer Res. 2014;34(3):1163–6.
  14. Kelly JL, Salles G, Goldman B, Fisher RI, Brice P, Press O, et al. Low serum vitamin D levels are associated with inferior survival in follicular lymphoma: A prospective evaluation in SWOG and LYSA studies. J Clin Oncol. 2015;33(13):1482–90. doi:.https://doi.org/10.1200/JCO.2014.57.5092
  15. Palmer JR, Gerlovin H, Bethea TN, Bertrand KA, Holick MF, Ruiz-Narvaez EN, et al. Predicted 25-hydroxyvitamin D in relation to incidence of breast cancer in a large cohort of African American women. Breast Cancer Res. 2016;18(1):86. doi:.https://doi.org/10.1186/s13058-016-0745-x
  16. Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer. 2014;14(5):342–57. doi:.https://doi.org/10.1038/nrc3691
  17. Yao S, Kwan ML, Ergas IJ, Roh JM, Cheng TD, Hong C-C, et al. Association of serum level of vitamin D at diagnosis with breast cancer survival. A case-cohort analysis in the Pathways Study. JAMA Oncol. 2017;3(3):351–7. Published online November 10, 2016. doi:.https://doi.org/10.1001/jamaoncol.2016.4188
  18. Barker T, Martins TB, Kjeldsberg CR, Trawick RH, Hill HR. Circulating interferon-γ correlates with 1,25(OH)D and the 1,25(OH)D-to-25(OH)D ratio. Cytokine. 2012;60(1):23–6. doi:.https://doi.org/10.1016/j.cyto.2012.05.015
  19. Rejnmark L, Vestergaard P, Heickendorff L, Mosekilde L. Plasma 1,25(OH)2D levels decrease in postmenopausal women with hypovitaminosis D. Eur J Endocrinol. 2008;158(4):571–6. doi:.https://doi.org/10.1530/EJE-07-0844
  20. Xu Y, Hashizume T, Shuhart MC, Davis CL, Nelson WL, Sakaki T, et al. Intestinal and hepatic CYP3A4 catalyze hydroxylation of 1alpha,25-dihydroxyvitamin D(3): implications for drug-induced osteomalacia. Mol Pharmacol. 2006;69(1):56–65.
  21. Wang Z, Lin YS, Dickmann LJ, Poulton EJ, Eaton DL, Lampe JW, et al. Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: implications for drug-induced osteomalacia. J Bone Miner Res. 2013;28(5):1101–16. doi:.https://doi.org/10.1002/jbmr.1839
  22. Afzal S, Bojesen SE, Nordestgaard BG. Low plasma 25-hydroxyvitamin D and risk of tobacco-related cancer. Clin Chem. 2013;59(5):771–80. doi:.https://doi.org/10.1373/clinchem.2012.201939
  23. Deschasaux M, Souberbielle JC, Latino-Martel P, Sutton A, Charnaux N, Druesne-Pecollo N, et al. Prospective associations between vitamin D status, vitamin D-related gene polymorphisms, and risk of tobacco-related cancers. Am J Clin Nutr. 2015;102(5):1207–15. doi:.https://doi.org/10.3945/ajcn.115.110510
  24. Deschasaux M, Souberbielle JC, Latino-Martel P, Sutton A, Charnaux N, Druesne-Pecollo N, et al. Weight status and alcohol intake modify the association between vitamin D and breast cancer risk. J Nutr. 2016;146(3):576–85. doi:.https://doi.org/10.3945/jn.115.221481
  25. Gandini S, Gnagnarella P, Serrano D, Pasquali E, Raimondi S. Vitamin D receptor polymorphisms and cancer. Adv Exp Med Biol. 2014;810:69–105.
  26. Berlanga-Taylor AJ, Knight JC. An integrated approach to defining genetic and environmental determinants for major clinical outcomes involving vitamin D. Mol Diagn Ther. 2014;18(3):261–72. doi:.https://doi.org/10.1007/s40291-014-0087-2
  27. Templeton AJ, Thürlimann B, Baumann M, Mark M, Stoll S, Schwizer M, et al. Cross-sectional study of self-reported physical activity, eating habits and use of complementary medicine in breast cancer survivors. BMC Cancer. 2013;13(1):153. doi:.https://doi.org/10.1186/1471-2407-13-153
  28. Shah I, James R, Barker J, Petroczi A, Naughton DP. Misleading measures in Vitamin D analysis: a novel LC-MS/MS assay to account for epimers and isobars. Nutr J. 2011;10(1):46. doi:.https://doi.org/10.1186/1475-2891-10-46
  29. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005;135(2):317–22.
