Advertisement

Multiple vitamin deficiencies additively increase the risk of incident fractures in Japanese postmenopausal women

  • T. KurodaEmail author
  • K. Uenishi
  • H. Ohta
  • M. Shiraki
Original Article
  • 84 Downloads

Abstract

Summary

The associations of multiple vitamin deficiencies on incident fractures were uncertain, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women. The number of deficiencies was additively associated with incident fracture after adjustment for possible confounding factors including the treatment of osteoporosis.

Introduction

To evaluate the associations of multiple vitamin deficiencies on incident fractures, the relationships between serum vitamin markers and incident bone fractures were investigated in Japanese postmenopausal women.

Methods

This analysis used a subset of the ongoing cohort maintained by a primary care institution. Inclusion criteria of the present study were postmenopausal women aged ≥ 50 years, without vitamin supplementation and secondary osteoporosis. Baseline serum concentrations of 25-hydroxyvitamin D (25(OH)D), undercarboxylated osteocalcin (ucOC), and homocysteine (Hcy) were measured to assess vitamin D, vitamin K, and vitamin B, respectively. Since 25(OH) D positively relates to vitamin D, ucOC and Hcy negatively relate to vitamin K and vitamin B nutrients, respectively, the subjects with lower (25(OH)D) or higher (ucOC or Hcy) values than each median value was defined as subjects with the corresponding vitamin deficiency. Subjects were divided into four groups according to the number of deficiency: no deficiency, single deficiency, double deficiencies, and triple deficiencies. Relationships between the vitamin deficiencies and incident fractures were evaluated by Cox regression analysis.

Results

A total of 889 subjects were included in this analysis; their mean and SD age was 68.3 ± 9.5 years, and the follow-up period was 6.3 ± 5.1 years. The numbers of subjects in the four groups were 139 (15.6%), 304 (34.2%), 316 (35.5%), and 130 (14.6%) for the groups with no, single, double, and triple deficiencies, respectively. Incident fractures were observed in 264 subjects (29.7%) during the observation period. The number of deficiencies was significantly associated with incident fracture (hazard ratio 1.25, 95% confidence interval 1.04–1.50, P = 0.018) after adjustment for possible confounding factors including the treatment of osteoporosis.

Conclusion

Accumulation of vitamin deficiencies was related to incident fractures.

Keywords

Fracture Vitamin B Vitamin D Vitamin K 

Notes

Acknowledgments

This work was partly supported by grants from the Japan Osteoporosis Foundation. We appreciate all the volunteers for contributing the clinical data and samples analyzed in this study.

