Osteoporosis International

, Volume 25, Issue 11, pp 2545–2554 | Cite as

Low serum concentrations of alpha-tocopherol are associated with increased risk of hip fracture. A NOREPOS study

  • K. Holvik
  • C. G. Gjesdal
  • G. S. Tell
  • G. Grimnes
  • B. Schei
  • E. M. Apalset
  • S. O. Samuelsen
  • R. Blomhoff
  • K. Michaëlsson
  • H. E. Meyer
Original Article

Abstract

Summary

We investigated the risk of hip fracture according to circulating alpha-tocopherol, a plant-derived substance with antioxidant properties, in community-dwelling older Norwegians. We found a linear increasing risk of hip fracture with lower serum alpha-tocopherol concentrations, with a 51 % higher risk in the lowest compared to the highest quartile.

Introduction

Oxidative stress is a suggested contributing cause of osteoporosis and fractures. Vitamin E (α-tocopherol) has potent antioxidant properties in humans. The relationship between circulating α-tocopherol and fracture risk is not established. The aim of this study was to investigate the association between serum α-tocopherol concentrations and risk of hip fracture during up to 11 years of follow-up.

Methods

We performed a case-cohort analysis among 21,774 men and women aged 65–79 years who participated in four community-based health studies in Norway 1994–2001. Serum α-tocopherol concentrations at baseline were determined in 1,168 men and women who subsequently suffered hip fractures (median follow-up 8.2 years) and in a random sample (n = 1,434) from the same cohort. Cox proportional hazard regression adapted for gender-stratified case-cohort data was performed.

Results

Median (25, 75 percentile) serum α-tocopherol was 30.0 (22.6, 38.3) μmol/L, and it showed a linear inverse association with hip fracture: hazard ratio (HR) 1.11 (95 % confidence interval (CI) 1.04–1.20) per 10-μmol/L decrease in serum α-tocopherol, adjusted for gender and study center. The lowest compared to the highest quartile conferred an HR of 1.51 (95 % CI 1.17–1.95), adjusted for gender and study center. Adjustment for smoking, month of blood sample, BMI, education, physical inactivity, self-rated health, and serum 25-hydroxyvitamin D (25(OH)D) yielded similar results. Taking serum total cholesterol concentration into account attenuated the association somewhat: HR of hip fracture was 1.37 (95 % CI 1.05–1.77) in first versus fourth quartile of serum α-tocopherol/total cholesterol ratio.

Conclusions

Low serum concentrations of α-tocopherol were associated with increased risk of hip fracture in older Norwegians.

Keywords

Alpha-tocopherol Case-cohort Hip fracture Norway Vitamin E 

Notes

Acknowledgments

This NOREPOS study was funded by a grant from the Research Council of Norway. The serum sample analyses in HUNT 2 were partly funded by a grant from Central Norway Regional Health Authority. KH’s salary while writing the manuscript was funded by the Norwegian Institute of Public Health. We would like to acknowledge the people involved in carrying out the data collection in Tromsø IV, HUNT 2, HUSK, and HUBRO, those involved in establishing and maintaining the four respective hip fracture follow-up registers, those involved in data management, those involved in biobanks and blood sample handling, and the laboratory AS Vitas, Oslo, Norway, for performing the serum sample analyses. Finally, we would like to thank the participants in the health studies in Norway.

Conflicts of interest

KH, CGG, GST, GG, BS, EMA, SOS, KM, and HEM have nothing to declare. RB has interests in Vitas AS, a company established by Oslo Innovation Center.

