Osteoporosis International

, Volume 26, Issue 3, pp 1175–1186 | Cite as

Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials

  • Z.-B. Huang
  • S.-L. Wan
  • Y.-J. Lu
  • L. Ning
  • C. Liu
  • S.-W. Fan
Original Article

Abstract

Summary

To identify the role of vitamin K2 for the prevention and treatment of osteoporosis in postmenopausal women, we conducted this meta-analysis of 19 randomized controlled trials. Our results showed that vitamin K2 might play a role in maintaining the bone mineral density and in reducing the incidence of fractures for postmenopausal women with osteoporosis.

Introduction

Vitamin K2 has been revealed to be effective in the prevention and treatment of osteoporosis in Japan, which was not confirmed in western countries. Thus, we conduct this meta-analysis to verify the hypothesis that vitamin K2 plays a role in the prevention and treatment of osteoporosis for postmenopausal women.

Methods

We searched the Cochrane Library, Pub Med, EMBASE, and ISI web of knowledge (until December 1, 2013) and reference lists of eligible articles. A meta-analysis of all-including randomized controlled trials was then performed.

Results

Nineteen randomized controlled trials encompassing 6759 participants have met the inclusion criteria. Subgroup analysis of postmenopausal women with osteoporosis revealed a significant improvement of vertebral BMD for both medium-term and long-term results favoring vitamin K2 group (p < 0.00001 and p = 0.0005). However, no significant difference in BMD changes was revealed for the non-osteoporosis subgroup analysis. As for the incidence of fractures, pooled analysis of the seven related studies demonstrated no significant difference in the incidence of fractures favoring vitamin K2 (RR = 0.63, p = 0.08). However, sensitivity analysis by rejecting the study inducing heterogeneity demonstrated a significant difference in the incidence of fractures favoring vitamin K2 (RR = 0.50, p = 0.0005). Significant differences were found in undercarboxylated osteocalcin reduction and osteocalcin increment. The result of adverse reaction analysis showed that vitamin K2 group seemed to have a higher adverse reaction rate (RR = 1.22, p = 0.06).

Conclusions

This meta-analysis seemed to support the hypothesis that vitamin K2 plays kind of a role in the maintenance and improvement of vertebral BMD and the prevention of fractures in postmenopausal women with osteoporosis. The reduction of undercarboxylated osteocalcin and increment of osteocalcin may have some relation to the process of bone mineralization. However, the effect of vitamin K2 for postmenopausal women without osteoporosis had not been identified. Further high-quality RCTs with large sample size are needed to confirm the role of vitamin K2 in osteoporosis for postmenopausal women.

