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Effect of vitamin K on bone mineral density: a meta-analysis of randomized controlled trials

Abstract

A number of randomized controlled trials (RCTs) examining the role of vitamin K on bone mineral density (BMD) have yielded inconsistent results. We performed a meta-analysis of these trials to assess the effect of vitamin K on BMD. We searched MEDLINE, EMBASE and CENTRAL for relevant studies of RCTs examining the role of vitamin K on BMD. Data on participants, interventions, and outcomes were extracted and the quality of all included trials assessed. Primary outcomes for analysis were absolute changes in BMD (mg/cm2) at the lumbar spine and femoral neck. Relative changes (percentage change) in BMD at the lumbar spine were also assessed. Vitamin K supplementation was shown to be efficacious in increasing BMD at the lumbar spine but not the femoral neck. The weighted mean difference (WMD) in BMD absolute change was 21.60 mg/cm2 [95% confidence interval (CI) 3.63, 39.56] at the lumbar spine and 0.25 mg/cm2 (95% CI −2.64, 3.14) at the femoral neck. The WMD in BMD relative change was 1.27% (95% CI 0.47, 2.06) at the lumbar spine and 0.17 (95% CI −0.21, 0.54) at the femoral neck. Subgroup analysis revealed that ethnic difference, gender, and vitamin K type were associated with variable effects on BMD at the lumbar spine. The modest overall treatment effects for vitamin K on BMD observed in this review may be biased and should be interpreted with caution. Further studies are required to address factors relating to the observed effects of vitamin K on BMD.

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References

  1. 1.

    Vermeer C, Braam L (2001) Role of K vitamins in the regulation of tissue calcification. J Bone Miner Metab 19:201–206

  2. 2.

    Stenflo J (1974) Vitamin K and the biosynthesis of prothrombin. IV. Isolation of peptides containing prosthetic groups from normal prothrombin and the corresponding peptides from dicoumarol-induced prothrombin. J Biol Chem 249:5527–5535

  3. 3.

    Stenflo J, Fernlund P, Egan W, Roepstorff P (1974) Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci USA 71:2730–2733

  4. 4.

    Swanson JC, Suttie JW (1982) Vitamin K dependent in vitro production of prothrombin. Biochemistry 21:6011–6018

  5. 5.

    Boskey AL, Gadaleta S, Gundberg C, Doty SB, Ducy P, Karsenty G (1998) Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the function of osteocalcin. Bone 23:187–196

  6. 6.

    Akiyama Y, Hara K, Kobayashi M, Tomiuga T, Nakamura T (1999) Inhibitory effect of vitamin K2 (menatetrenone) on bone resorption in ovariectomized rats: a histomorphometric and dual energy X-ray absorptiometric study. Jpn J Pharmacol 80:67–74

  7. 7.

    Martyn-St James M, Carroll S (2006) Progressive high-intensity resistance training and bone mineral density changes among premenopausal women: evidence of discordant site-specific skeletal effects. Sports Med 36:683–704

  8. 8.

    Booth SL, Broe KE, Gagnon DR, Tucker KL, Hannan MT, McLean RR, Dawson-Hughes B, Wilson PW, Cupples LA, Kiel DP (2003) Vitamin K intake and bone mineral density in women and men. Am J Clin Nutr 77:512–516

  9. 9.

    Feskanich D, Weber P, Willett WC, Rockett H, Booth SL, Colditz GA (1999) Vitamin K intake and hip fractures in women: a prospective study. Am J Clin Nutr 69:74–79

  10. 10.

    Iwamoto I, Kosha S, Noguchi S, Murakami M, Fujino T, Douchi T, Nagata Y (1999) A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy. Maturitas 31:161–164

  11. 11.

    Nishiguchi S, Shimoi S, Kurooka H, Tamori A, Habu D, Takeda T, Kubo S (2001) Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis. J Hepatol 35:543–545

  12. 12.

    Ushiroyama T, Ikeda A, Ueki M (2002) Effect of continuous combined therapy with vitamin K(2) and vitamin D(3) on bone mineral density and coagulofibrinolysis function in postmenopausal women. Maturitas 41:211–221

  13. 13.

