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Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial

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Abstract

Summary

Vitamin K2 may preserve bone strength and reduce fracture risk. In this randomised double-blind placebo-controlled trial among healthy postmenopausal Norwegian women, 1 year supplementation of vitamin K2 in the form of Natto capsules had no effect on bone loss rates.

Introduction

Japanese studies indicate that vitamin K2 (menaquinone-7 (MK-7)) intake may preserve bone strength, but this has not been documented in Europeans. The aim of this study was to assess the effect of MK-7 on bone mineral density (BMD) changes in postmenopausal Norwegian women.

Methods

Three hundred thirty-four healthy women between 50 and 60 years, 1–5 years after menopause, were recruited to a randomised double-blind placebo-controlled trial. The participants were randomly assigned into two groups, one receiving 360 µg MK-7 in the form of Natto capsules and the other the same amount of identical-looking placebo capsules containing olive oil. BMD was measured at total hip, femoral neck, lumbar spine and total body at baseline and 12 months together with serum levels of bone-specific alkaline phosphatase, Crosslaps, total osteocalcin (N-mid OC), carboxylated (cOC) and under-carboxylated osteocalcin (ucOC).

Results

After 12 months, there were no statistical differences in bone loss rates between the groups at the total hip or any other measurement site. Serum levels of cOC increased and ucOC decreased in the treatment versus the placebo group (p < 0.001).

Conclusion

MK-7 taken as Natto over 1 year reduced serum levels of ucOC but did not influence bone loss rates in early menopausal women.

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References

  1. Kanis JA, Johnell O, De Laet C, Jonsson B, Oden A, Ogelsby AK (2002) International variations in hip fracture probabilities: implications for risk assessment. J Bone Miner Res 17:1237–1244

    Article  PubMed  Google Scholar 

  2. Kanis JA, Borgstrom F, De Laet C, Johansson H, Johnell O, Jonsson B, Oden A, Zethraeus N, Pfleger B, Khaltaev N (2005) Assessment of fracture risk. Osteoporos Int 16:581–589

    Article  PubMed  Google Scholar 

  3. Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 17:1726–1733

    Article  CAS  PubMed  Google Scholar 

  4. Johnell O, Kanis JA, Oden A, Johansson H, De Laet C, Delmas P, Eisman JA, Fujiwara S, Kroger H, Mellstrom D, Meunier PJ, Melton LJ III, O’Neill T, Pols H, Reeve J, Silman A, Tenenhouse A (2005) Predictive value of BMD for hip and other fractures. J Bone Miner Res 20:1185–1194

    Article  PubMed  Google Scholar 

  5. Chapurlat RD, Gamero P, Sornay-Rendu E, Arlot ME, Claustrat B, Delmas PD (2000) Longitudinal study of bone loss in pre- and perimenopausal women: evidence for bone loss in perimenopausal women. Osteoporos Int 11:493–498

    Article  CAS  PubMed  Google Scholar 

  6. Guthrie JR, Ebeling PR, Hopper JL, Barrett-Connor E, Dennerstein L, Dudley EC, Burger HG, Wark JD (1998) A prospective study of bone loss in menopausal Australian-born women. Osteoporos Int 8:282–290

    Article  CAS  PubMed  Google Scholar 

  7. Sowers M, Crutchfield M, Bandekar R, Randolph JF, Shapiro B, Schork MA, Jannausch M (1998) Bone mineral density and its change in pre-and perimenopausal white women: the Michigan Bone Health Study. J Bone Miner Res 13:1134–1140

    Article  CAS  PubMed  Google Scholar 

  8. Seeman E (2003) The structural and biomechanical basis of the gain and loss of bone strength in women and men. Endocrinol Metab Clin North Am 32:25–38

    Article  CAS  PubMed  Google Scholar 

  9. Booth SL, Broe KE, Gagnon DR, Tucker KL, Hannan MT, McLean RR, wson-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