Keywords

Bone mineral density Fracture Meta-analysis Osteoporosis Vitamin K2 

References

  1. 1.
    National Osteoporosis Foundation. Fast facts. http://www.nof.org/connect/get-the-facts. Accessed 24 Jan (2014)
  2. 2.
    Meunier PJ, Roux C, Ortolani S et al (2009) Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis. Osteoporos Int 20:1663–1673CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Meunier PJ, Roux C, Seeman E et al (2004) The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 350:459–468CrossRefPubMedGoogle Scholar
  4. 4.
    Delmas PD (2002) Treatment of postmenopausal osteoporosis. Lancet 359:2018–2026CrossRefPubMedGoogle Scholar
  5. 5.
    Neer RM, Arnaud CD, Zanchetta JR et al (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441CrossRefPubMedGoogle Scholar
  6. 6.
    McClung MR, Geusens P, Miller PD, Hip Intervention Program Study Group et al (2001) Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 344:333–340CrossRefPubMedGoogle Scholar
  7. 7.
    Black DM, Cummings SR, Karpf DB, Fracture Intervention Trial Research Group et al (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348:1535–1541CrossRefPubMedGoogle Scholar
  8. 8.
    Suttie JW (2009) Vitamin K in health and disease. Chapter 5:93–132Google Scholar
  9. 9.
    Kaneki M, Hodges SJ, Hosoi T et al (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 17:315–321CrossRefPubMedGoogle Scholar
  10. 10.
    Yamaguchi M, Kakuda H, Gao YH, Tsukamoto Y (2000) Prolonged intake of fermented soybean (natto) diets containing vitamin K2 (menaquinone-7) prevents bone loss in ovariectomized rats. J Bone Miner Metab 18:71–76CrossRefPubMedGoogle Scholar
  11. 11.
    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 15:515–521CrossRefPubMedGoogle Scholar
  12. 12.
    Mawatari T, Miura H, Higaki H, Moro-Oka T, Kurata K, Murakami T, Iwamoto Y (2000) Effect of vitamin K2 on three-dimensional trabecular microarchitecture in ovariectomized rats. J Bone Miner Res 15:1810–1817CrossRefPubMedGoogle Scholar
  13. 13.
    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 31:161–164CrossRefPubMedGoogle Scholar
  14. 14.
    Tasci AG, Bilgili H, Altunay H, Gecit MR, Keskin D (2011) Prospective evaluation of vitamin K2, raloxifene and their co-administration in osteoporotic rats. Eur J Pharm Sci 43:270–277CrossRefPubMedGoogle Scholar
  15. 15.
    Hauschka PV, Lian JB, Cole DE, Gundberg CM (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69:990–1047PubMedGoogle Scholar
  16. 16.
    Urayama S, Kawakami A, Nakashima T et al (2000) Effect of vitamin K2 on osteoblast apoptosis: vitamin K2 inhibits apoptotic cell death of human osteoblasts induced by Fas, proteasome inhibitor, etoposide, and staurosporine. J Lab Clin Med 136:181–193CrossRefPubMedGoogle Scholar
  17. 17.
    Ichikawa T, Horie-Inoue K, Ikeda K, Blumberg B, Inoue S (2007) Vitamin K2 induces phosphorylation of protein kinase A and expression of novel target genes in osteoblastic cells. J Mol Endocrinol 39:239–247CrossRefPubMedGoogle Scholar
  18. 18.
    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 5:546–551CrossRefPubMedGoogle Scholar
  19. 19.
    Iwamoto J, Takeda T, Ichimura S (2001) Effect of menatetrenone on bone mineral density and incidence of vertebral fractures in postmenopausal women with osteoporosis: a comparison with the effect of etidronate. J Orthop Sci 6:487–492CrossRefPubMedGoogle Scholar
  20. 20.
    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 117:549–555CrossRefPubMedGoogle Scholar
  21. 21.
    Orimo H, Shiraki M, Tomita A, Morii H, Fujita T, Ohata M (1998) Effects of menatetrenone on the bone and calcium metabolism in osteoporosis: a double-blind placebo-controlled study. J Bone Miner Metab 16:106–112CrossRefGoogle Scholar
  22. 22.
    Emaus N, Gjesdal CG, Almas B, Christensen M, Grimsgaard AS, Berntsen GK, Salomonsen L, Fonnebo V (2010) Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial. Osteoporos Int 21:1731–1740CrossRefPubMedGoogle Scholar
  23. 23.
    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 24:983–991CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    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 166:1256–1261CrossRefPubMedGoogle Scholar
  25. 25.
    Iwamoto J, Matsumoto H, Takeda T (2009) Efficacy of menatetrenone (vitamin K2) against non-vertebral and hip fractures in patients with neurological diseases: meta-analysis of three randomized, controlled trials. Clin Drug Investig 29:471–479CrossRefPubMedGoogle Scholar
  26. 26.