    Sasaki N, Kusano E, Takahashi H, Ando Y, Yano K, Tsuda E, Asano Y (2005) Vitamin K2 inhibits glucocorticoid-induced bone loss partly by preventing the reduction of osteoprotegerin (OPG). J Bone Miner Metab 23:41–47

  14. 14.

    Purwosunu Y, Muharram, Rachman IA, Reksoprodjo S, Sekizawa A (2006) Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia. J Obstet Gynaecol Res 32:230–234

  15. 15.

    Forli L, Bollerslev J, Simonsen S, Isaksen GA, Kvamsdal KE, Godang K, Gadeholt G, Pripp AH, Bjortuft O (2010) Dietary vitamin K2 supplement improves bone status after lung and heart transplantation. Transplantation 89:458–464

  16. 16.

    Somekawa Y, Chigughi M, Harada M, Ishibashi T (1999) Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide. J Clin Endocrinol Metab 84:2700–2704

  17. 17.

    Shiraki M, Shiraki Y, Aoki C, Miura M (2000) Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res 15:515–521

  18. 18.

    Braam LA, Knapen MH, Geusens P, Brouns F, Hamulyak K, Gerichhausen MJ, Vermeer C (2003) Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int 73:21–26

  19. 19.

    Braam LA, Knapen MH, Geusens P, Brouns F, Vermeer C (2003) Factors affecting bone loss in female endurance athletes: a two-year follow-up study. Am J Sports Med 31:889–895

  20. 20.

    Bolton-Smith C, McMurdo ME, Paterson CR, Mole PA, Harvey JM, Fenton ST, Prynne CJ, Mishra GD, Shearer MJ (2007) Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. J Bone Miner Res 22:509–519

  21. 21.

    Knapen MH, Schurgers LJ, Vermeer C (2007) Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int 18:963–972

  22. 22.

    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:e196

  23. 23.

    Shea MK, Dallal GE, Dawson-Hughes B, Ordovas JM, O’Donnell CJ, Gundberg CM, Peterson JW, Booth SL (2008) Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am J Clin Nutr 88:356–363

  24. 24.

    Volpe SL, Leung MM, Giordano H (2008) Vitamin K supplementation does not significantly impact bone mineral density and biochemical markers of bone in pre- and perimenopausal women. Nutr Res 28:577–582

  25. 25.

    Binkley N, Harke J, Krueger D, Engelke J, Vallarta-Ast N, Gemar D, Checovich M, Chappell R, Suttie J (2009) Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women. J Bone Miner Res 24:983–991

  26. 26.

    Emaus N, Gjesdal CG, Almas B, Christensen M, Grimsgaard AS, Berntsen GK, Salomonsen L, Fonnebo V (2009) Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial. Osteoporos Int 21:1731–1740

  27. 27.

    Linde K, Jonas WB, Melchart D, Willich S (2001) The methodological quality of randomized controlled trials of homeopathy, herbal medicines and acupuncture. Int J Epidemiol 30:526–531

  28. 28.

    Shadish WR, Brasil IC, Illingworth DA, White KD, Galindo R, Nagler ED, Rindskopf DM (2009) Using UnGraph to extract data from image files: verification of reliability and validity. Behav Res Methods 41:177–183

  29. 29.

    Martyn-St James M, Carroll S (2006) High-intensity resistance training and postmenopausal bone loss: a meta-analysis. Osteoporos Int 17:1225–1240

  30. 30.

    Higgins JP, Green S (eds) (2006) Cochrane handbook for systematic reviews of interventions 4.2.6. In: The Cochrane Library, Issue 4. Wiley, Chichester (updated September 2006)

  31. 31.

    Suttie JW (1990) Warfarin and vitamin K. Clin Cardiol 13:VI16–VI18

  32. 32.

    Hoang QQ, Sicheri F, Howard AJ, Yang DS (2003) Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature 425:977–980

  33. 33.

    Nakao M, Nishiuchi Y, Nakata M, Kimura T, Sakakibara S (1994) Synthesis of human osteocalcins: gamma-carboxyglutamic acid at position 17 is essential for a calcium-dependent conformational transition. Pept Res 7:171–174

  34. 34.