Compliance with ethical standards

Conflicts of interest

H.O. received lecture fees from Pfizer. M.S. received consulting fees from Asahi Kasei Pharma and Teijin Pharma. T.K. is an employee of Asahi Kasei Corporation. K. U. and M. S. have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Black DM, Rosen CJ (2016) Postmenopausal osteoporosis. N Engl J Med 374:2096–2097CrossRefGoogle Scholar
  2. 2.
    Yoshimura M, Moriwaki K, Noto S, Takiguchi T (2017) A model-based cost-effectiveness analysis of osteoporosis screening and treatment strategy for postmenopausal Japanese women. Osteoporos Int 28:643–652CrossRefGoogle Scholar
  3. 3.
    Imai T, Tanaka S, Kawakami K, Miyazaki T, Hagino H, Shiraki M, A-TOP (Adequate Treatment of Osteoporosis) Research Group (2017) Health state utility values and patient-reported outcomes before and after vertebral and non-vertebral fractures in an osteoporosis clinical trial. Osteoporos Int 28:1893–1901CrossRefGoogle Scholar
  4. 4.
    Lock CA, Lecouturier J, Mason JM, Dickinson HO (2006) Lifestyle interventions to prevent osteoporotic fractures: a systematic review. Osteoporos Int 17:20–28CrossRefGoogle Scholar
  5. 5.
    Rizzoli R, Bischoff-Ferrari H, Dawson-Hughes B, Weaver C (2014) Nutrition and bone health in women after the menopause. Womens Health (Lond) 10:599–608CrossRefGoogle Scholar
  6. 6.
    Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96:1911–1930CrossRefGoogle Scholar
  7. 7.
    Dawson-Hughes B, Mithal A, Bonjour JP, Boonen S, Burckhardt P, Fuleihan GE, Josse RG, Lips P, Morales-Torres J, Yoshimura N (2010) IOF position statement: vitamin D recommendations for older adults. Osteoporos Int 21:1151–1154CrossRefGoogle Scholar
  8. 8.
    Okazaki R, Sugimoto T, Kaji H, Fujii Y, Shiraki M, Inoue D, Endo I, Okano T, Hirota T, Kurahashi I, Matsumoto T (2011) Vitamin D insufficiency defined by serum 25-hydroxyvitamin D and parathyroid hormone before and after oral vitamin D3 load in Japanese subjects. J Bone Miner Metab 29:103–110CrossRefGoogle Scholar
  9. 9.
    Kuroda T, Shiraki M, Tanaka S, Ohta H (2009) Contributions of 25-hydroxyvitamin D, co-morbidities and bone mass to mortality in Japanese postmenopausal women. Bone 44:168–172CrossRefGoogle Scholar
  10. 10.
    Tamaki J, Iki M, Sato Y, Kajita E, Nishino H, Akiba T, Matsumoto T, Kagamimori S, JPOS Study Group (2017) Total 25-hydroxyvitamin D levels predict fracture risk: results from the 15-year follow-up of the Japanese Population-based Osteoporosis (JPOS) Cohort Study. Osteoporos Int 28:1903–1913CrossRefGoogle Scholar
  11. 11.
    Tanaka S, Kuroda T, Yamazaki Y, Shiraki Y, Yoshimura N, Shiraki M (2014) Serum 25-hydroxyvitamin D below 25 ng/mL is a risk factor for long bone fracture comparable to bone mineral density in Japanese postmenopausal women. J Bone Miner Metab 32:514–523CrossRefGoogle Scholar
  12. 12.
    Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD (1993) Circulating levels of vitamins K1 and K2 decreased in elderly women with hip fracture. J Bone Miner Res 8:1241–1245CrossRefGoogle Scholar
  13. 13.
    Tamatani M, Morimoto S, Nakajima M, Fukuo K, Onishi T, Kitano S, Niinobu T, Ogihara T (1998) Decreased circulating levels of vitamin K and 25-hydroxyvitamin D in osteopenic elderly men. Metabolism 47:195–199CrossRefGoogle Scholar
  14. 14.
    Apalset EM, Gjesdal CG, Eide GE, Tell GS (2011) Intake of vitamin K1 and K2 and risk of hip fractures: the Hordaland Health Study. Bone 49:990–995CrossRefGoogle Scholar
  15. 15.
    Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein S, Gundberg C, Bradley A, Karsenty G (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382:448–452CrossRefGoogle Scholar
  16. 16.
    Vermeer C, Braam L (2001) Role of K vitamins in the regulation of tissue calcification. J Bone Miner Metab 19:201–206CrossRefGoogle Scholar