    Fang Y, Hu C, Tao X, Wan Y, Tao F (2012) Effect of vitamin K on bone mineral density: a meta-analysis of randomized controlled trials. J Bone Miner Metab 30:60–68CrossRefPubMedGoogle Scholar
  27. 27.
    Furlan AD, Pennick V, Bombardier C, van Tulder M (2009) 2009 updated method guidelines for systematic reviews in the Cochrane Back Review Group. Spine (Phila Pa 1976) 34:1929–1941CrossRefGoogle Scholar
  28. 28.
    Higgins JPT DJe Chapter 7: Selecting studies and collecting data. In: Higgins JPT, Green S (editors), Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org
  29. 29.
    Higgins JPT DJ, Altman DG (editors). Chapter 16: special topics in statistics. In: Higgins JPT, Green S (editors). Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org
  30. 30.
    Koitaya N, Sekiguchi M, Tousen Y et al (2013) Low-dose vitamin K (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. J Bone Miner Metab 24:24Google Scholar
  31. 31.
    Kasukawa Y, Miyakoshi N, Ebina T, Aizawa T, Hongo M, Nozaka K, Ishikawa Y, Saito H, Chida S, Shimada Y (2013) Effects of risedronate alone or combined with vitamin K on serum undercarboxylated osteocalcin and osteocalcin levels in postmenopausal osteoporosis. J Bone Miner Metab 12:12Google Scholar
  32. 32.
    Kanellakis S, Moschonis G, Tenta R, Schaafsma A, van den Heuvel EG, Papaioannou N, Lyritis G, Manios Y (2012) Changes in parameters of bone metabolism in postmenopausal women following a 12-month intervention period using dairy products enriched with calcium, vitamin D, and phylloquinone (vitamin K(1)) or menaquinone-7 (vitamin K (2)): the Postmenopausal Health Study II. Calcif Tissue Int 90:251–262CrossRefPubMedGoogle Scholar
  33. 33.
    Moschonis G, Kanellakis S, Papaioannou N, Schaafsma A, Manios Y (2011) Possible site-specific effect of an intervention combining nutrition and lifestyle counselling with consumption of fortified dairy products on bone mass: the Postmenopausal Health Study II. J Bone Miner Metab 29:501–506CrossRefPubMedGoogle Scholar
  34. 34.
    Je SH, Joo NS, Choi BH, Kim KM, Kim BT, Park SB, Cho DY, Kyu-nam-Kim LDJ (2011) Vitamin K supplement along with vitamin d and calcium reduced serum concentration of undercarboxylated osteocalcin while increasing bone mineral density in Korean postmenopausal women over sixty-years-old. J Korean Med Sci 26:1093–1098CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Shiraki M, Itabashi A (2009) Short-term menatetrenone therapy increases gamma-carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis: a randomized prospective study. J Bone Miner Metab 27:333–340CrossRefPubMedGoogle Scholar
  36. 36.
    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 27:66–75CrossRefPubMedGoogle Scholar
  37. 37.
    Hirao M, Hashimoto J, Ando W, Ono T, Yoshikawa H (2008) Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women. J Bone Miner Metab 26:260–264CrossRefPubMedGoogle Scholar
  38. 38.
    Knapen MH, Schurgers LJ, Vermeer C (2007) Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int 18:963–972CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Purwosunu Y, Muharram RIA, Reksoprodjo S, Sekizawa A (2006) Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia. J Obstet Gynaecol Res 32:230–234CrossRefPubMedGoogle Scholar
  40. 40.
    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 41:211–221CrossRefPubMedGoogle Scholar
  41. 41.
    Knapen MH, Drummen NE, Smit E, Vermeer C, Theuwissen E (2013) Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int 24:2499–2507CrossRefPubMedGoogle Scholar
  42. 42.
    Stevenson M, Lloyd-Jones M, Papaioannou D (2009) Vitamin K to prevent fractures in older women: systematic review and economic evaluation. Health Technol Assess 13:1–134CrossRefPubMedGoogle Scholar
  43. 43.
    Iwamoto J, Takeda T, Sato Y (2006) Role of vitamin K2 in the treatment of postmenopausal osteoporosis. Curr Drug Saf 1:87–97CrossRefPubMedGoogle Scholar
  44. 44.
    Yamauchi M, Yamaguchi T, Nawata K, Takaoka S, Sugimoto T (2010) Relationships between undercarboxylated osteocalcin and vitamin K intakes, bone turnover, and bone mineral density in healthy women. Clin Nutr 29:761–765CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2014

Authors and Affiliations

  • Z.-B. Huang
    • 1
    • 2
  • S.-L. Wan
    • 2
  • Y.-J. Lu
    • 3
  • L. Ning
    • 2
  • C. Liu
    • 2
  • S.-W. Fan
    • 2
  1. 1.Department of OrthopaedicsHangzhou Xiasha HospitalHangzhouChina
  2. 2.Department of Orthopaedics, Sir Run Run Shaw Hospital, School of MedicineZhejiang UniversityHangzhouChina
  3. 3.Department of OrthopaedicsShangyu People’ s HospitalShaoxingChina

Personalised recommendations