    CAS  PubMed  Google Scholar 

  10. 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

    CAS  PubMed  Google Scholar 

  11. Katsuyama H, Otsuki T, Tomita M, Fukunaga M, Fukunaga T, Suzuki N, Saijoh K, Fushimi S, Sunami S (2005) Menaquinone-7 regulates the expressions of osteocalcin, OPG, RANKL and RANK in osteoblastic MC3T3E1 cells. Int J Mol Med 15:231–236

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Vergnaud P, Garnero P, Meunier PJ, Breart G, Kamihagi K, Delmas PD (1997) Undercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS Study. J Clin Endocrinol Metab 82:719–724

    Article  CAS  PubMed  Google Scholar 

  14. Gundberg CM, Nieman SD, Abrams S, Rosen H (1998) Vitamin K status and bone health: an analysis of methods for determination of undercarboxylated osteocalcin. J Clin Endocrinol Metab 83:3258–3266

    Article  CAS  PubMed  Google Scholar 

  15. 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 9:1591–1595

    Article  CAS  PubMed  Google Scholar 

  16. Szulc P, Chapuy MC, Meunier PJ, Delmas PD (1993) Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest 91:1769–1774

    Article  CAS  PubMed  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. Booth SL, Dallal G, Shea MK, Gundberg C, Peterson JW, wson-Hughes B (2008) Effect of vitamin K supplementation on bone loss in elderly men and women. J Clin Endocrinol Metab 93:1217–1223

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. Katsuyama H, Ideguchi S, Fukunaga M, Fukunaga T, Saijoh K, Sunami S (2004) Promotion of bone formation by fermented soybean (Natto) intake in premenopausal women. J Nutr Sci Vitaminol (Tokyo) 50:114–120

    CAS  Google Scholar 

  21. Yamaguchi M, Sugimoto E, Hachiya S (2001) Stimulatory effect of menaquinone-7 (vitamin K2) on osteoblastic bone formation in vitro. Mol Cell Biochem 223:131–137

    Article  CAS  PubMed  Google Scholar 

  22. Kaneki M, Hedges SJ, Hosoi T, Fujiwara S, Lyons A, Crean SJ, Ishida N, Nakagawa M, Takechi M, Sano Y, Mizuno Y, Hoshino S, Miyao M, Inoue S, Horiki K, Shiraki M, Ouchi Y, Orimo H (2001) Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk. Nutrition 17:315–321

    Article  CAS  PubMed  Google Scholar 

  23. Katsuyama H, Ideguchi S, Fukunaga M, Saijoh K, Sunami S (2002) Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women. J Nutr Sci Vitaminol (Tokyo) 48:207–215

    CAS  Google Scholar 

  24. Bonjour JP, Gueguen L, Palacios C, Shearer MJ, Weaver CM (2009) Minerals and vitamins in bone health: the potential value of dietary enhancement. Br J Nutr 101:1581–1596

    Article  CAS  PubMed  Google Scholar 

  25. Kanis JA, Gluer CC (2000) An update on the diagnosis and assessment of osteoporosis with densitometry. Committee of Scientific Advisors, International Osteoporosis Foundation. Osteoporos Int 11:192–202

    Article  CAS  PubMed  Google Scholar 

  26. Tsugawa N, Shiraki M, Suhara Y, Kamao M, Tanaka K, Okano T (2006) Vitamin K status of healthy Japanese women: age-related vitamin K requirement for gamma-carboxylation of osteocalcin. Am J Clin Nutr 83:380–386

    CAS  PubMed  Google Scholar 

  27. Omsland TK, Emaus N, Gjesdal CG, Falch JA, Tell GS, Forsen L, Berntsen GK, Meyer HE (2008) In vivo and in vitro comparison of densitometers in the NOREPOS study. J Clin Densitom 11:276–282

    Article  PubMed  Google Scholar 

  28. Emaus N, Berntsen GK, Joakimsen R, Fonnebo V (2006) Longitudinal changes in forearm bone mineral density in women and men aged 45–84 years: the Tromso Study, a population-based study. Am J Epidemiol 163:441–449

    Article  CAS  PubMed  Google Scholar 

  29. Shepherd JA, Lu Y (2007) A generalized least significant change for individuals measured on different DXA systems. J Clin Densitom 10:249–258