  17. 17.
    Cheung AM, Tile L, Lee Y, Tomlinson G, Hawker G, Scher J, Hu H, Vieth R, Thompson L, Jamal S, Josse R (2008) Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med 5:e196CrossRefGoogle Scholar
  18. 18.
    Szulc P, Arlot M, Chapuy MC, Duboeuf F, Meunier PJ, Delmas PD (1994) Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women. J Bone Miner Res 1591–1595CrossRefGoogle Scholar
  19. 19.
    Matsunaga S, Ito H, Sakou T (1999) The effect of vitamin K and D supplementation on ovariectomy-induced bone loss. Calcif Tissue Int 65:285–289CrossRefGoogle Scholar
  20. 20.
    Koehler KM, Romero LJ, Stauber PM, Pareo-Tubbeh SL, Liang HC, Baumgartner RN, Garry PJ, Allen RH, Stabler SP (1996) Vitamin supplementation and other variables affecting serum homocysteine and methylmalonic acid concentrations in elderly men and women. J Am Coll Nutr 15:364–376CrossRefGoogle Scholar
  21. 21.
    van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, van der Klift M, de Jonge R, Lindemans J, de Groot LC, Hofman A, Witteman JC, van Leeuwen JP, Breteler MM, Lips P, Pols HA, Uitterlinden AG (2004) Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med 350:2033–2041CrossRefGoogle Scholar
  22. 22.
    Shiraki M, Urano T, Kuroda T, Saito M, Tanaka S, Miyao-Koshizuka M, Inoue S (2008) The synergistic effect of bone mineral density and methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) on fractures. J Bone Miner Metab 26:595–602CrossRefGoogle Scholar
  23. 23.
    McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE, Hannan MT, Cupples LA, Kiel DP (2004) Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 350:2042–2049CrossRefGoogle Scholar
  24. 24.
    Zhao JG, Zeng XT, Wang J, Liu L (2017) Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis. JAMA 318:2466–2482CrossRefGoogle Scholar
  25. 25.
    Weaver CM, Alexander DD, Boushey CJ, Dawson-Hughes B, Lappe JM, LeBoff MS, Liu S, Looker AC, Wallace TC, Wang DD (2016) Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Osteoporos Int 27:367–376CrossRefGoogle Scholar
  26. 26.
    Huang ZB, Wan SL, Lu YJ, Ning L, Liu C, Fan SW (2015) Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials. Osteoporos Int 26:1175–1186CrossRefGoogle Scholar
  27. 27.
    Cockayne S, Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ (2006) Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 166:1256–1261CrossRefGoogle Scholar
  28. 28.
    van Wijngaarden JP, Swart KM, Enneman AW, Dhonukshe-Rutten RA, van Dijk SC, Ham AC, Brouwer-Brolsma EM, van der Zwaluw NL, Sohl E, van Meurs JB, Zillikens MC, van Schoor NM, van der Velde N, Brug J, Uitterlinden AG, Lips P, de Groot LC (2014) Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. Am J Clin Nutr 100:1578–1586CrossRefGoogle Scholar
  29. 29.
    Gommans J, Yi Q, Eikelboom JW, Hankey GJ, Chen C, Rodgers H, VITATOPS trial study group (2013) The effect of homocysteine-lowering with B-vitamins on osteoporotic fractures in patients with cerebrovascular disease: substudy of VITATOPS, a randomised placebo-controlled trial. BMC Geriatr 13:88CrossRefGoogle Scholar
  30. 30.
    Ruan J, Gong X, Kong J, Wang H, Zheng X, Chen T (2015) Effect of B vitamin (folate, B6, and B12) supplementation on osteoporotic fracture and bone turnover markers: a meta-analysis. Med Sci Monit 21:875–881CrossRefGoogle Scholar
  31. 31.
    Shiraki M, Shiraki Y, Aoki C, Hosoi T, Inoue S, Kaneki M, Ouchi Y (1997) Association of bone mineral density with apolipoprotein E phenotype. J Bone Miner Res 12:1438–1445CrossRefGoogle Scholar
  32. 32.
    Yoshihara K, Nakamura K, Kanai M, Nagayama Y, Takahashi S, Saito N, Nagata M (1998) Determination of urinary and serum pentosidine and its application to elder patients. Biol Pharm Bull 21:1005–1008CrossRefGoogle Scholar