References

  1. 1.
    Cauley JA (2013) Public health impact of osteoporosis. J Gerontol A Biol Sci Med Sci 68:1243–1251PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Manolagas SC (2010) From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev 31:266–300PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84PubMedCrossRefGoogle Scholar
  4. 4.
    Da Costa LA, Badawi A, El-Sohemy A (2012) Nutrigenetics and modulation of oxidative stress. Ann Nutr Metab 60(uppl 3):27–36PubMedCrossRefGoogle Scholar
  5. 5.
    Garrett IR, Boyce BF, Oreffo RO, Bonewald L, Poser J, Mundy GR (1990) Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest 85:632–639PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Kim HJ, Chang EJ, Kim HM, Lee SB, Kim HD, Su Kim G, Kim HH (2006) Antioxidant alpha-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-kappaB DNA binding and prevents in vivo bone resorption induced by receptor activator of nuclear factor-kappaB ligand and tumor necrosis factor-alpha. Free Radic Biol Med 40:1483–1493PubMedCrossRefGoogle Scholar
  7. 7.
    Nieves JW (2013) Skeletal effects of nutrients and nutraceuticals, beyond calcium and vitamin D. Osteoporos Int 24:771–786PubMedCrossRefGoogle Scholar
  8. 8.
    Niki E, Traber MG (2012) A history of vitamin E. Ann Nutr Metab 61:207–212PubMedCrossRefGoogle Scholar
  9. 9.
    Goyal A, Terry MB, Siegel AB (2013) Serum antioxidant nutrients, vitamin a, and mortality in u.s. Adults. Cancer Epidemiol Biomarkers Prev 22:2202–2211PubMedCrossRefGoogle Scholar
  10. 10.
    Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 142:37–46PubMedCrossRefGoogle Scholar
  11. 11.
    Jenab M, Salvini S, van Gils CH et al (2009) Dietary intakes of retinol, beta-carotene, vitamin D and vitamin E in the European Prospective Investigation into Cancer and Nutrition cohort. Eur J Clin Nutr 63(Suppl 4):S150–S178PubMedCrossRefGoogle Scholar
  12. 12.
    Freisling H, Fahey MT, Moskal A et al (2010) Region-specific nutrient intake patterns exhibit a geographical gradient within and between European countries. J Nutr 140:1280–1286PubMedCrossRefGoogle Scholar
  13. 13.
    Totland TH, Melnæs BK, Lundberg-Hallén N, Helland-Kigen KM, Lund-Blix NA, Myhre JB, Johansen AMW, Løken EB, Andersen LF (2012) Norkost 3. A nationwide dietary survey among men and women in Norway aged 18-70 years. pp 1-68Google Scholar
  14. 14.
    Fujita K, Iwasaki M, Ochi H et al (2012) Vitamin E decreases bone mass by stimulating osteoclast fusion. Nat Med 18:589–594PubMedCrossRefGoogle Scholar
  15. 15.
    Ahmadieh H, Arabi A (2011) Vitamins and bone health: beyond calcium and vitamin D. Nutr Rev 69:584–598PubMedCrossRefGoogle Scholar
  16. 16.
    Zhang J, Munger RG, West NA, Cutler DR, Wengreen HJ, Corcoran CD (2006) Antioxidant intake and risk of osteoporotic hip fracture in Utah: an effect modified by smoking status. Am J Epidemiol 163:9–17PubMedCrossRefGoogle Scholar
  17. 17.
    Melhus H, Michaëlsson K, Holmberg L, Wolk A, Ljunghall S (1999) Smoking, antioxidant vitamins, and the risk of hip fracture. J Bone Miner Res 14:129–135PubMedCrossRefGoogle Scholar
  18. 18.
    Michaëlsson K, Wolk A, Byberg L, Arnlöv J, Melhus H (2014) Intake and serum concentrations of alpha-tocopherol in relation to fractures in elderly women and men: 2 cohort studies. Am J Clin Nutr 99:107–114PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Jørgensen L, Joakimsen R, Ahmed L, Størmer J, Jacobsen BK (2011) Smoking is a strong risk factor for non-vertebral fractures in women with diabetes: the Tromsø study. Osteoporos Int 22:1247–1253PubMedCrossRefGoogle Scholar
  20. 20.
    Borgan Ø, Langholz B, Samuelsen SO, Goldstein L, Pogoda J (2000) Exposure stratified case-cohort designs. LifetimeData Anal 6:39–58CrossRefGoogle Scholar
  21. 21.
    Cologne J, Preston DL, Imai K, Misumi M, Yoshida K, Hayashi T, Nakachi K (2012) Conventional case-cohort design and analysis for studies of interaction. Int J Epidemiol 41:1174–1186PubMedCrossRefGoogle Scholar
  22. 22.
    Næss Ø, Søgaard AJ, Arnesen E et al (2008) Cohort profile: cohort of Norway (CONOR). Int J Epidemiol 37:481–485PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Holvik K, Ahmed LA, Forsmo S, Gjesdal CG, Grimnes G, Samuelsen SO, Schei B, Blomhoff R, Tell GS, Meyer HE (2013) Low serum levels of 25-hydroxyvitamin D predict hip fracture in the elderly: A NOREPOS study. J Clin Endocrinol Metab 98:3341–3350PubMedCrossRefGoogle Scholar
  24. 24.
    Ahmed LA, Emaus N, Berntsen GK, Bjørnerem Å, Fønnebø V, Jørgensen L, Schirmer H, Størmer J, Joakimsen RM (2010) Bone loss and the risk of non-vertebral fractures in women and men: the Tromsø study. Osteoporos Int 21:1503–1511PubMedCrossRefGoogle Scholar
  25. 25.
    Grønskag AB, Forsmo S, Romundstad P, Langhammer A, Schei B (2010) Incidence and seasonal variation in hip fracture incidence among elderly women in Norway. HUNT Study Bone 46:1294–1298CrossRefGoogle Scholar
  26. 26.
    Gjesdal CG, Vollset SE, Ueland PM, Refsum H, Meyer HE, Tell GS (2007) Plasma homocysteine, folate, and vitamin B 12 and the risk of hip fracture: the hordaland homocysteine study. J Bone Miner Res 22:747–756PubMedCrossRefGoogle Scholar