    Wada S, Kamiya S (2006) Bone and bone related biochemical examinations. Bone and collagen related metabolites. Osteocalcin (OC). Clin Calcium 16:1017–1021

  35. 35.

    Macdonald HM, McGuigan FE, Lanham-New SA, Fraser WD, Ralston SH, Reid DM (2008) Vitamin K1 intake is associated with higher bone mineral density and reduced bone resorption in early postmenopausal Scottish women: no evidence of gene-nutrient interaction with apolipoprotein E polymorphisms. Am J Clin Nutr 87:1513–1520

  36. 36.

    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 26:79–85

  37. 37.

    Inoue T, Fujita T, Kishimoto H, Makino T, Nakamura T, Sato T, Yamazaki K (2009) Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab 27:66–75

  38. 38.

    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 166:1256–1261

  39. 39.

    Nam HS, Shin MH, Zmuda JM, Leung PC, Barrett-Connor E, Orwoll ES, Cauley JA (2010) Race/ethnic differences in bone mineral densities in older men. Osteoporos Int 21:2115–2123

  40. 40.

    Dvornyk V, Liu XH, Shen H, Lei SF, Zhao LJ, Huang QR, Qin YJ, Jiang DK, Long JR, Zhang YY, Gong G, Recker RR, Deng HW (2003) Differentiation of Caucasians and Chinese at bone mass candidate genes: implication for ethnic difference of bone mass. Ann Hum Genet 67:216–227

  41. 41.

    Suttie JW (1995) The importance of menaquinones in human nutrition. Annu Rev Nutr 15:399–417

  42. 42.

    Hara K, Akiyama Y, Nakamura T, Murota S, Morita I (1995) The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain. Bone 16:179–184

  43. 43.

    Kameda T, Miyazawa K, Mori Y, Yuasa T, Shiokawa M, Nakamaru Y, Mano H, Hakeda Y, Kameda A, Kumegawa M (1996) Vitamin K2 inhibits osteoclastic bone resorption by inducing osteoclast apoptosis. Biochem Biophys Res Commun 220:515–519

  44. 44.

    Reid IR (1997) Glucocorticoid osteoporosis—mechanisms and management. Eur J Endocrinol 137:209–217

  45. 45.

    Johansen JS, Riis BJ, Hassager C, Moen M, Jacobson J, Christiansen C (1988) The effect of a gonadotropin-releasing hormone agonist analog (nafarelin) on bone metabolism. J Clin Endocrinol Metab 67:701–706

  46. 46.

    Lakatos PL, Firneisz G, Lakatos P, Horvath C, Szalay F (2001) Follow-up study of bone mineral density in postmenopausal patients with primary biliary cirrhosis. Orv Hetil 142:503–508

  47. 47.

    Aringer M, Kiener HP, Koeller MD, Artemiou O, Zuckermann A, Wieselthaler G, Klepetko W, Seidl G, Kainberger F, Bernecker P, Smolen JS, Pietschmann P (1998) High turnover bone disease following lung transplantation. Bone 23:485–488

  48. 48.

    Anijar JR, Szejnfeld VL, Almeida DR, Fernandes AR, Ferraz MB (1999) Reduced bone mineral density in men after heart transplantation. Braz J Med Biol Res 32:413–420

  49. 49.

    Soen S (2009) Drug therapy of secondary osteoporosis: glucocorticoid-induced osteoporosis. Nippon Rinsho 67:985–990

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Acknowledgments

We thank Yan Wang for her assistance with the design and implementation of search strategy for this protocol, and Meiyun Guan for statistical advice.

Conflict of interest

There are no identified conflicts of interest with any of the authors.

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Correspondence to Chuanlai Hu.

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Fang, Y., Hu, C., Tao, X. et al. Effect of vitamin K on bone mineral density: a meta-analysis of randomized controlled trials. J Bone Miner Metab 30, 60–68 (2012) doi:10.1007/s00774-011-0287-3

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Keywords

  • Vitamin K
  • Bone mineral density
  • Osteoporosis
  • Meta-analysis
  • Subgroup-analysis