  30. Vieth R. What is the optimal vitamin D status for health? Prog Biophys Mol Biol. 2006;92(1):26–32. doi:.https://doi.org/10.1016/j.pbiomolbio.2006.02.003
  31. Duque G, Daly RM, Sanders K, Kiel DP. Vitamin D, bones and muscle: myth versus reality. Australas J Ageing. 2017;36(Suppl 1):8–13. doi:.https://doi.org/10.1111/ajag.12408
  32. Maïmoun L, Simar D, Malatesta D, Caillaud C, Peruchon E, Couret I, et al. Response of bone metabolism related hormones to a single session of strenuous exercise in active elderly subjects. Br J Sports Med. 2005;39(8):497–502. doi:.https://doi.org/10.1136/bjsm.2004.013151
  33. Veldurthy V, Wei R, Oz L, Dhawan P, Jeon YH, Christakos S. Vitamin D, calcium homeostasis and aging. Bone Res. 2016;4:16041. doi:.https://doi.org/10.1038/boneres.2016.41
  34. Zhen D, Liu L, Guan C, Zhao N, Tang X. High prevalence of vitamin D deficiency among middle-aged and elderly individuals in northwestern China: its relationship to osteoporosis and lifestyle factors. Bone. 2015;71:1–6. doi:.https://doi.org/10.1016/j.bone.2014.09.024
  35. Van Pottelbergh G, Matheï C, Vaes B, Adriaensen W, Gruson D, Degryse JM. The influence of renal function on vitamin D metabolism in the very elderly. J Nutr Health Aging. 2013;17(2):107–11. doi:.https://doi.org/10.1007/s12603-012-0094-0
  36. Aguirre M, Manzano N, Salas Y, Angel M, Díaz-Couselo FA, Zylberman M. Vitamin D deficiency in patients admitted to the general ward with breast, lung, and colorectal cancer in Buenos Aires, Argentina. Arch Osteoporos. 2016;11(1):4. doi:.https://doi.org/10.1007/s11657-015-0256-x
  37. Shirazi L, Almquist M, Malm J, Wirfält E, Manjer J. Determinants of serum levels of vitamin D: a study of life-style, menopausal status, dietary intake, serum calcium, and PTH. BMC Womens Health. 2013;13(1):33. doi:.https://doi.org/10.1186/1472-6874-13-33
  38. Miller GJ, Stapleton GE, Hedlund TE, Moffat KA. Vitamin D receptor expression, 24-hydroxylase activity, and inhibition of growth by 1alpha,25-dihydroxyvitamin D3 in seven human prostatic carcinoma cell lines. Clin Cancer Res. 1995;1(9):997–1003.
  39. Friedrich M, Diesing D, Cordes T, Fischer D, Becker S, Chen TC, et al. Analysis of 25-hydroxyvitamin D3-1alpha-hydroxylase in normal and malignant breast tissue. Anticancer Res. 2006;26(4A):2615–20.
  40. Li J, Luco AL, Ochietti B, Fadhil I, Camirand A, Reinhardt TA, et al. Tumoral vitamin D synthesis by CYP27B1 1-α-hydroxylase delays mammary tumor progression in the PyMT-MMTV mouse model and its action involves NF-κB modulation. Endocrinology. 2016;157(6):2204–16. doi:.https://doi.org/10.1210/en.2015-1824
  41. Mawer EB, Lumb GA, Stanbury SW. Long biological half-life of vitamin D3 and its polar metabolites in human serum. Nature. 1969;222(5192):482–3. doi:.https://doi.org/10.1038/222482a0
  42. Gray RW, Weber HP, Dominguez JH, Lemann J, Jr. The metabolism of vitamin D3 and 25-hydroxyvitamin D3 in normal and anephric humans. J Clin Endocrinol Metab. 1974;39(6):1045–56. doi:.https://doi.org/10.1210/jcem-39-6-1045
  43. Jung RT, Davie M, Hunter JO, Chalmers TM, Lawson DE. Abnormal vitamin D metabolism in cirrhosis. Gut. 1978;19(4):290–3. doi:.https://doi.org/10.1136/gut.19.4.290
  44. Kobayashi T, Okano T, Shida S, Okada K, Suginohara T, Nakao H, et al. Variation of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 levels in human plasma obtained from 758 Japanese healthy subjects. J Nutr Sci Vitaminol (Tokyo). 1983;29(3):271–81. doi:.https://doi.org/10.3177/jnsv.29.271
  45. Vicchio D, Yergey A, O’Brien K, Allen L, Ray R, Holick M. Quantification and kinetics of 25-hydroxyvitamin D3 by isotope dilution liquid chromatography/thermospray mass spectrometry. Biol Mass Spectrom. 1993;22(1):53–8. doi:.https://doi.org/10.1002/bms.1200220107
  46. Kennedy DA, Cooley K, Skidmore B, Fritz H, Campbell T, Seely D. Vitamin d: pharmacokinetics and safety when used in conjunction with the pharmaceutical drugs used in cancer patients: a systematic review. Cancers (Basel). 2013;5(1):255–80. doi:.https://doi.org/10.3390/cancers5010255
  47. Jones KS, Assar S, Harnpanich D, Bouillon R, Lambrechts D, Prentice A, et al. 25(OH)D2 half-life is shorter than 25(OH)D3 half-life and is influenced by DBP concentration and genotype. J Clin Endocrinol Metab. 2014;99(9):3373–81. doi:.https://doi.org/10.1210/jc.2014-1714
  48. Bailie GR, Johnson CA. Comparative review of the pharmacokinetics of vitamin D analogues. Semin Dial. 2002;15(5):352–7. doi:.https://doi.org/10.1046/j.1525-139X.2002.00086.x
  49. Pitson GA, Lugg DJ, Roy CR. Effect of seasonal ultraviolet radiation fluctuations on vitamin D homeostasis during an Antarctic expedition. Eur J Appl Physiol Occup Physiol. 1996;72(3):231–4. doi:.https://doi.org/10.1007/BF00838644
  50. Hollis BW. Short-term and long-term consequences and concerns regarding valid assessment of vitamin D deficiency: comparison of recent food supplementation and clinical guidance reports. Curr Opin Clin Nutr Metab Care. 2011;14(6):598–604. doi:.https://doi.org/10.1097/MCO.0b013e32834be798
  51. Hollis BW, Wagner CL. Clinical review: The role of the parent compound vitamin D with respect to metabolism and function: Why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab. 2013;98(12):4619–28. doi:.https://doi.org/10.1210/jc.2013-2653
  52. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi:.https://doi.org/10.1136/bmj.i6583
  53. Duque G, Daly RM, Sanders K, Kiel DP. Vitamin D, bones and muscle: myth versus reality. Australas J Ageing. 2017;36(Suppl 1):8–13. doi:.https://doi.org/10.1111/ajag.12408
  54. 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;73(2):288–94.