  27. 27.
    Foss OP, Urdal P (2003) Cholesterol for more than 25 years: could the results be compared throughout all this time? Nor J Epidemiol 13:85–88Google Scholar
  28. 28.
    R Core Team (2013) The R Project for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org. Accessed 26 June 2014
  29. 29.
    Breslow N (2013) “cch: Fits proportional hazards regression model to case-cohort data”. Function in Therneau T: “Package ‘survival’: Survival analysis, including penalised likelihood”. http://cran.r-project.org/web/packages/survival/survival.pdf. Accessed 26.06.2014
  30. 30.
    Thurnham DI, Davies JA, Crump BJ, Situnayake RD, Davis M (1986) The use of different lipids to express serum tocopherol: lipid ratios for the measurement of vitamin E status. Ann Clin Biochem 23(Pt 5):514–520PubMedCrossRefGoogle Scholar
  31. 31.
    Vogel S, Contois JH, Tucker KL, Wilson PW, Schaefer EJ, Lammi-Keefe CJ (1997) Plasma retinol and plasma and lipoprotein tocopherol and carotenoid concentrations in healthy elderly participants of the Framingham Heart Study. Am J Clin Nutr 66:950–958PubMedGoogle Scholar
  32. 32.
    Sinha R, Patterson BH, Mangels AR, Levander OA, Gibson T, Taylor PR, Block G (1993) Determinants of plasma vitamin E in healthy males. Cancer Epidemiol Biomarkers Prev 2:473–479PubMedGoogle Scholar
  33. 33.
    Maggio D, Barabani M, Pierandrei M, Polidori MC, Catani M, Mecocci P, Senin U, Pacifici R, Cherubini A (2003) Marked decrease in plasma antioxidants in aged osteoporotic women: results of a cross-sectional study. J Clin Endocrinol Metab 88:1523–1527PubMedCrossRefGoogle Scholar
  34. 34.
    Chuin A, Labonté M, Tessier D, Khalil A, Bobeuf F, Doyon CY, Rieth N, Dionne IJ (2009) Effect of antioxidants combined to resistance training on BMD in elderly women: a pilot study. Osteoporos Int 20:1253–1258PubMedCrossRefGoogle Scholar
  35. 35.
    Pasco JA, Henry MJ, Wilkinson LK, Nicholson GC, Schneider HG (2002) Kotowicz MA (2006) Antioxidant vitamin supplements and markers of bone turnover in a community sample of nonsmoking women. J Womens Health 15:295–300CrossRefGoogle Scholar
  36. 36.
    Hamidi MS, Corey PN, Cheung AM (2012) Effects of vitamin E on bone turnover markers among US postmenopausal women. J Bone Miner Res 27:1368–1380PubMedCrossRefGoogle Scholar
  37. 37.
    Wolf RL, Cauley JA, Pettinger M et al (2005) Lack of a relation between vitamin and mineral antioxidants and bone mineral density: results from the Women's Health Initiative. Am J Clin Nutr 82:581–588PubMedGoogle Scholar
  38. 38.
    Mullie P, Clarys P, Hulens M, Vansant G (2011) Socioeconomic, health, and dietary determinants of multivitamin supplements use in Belgium. Int J Public Health 56:289–294PubMedCrossRefGoogle Scholar
  39. 39.
    Pouchieu C, Andreeva VA, Péneau S, Kesse-Guyot E, Lassale C, Hercberg S, Touvier M (2013) Sociodemographic, lifestyle and dietary correlates of dietary supplement use in a large sample of French adults: results from the NutriNet-Santé cohort study. Br J Nutr 110:1480–1491PubMedCrossRefGoogle Scholar
  40. 40.
    Talwar D, McConnachie A, Welsh P, Upton M, O'Reilly D, Davey SG, Watt G, Sattar N (2010) Which circulating antioxidant vitamins are confounded by socioeconomic deprivation? The MIDSPAN family study. PLoS One 5:e11312PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Langsted A, Freiberg JJ, Nordestgaard BG (2008) Fasting and nonfasting lipid levels: influence of normal food intake on lipids, lipoproteins, apolipoproteins, and cardiovascular risk prediction. Circulation 118:2047–2056PubMedCrossRefGoogle Scholar
  42. 42.
    Sidhu D, Naugler C (2012) Fasting time and lipid levels in a community-based population: a cross-sectional study. Arch Intern Med 172:1707–1710PubMedCrossRefGoogle Scholar
  43. 43.
    Jezequel-Cuer M, Le Moël G, Covi G, Lepage S, Peynet J, Gousson-Evstigneeff T, Laureaux C, Troupel S (1994) Stability of alpha-tocopherol: pre-analytical conditions in its determination in blood samples. Ann Biol Clin 52:271–276Google Scholar
  44. 44.
    Ocké MC, Schrijver J, Obermann-de Boer GL, Bloemberg BP, Haenen GR, Kromhout D (1995) Stability of blood (pro)vitamins during four years of storage at -20 degrees C: consequences for epidemiologic research. J Clin Epidemiol 48:1077–1085PubMedCrossRefGoogle Scholar
  45. 45.
    Comstock GW, Alberg AJ, Helzlsouer KJ (1993) Reported effects of long-term freezer storage on concentrations of retinol, beta-carotene, and alpha-tocopherol in serum or plasma summarized. Clin Chem 39:1075–1078PubMedGoogle Scholar
  46. 46.
    Andersen LF, Solvoll K, Johansson LR, Salminen I, Aro A, Drevon CA (1999) Evaluation of a food frequency questionnaire with weighed records, fatty acids, and alpha-tocopherol in adipose tissue and serum. Am J Epidemiol 150:75–87PubMedCrossRefGoogle Scholar
  47. 47.
    Løken-Amsrud KI, Myhr KM, Bakke SJ et al (2013) Alpha-tocopherol and MRI outcomes in multiple sclerosis–association and prediction. PLoS One 8:e54417PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2014