  33. 33.
    Haddad JG, Chyu KJ (1971) Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol Metab 33:992–995CrossRefGoogle Scholar
  34. 34.
    Tsugawa N, Shiraki M, Suhara Y, Kamao M, Ozaki R, Tanaka K, Okano T (2008) Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women. J Bone Miner Metab 26:79–85CrossRefGoogle Scholar
  35. 35.
    Vester B, Rasmussen K (1991) High performance liquid chromatography method for rapid and accurate determination of homocysteine in plasma and serum. Eur J Clin Chem Clin Biochem 29:549–554PubMedGoogle Scholar
  36. 36.
    Soen S, Fukunaga M, Sugimoto T, Sone T, Fujiwara S, Endo N, Gorai I, Shiraki M, Hagino H, Hosoi T, Ohta H, Yoneda T, Tomomitsu T, Japanese Society for Bone and Mineral Research and Japan Osteoporosis Society Joint Review Committee for the Revision of the Diagnostic Criteria for Primary Osteoporosis (2013) Diagnostic criteria for primary osteoporosis: year 2012 revision. J Bone Miner Metab 31:247–257CrossRefGoogle Scholar
  37. 37.
    Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RS, Black D, Cummings SR (1996) Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. The Study of Osteoporotic Fractures Research Group. J Bone Miner Res 11:984–996CrossRefGoogle Scholar
  38. 38.
    Nanri A, Mizoue T, Shimazu T, Ishihara J, Takachi R, Noda M, Iso H, Sasazuki S, Sawada N, Tsugane S, Japan Public Health Center-Based Prospective Study Group (2017) Dietary patterns and all-cause, cancer, and cardiovascular disease mortality in Japanese men and women: the Japan public health center-based prospective study. PLoS One 12(4):e0174848CrossRefGoogle Scholar
  39. 39.
    Garcia Lopez M, Bønaa KH, Ebbing M, Eriksen EF, Gjesdal CG, Nygård O, Tell GS, Ueland PM, Meyer HE (2017) Vitamins and hip fracture: secondary analyses and extended follow-up of two large randomized controlled trials. J Bone Miner Res 32:1981–1989CrossRefGoogle Scholar
  40. 40.
    Scott D, Blizzard L, Fell J, Ding C, Winzenberg T, Jones G (2010) A prospective study of the associations between 25-hydroxy-vitamin D, sarcopenia progression and physical activity in older adults. Clin Endocrinol 73:581e7CrossRefGoogle Scholar
  41. 41.
    Visser M, Deeg DJ, Lips P, A. Longitudinal Aging Study (2003) Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 88:5766e72CrossRefGoogle Scholar
  42. 42.
    Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, Vermeer C, Elias SG, Velthuis BK, de Jong PA, Beulens JW (2013) Circulating species of matrix Gla protein and the risk of vascular calcification in healthy women. Int J Cardiol 168:e168–e170CrossRefGoogle Scholar
  43. 43.
    Caluwé R, Pyfferoen L, De Boeck K, De Vriese AS (2016) The effects of vitamin K supplementation and vitamin K antagonists on progression of vascular calcification: ongoing randomized controlled trials. Clin Kidney J 9:273–279CrossRefGoogle Scholar
  44. 44.
    Kuo HK, Liao KC, Leveille SG, Bean JF, Yen CJ, Chen JH, Yu YH, Tai TY (2007) Relationship of homocysteine levels to quadriceps strength, gait speed, and late-life disability in older adults. J Gerontol A Biol Sci Med Sci 62:434–439CrossRefGoogle Scholar
  45. 45.
    Kado DM, Bucur A, Selhub J, Rowe JW, Seeman T (2002) Homocysteine levels and decline in physical function: MacArthur Studies of Successful Aging. Am J Med 113:537–542CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  1. 1.Public Health Research FoundationTokyoJapan
  2. 2.Division of Nutritional PhysiologyKagawa Nutrition UniversitySakado CityJapan
  3. 3.Clinical Medical Research Center, Women’s Medical Center, Sanno Medical CenterInternational University of Health and WelfareTokyoJapan
  4. 4.Department of Internal MedicineResearch Institute and Practice for Involutional DiseasesNaganoJapan

Personalised recommendations