    Article  PubMed  Google Scholar 

  30. Hansen MA, Overgaard K, Christiansen C (1995) Spontaneous postmenopausal bone loss in different skeletal areas—followed up for 15 years. J Bone Miner Res 10:205–210

    Article  CAS  PubMed  Google Scholar 

  31. Melton LJ III, Atkinson EJ, O’Connor MK, O’Fallon WM, Riggs BL (2000) Determinants of bone loss from the femoral neck in women of different ages. J Bone Miner Res 15:24–31

    Article  PubMed  Google Scholar 

  32. Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42:606–615

    Article  CAS  PubMed  Google Scholar 

  33. Law MR, Hackshaw AK (1997) A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect. BMJ 315:841–846

    CAS  PubMed  Google Scholar 

  34. Shields M, Shooshtari S (2001) Determinants of self-perceived health. Health Rep 13:35–52

    CAS  PubMed  Google Scholar 

  35. Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B, Dawson A (2002) Ten-year risk of osteoporotic fracture and the effect of risk factors on screening strategies. Bone 30:251–258

    Article  CAS  PubMed  Google Scholar 

  36. Ammann P, Rizzoli R (2003) Bone strength and its determinants. Osteoporos Int 14(Suppl 3):S13–S18

    PubMed  Google Scholar 

  37. Bischoff-Ferrari HA, wson-Hughes B, Baron JA, Burckhardt P, Li R, Spiegelman D, Specker B, Orav JE, Wong JB, Staehelin HB, O’Reilly E, Kiel DP, Willett WC (2007) Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. Am J Clin Nutr 86:1780–1790

    CAS  PubMed  Google Scholar 

  38. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, wson-Hughes B (2005) Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 293:2257–2264

    Article  CAS  PubMed  Google Scholar 

  39. Lanham-New SA (2008) Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment. Proc Nutr Soc 67:163–176

    Article  CAS  PubMed  Google Scholar 

  40. Iwamoto J, Takeda T, Ichimura S (2000) Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J Orthop Sci 5:546–551

    Article  CAS  PubMed  Google Scholar 

  41. Miyake N, Hoshi K, Sano Y, Kikuchi K, Tadano K, Koshihara Y (2001) 1, 25-Dihydroxyvitamin D3 promotes vitamin K2 metabolism in human osteoblasts. Osteoporos Int 12:680–687

    Article  CAS  PubMed  Google Scholar 

  42. 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

    Article  CAS  PubMed  Google Scholar 

  43. 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

    Article  CAS  PubMed  Google Scholar 

  44. Katsuyama H, Saijoh K, Otsuki T, Tomita M, Fukunaga M, Sunami S (2007) Menaquinone-7 regulates gene expression in osteoblastic MC3T3E1 cells. Int J Mol Med 19:279–284

    CAS  PubMed  Google Scholar 

  45. Sato Y, Honda Y, Kuno H, Oizumi K (1998) Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients. Bone 23:291–296

    Article  CAS  PubMed  Google Scholar 

  46. Sato Y, Honda Y, Kaji M, Asoh T, Hosokawa K, Kondo I, Satoh K (2002) Amelioration of osteoporosis by menatetrenone in elderly female Parkinson’s disease patients with vitamin D deficiency. Bone 31:114–118

    Article  CAS  PubMed  Google Scholar 

  47. Sato Y, Kanoko T, Satoh K, Iwamoto J (2005) Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer’s disease. Bone 36:61–68

    Article  CAS  PubMed  Google Scholar 

  48. Shiomi S, Nishiguchi S, Kubo S, Tamori A, Habu D, Takeda T, Ochi H (2002) Vitamin K2 (menatetrenone) for bone loss in patients with cirrhosis of the liver. Am J Gastroenterol 97:978–981

    Article  CAS  PubMed  Google Scholar 

  49. Yonemura K, Kimura M, Miyaji T, Hishida A (2000) Short-term effect of vitamin K administration on prednisolone-induced loss of bone mineral density in patients with chronic glomerulonephritis. Calcif Tissue Int 66:123–128