Authors and Affiliations

  • K. Holvik
    • 1
    • 2
  • C. G. Gjesdal
    • 3
    • 4
  • G. S. Tell
    • 2
  • G. Grimnes
    • 5
  • B. Schei
    • 6
  • E. M. Apalset
    • 2
    • 3
  • S. O. Samuelsen
    • 1
    • 7
  • R. Blomhoff
    • 8
    • 9
  • K. Michaëlsson
    • 10
    • 11
  • H. E. Meyer
    • 1
    • 12
  1. 1.Division of EpidemiologyNorwegian Institute of Public HealthOsloNorway
  2. 2.Department of Global Public Health and Primary CareUniversity of BergenBergenNorway
  3. 3.Department of RheumatologyHaukeland University HospitalBergenNorway
  4. 4.Department of Clinical ScienceUniversity of BergenBergenNorway
  5. 5.Tromsø Endocrine Research Group, Department of Clinical MedicineUniversity of TromsøTromsøNorway
  6. 6.Department of Public Health and General PracticeNorwegian University of Science and TechnologyTrondheimNorway
  7. 7.Department of MathematicsUniversity of OsloOsloNorway
  8. 8.Department of Nutrition, Institute of Basic Medical SciencesUniversity of OsloOsloNorway
  9. 9.Division of Cancer, Surgery and TransplantationOslo University HospitalOsloNorway
  10. 10.Department of Surgical Sciences, Section of OrthopedicsUppsala UniversityUppsalaSweden
  11. 11.Uppsala Clinical Research CenterUppsala UniversityUppsalaSweden
  12. 12.Institute of Health and Society, Medical FacultyUniversity of OsloOsloNorway

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