  55. Romagnoli E, Mascia ML, Cipriani C, Fassino V, Mazzei F, D’Erasmo E, et al. Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J Clin Endocrinol Metab. 2008;93(8):3015–20. doi:.https://doi.org/10.1210/jc.2008-0350
  56. van Groningen L, Opdenoordt S, van Sorge A, Telting D, Giesen A, de Boer H. Cholecalciferol loading dose guideline for vitamin D-deficient adults. Eur J Endocrinol. 2010;162(4):805–11. doi:.https://doi.org/10.1530/EJE-09-0932
  57. Leidig-Bruckner G, Roth HJ, Bruckner T, Lorenz A, Raue F, Frank-Raue K. Are commonly recommended dosages for vitamin D supplementation too low? Vitamin D status and effects of supplementation on serum 25-hydroxyvitamin D levels--an observational study during clinical practice conditions. Osteoporos Int. 2011;22(1):231–40. doi:.https://doi.org/10.1007/s00198-010-1214-5
  58. Sakem B, Nock C, Stanga Z, Medina P, Nydegger UE, Risch M, et al. Serum concentrations of 25-hydroxyvitamin D and immunoglobulins in an older Swiss cohort: results of the Senior Labor Study. BMC Med. 2013;11(1):176. doi:.https://doi.org/10.1186/1741-7015-11-176
  59. Singh RJ, Taylor RL, Reddy GS, Grebe SK. C-3 epimers can account for a significant proportion of total circulating 25-hydroxyvitamin D in infants, complicating accurate measurement and interpretation of vitamin D status. J Clin Endocrinol Metab. 2006;91(8):3055–61. doi:.https://doi.org/10.1210/jc.2006-0710
  60. Nakagawa K, Sowa Y, Kurobe M, Ozono K, Siu-Caldera ML, Reddy GS, et al. Differential activities of 1alpha,25-dihydroxy-16-ene-vitamin D(3) analogs and their 3-epimers on human promyelocytic leukemia (HL-60) cell differentiation and apoptosis. Steroids. 2001;66(3-5):327–37. doi:.https://doi.org/10.1016/S0039-128X(00)00142-2
  61. Kamao M, Tatematsu S, Hatakeyama S, Sakaki T, Sawada N, Inouye K, et al. C-3 epimerization of vitamin D3 metabolites and further metabolism of C-3 epimers: 25-hydroxyvitamin D3 is metabolized to 3-epi-25-hydroxyvitamin D3 and subsequently metabolized through C-1alpha or C-24 hydroxylation. J Biol Chem. 2004;279(16):15897–907. doi:.https://doi.org/10.1074/jbc.M311473200
  62. Chailurkit LO, Aekplakorn W, Srijaruskul K, Ongphiphadhanakul B. Discrepant association of serum C-3 epimer of 25-hydroxyvitamin D versus non-epimeric 25-hydroxyvitamin D with serum lipid levels. Lipids Health Dis. 2016;15(1):157. doi:.https://doi.org/10.1186/s12944-016-0333-1
  63. Djekic-Ivankovic M, Lavery P, Agellon S, Weiler HA. The C-3α Epimer of 25-hydroxycholecalciferol from endogenous and exogenous sources supports normal growth and bone mineral density in weanling rats. J Nutr. 2017;147(2):141–51. doi:.https://doi.org/10.3945/jn.116.231753
  64. VITAL Study homepage: http://www.vitalstudy.org
  65. FIND Study homepage: https://www.uef.fi/web/nutritionepidemiologists/find-2012-
  66. ViDA Study homepage: https://www.fmhs.auckland.ac.nz/en/soph/about/our-departments/epidemiology-and-biostatistics/research/vida-study.html
  67. DOHealth Study homepage: http://do-health.eu/wordpress/
  68. VIDAL Study homepage: http://vidal.lshtm.ac.uk/home/

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