    Article  CAS  PubMed  Google Scholar 

  50. Ishida Y, Kawai S (2004) Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Am J Med 117:549–555

    Article  CAS  PubMed  Google Scholar 

  51. Orimo H, Shiraki M, Tomita A, Morii H, Fujita T, Ohata M (1998) Effects of menatetrenone on the bone and calcium metabolism in osteporosis: a double blind placebo controlled study. J Bone Miner Metab 16:106–112

    Article  CAS  Google Scholar 

  52. 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

    Article  CAS  PubMed  Google Scholar 

  53. Booth SL, Al RA (2008) Determinants of vitamin K status in humans. Vitam Horm 78:1–22

    Article  CAS  PubMed  Google Scholar 

  54. 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

    Article  CAS  PubMed  Google Scholar 

  55. 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

    Article  CAS  PubMed  Google Scholar 

  56. Ozuru R, Sugimoto T, Yamaguchi T, Chihara K (2002) Time-dependent effects of vitamin K2 (menatetrenone) on bone metabolism in postmenopausal women. Endocr J 49:363–370

    Article  CAS  PubMed  Google Scholar 

  57. Yasui T, Miyatani Y, Tomita J, Yamada M, Uemura H, Miura M, Irahara M (2006) Effect of vitamin K2 treatment on carboxylation of osteocalcin in early postmenopausal women. Gynecol Endocrinol 22:455–459

    Article  CAS  PubMed  Google Scholar 

  58. Inoue T, Fujita T, Kishimoto H, Makino T, Nakamura 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

    Article  CAS  PubMed  Google Scholar 

  59. Tamura T, Morgan SL, Takimoto H (2007) Vitamin K and the prevention of fractures. Arch Intern Med 167:94–95

    Article  PubMed  Google Scholar 

  60. Rejnmark L, Vestergaard P, Charles P, Hermann AP, Brot C, Eiken P, Mosekilde L (2006) No effect of vitamin K1 intake on bone mineral density and fracture risk in perimenopausal women. Osteoporos Int 17:1122–1132

    Article  CAS  PubMed  Google Scholar 

  61. Whelan AM, Jurgens TM, Bowles SK (2006) Natural health products in the prevention and treatment of osteoporosis: systematic review of randomized controlled trials. Ann Pharmacother 40:836–849

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are greatly thankful for the contributions from Margrete Garvik and Eva Mette Leknes at the Bone Laboratory, Marit Hjelmeland and professor Ernst Lien at the Hormone Laboratory at Haukeland University Hospital in Bergen, the chief study nurse Aslaug Jacobsen and her colleagues at the research unit at the University Hospital of North Norway, Tromsø, and to professor John Eisman at Garvan Institute of Medical Research, Sydney, for reading and critically commenting the manuscript.

Financial support

The study was financially supported by grants from the Norwegian Osteoporosis Association and Northern Norway Regional Health Authorities. NATURAL provided the study medication and Eckboe’s legacy provided support for blood analyses.

Conflicts of interest

None.

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Authors and Affiliations

  1. Institute of Community Medicine, University of Tromsø, Tromsø, 9037, Norway

    N. Emaus

  2. Haukeland University Hospital, Bergen, 5021, Norway

    C. G. Gjesdal, B. Almås & M. Christensen

  3. Institute of Medicine, University of Bergen, Bergen, 5021, Norway

    C. G. Gjesdal, B. Almås & M. Christensen

  4. University Hospital of North Norway, Tromsø, 9037, Norway

    A. S. Grimsgaard

  5. The National Research Centre in Complementary and Alternative Medicine (NAFKAM), University of Tromsø, Tromsø, 9037, Norway

    G. K. R. Berntsen, L. Salomonsen & V. Fønnebø

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  1. N. Emaus
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Emaus, N., Gjesdal, C.G., Almås, B. et al. Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial. Osteoporos Int 21, 1731–1740 (2010). https://doi.org/10.1007/s00198-009-1126-4

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