Effect of vitamin K on bone mineral density and fractures in adults: an updated systematic review and meta-analysis of randomised controlled trials

A Correction to this article is available

This article has been updated

Abstract

Summary

Vitamin K may affect bone mineral density and fracture incidence. Since publication of a previous systematic review the integrity of some of the previous evidence has been questioned and further trials have been published. Therefore an update to the systematic review was required.

Introduction

This systematic review was designed to assess the effectiveness of oral vitamin K supplementation for increasing bone mineral density and reducing fractures in adults.

Methods

MEDLINE, EMBASE, CENTRAL, CINAHL, clinicaltrials.gov, and WHO-ICTRP were searched for eligible trials. Randomised controlled trials assessing oral vitamin K supplementation that assessed bone mineral density or fractures in adult populations were included. A total of 36 studies were identified. Two independent reviewers extracted data using a piloted extraction form.

Results

For post-menopausal or osteoporotic patients, meta-analysis showed that the odds of any clinical fracture were lower for vitamin K compared to controls (OR, 0.72, 95%CI 0.55 to 0.95). Restricting the analysis to low risk of bias trials reduced the OR to 0.76 (95%CI, 0.58 to 1.01). There was no difference in vertebral fractures between the groups (OR 0.96, 95%CI 0.83 to 1.11). In the bone mineral density meta-analysis, percentage change from baseline at the lumbar spine was higher at 1 year (MD 0.93, 95%, CI − 0.02 to 1.89) and 2 years (MD 1.63%, 95%CI 0.10 to 3.16) for vitamin K compared to controls; however, removing trials at high risk of bias tended to result in smaller differences that were not statistically significant. At 6 months, it was higher in the hip (MD 0.42%, 95%CI 0.01 to 0.83) and femur (MD 0.29%, 95%CI 0.17 to 0.42). There was no significant difference at other anatomical sites.

Conclusions

For post-menopausal or osteoporotic patients, there is no evidence that vitamin K affects bone mineral density or vertebral fractures; it may reduce clinical fractures; however, the evidence is insufficient to confirm this. There are too few trials to draw conclusions for other patient groups.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Change history

  • 23 September 2020

    Following the work of Avenell et al. that has raised concerns about the integrity of the Yamaguchi Osteoporosis Prevention Study (YOPS) conducted by Ishida and Kawai we issue here an adjustment to all meta-analysis estimates that contained this work within our systematic review.

References

  1. 1.

    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(12):1256–1261. https://doi.org/10.1001/archinte.166.12.1256

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Torgerson DJ (2018) Caution to readers about systematic review on vitamin K and prevention of fractures that included problematic trials. JAMA Intern Med 178(6):863–864. https://doi.org/10.1001/jamainternmed.2018.1127

    Article  PubMed  Google Scholar 

  3. 3.

    Bolland MJ, Avenell A, Gamble GD, Grey A (2016) Systematic review and statistical analysis of the integrity of 33 randomized controlled trials. Neurology 87(23):2391–2402. https://doi.org/10.1212/WNL.0000000000003387

    Article  PubMed  Google Scholar 

  4. 4.

    Sato Y, Honda Y, Iwamoto J (2018) RETRACTED: etidronate for fracture prevention in amyotrophic lateral sclerosis: a randomized controlled trial. Bone 106:214. https://doi.org/10.1016/j.bone.2017.10.008

    Article  PubMed  Google Scholar 

  5. 5.

    Booth SL (2009) Roles for vitamin K beyond coagulation. Annu Rev Nutr 29:89–110. https://doi.org/10.1146/annurev-nutr-080508-141217

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Bügel S (2008) Vitamin K and bone health in adult humans. 78:393–416. https://doi.org/10.1016/s0083-6729(07)00016-7

  7. 7.

    Gundberg CM, Lian JB, Booth SL (2012) Vitamin K-dependent carboxylation of osteocalcin: friend or foe? Adv Nutr 3(2):149–157. https://doi.org/10.3945/an.112.001834

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Liu G, Peacock M (1998) Age-related changes in serum undercarboxylated osteocalcin and its relationships with bone density, bone quality, and hip fracture. Calcif Tissue Int 62(4):286–289. https://doi.org/10.1007/s002239900432

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    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(4):1769–1774. https://doi.org/10.1172/JCI116387

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    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(10):1591–1595. https://doi.org/10.1002/jbmr.5650091012

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    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(3):719–724. https://doi.org/10.1210/jcem.82.3.3805

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Booth SL, Broe KE, Peterson JW, Cheng DM, Dawson-Hughes B, Gundberg CM, Cupples LA, Wilson PW, Kiel DP (2004) Associations between vitamin K biochemical measures and bone mineral density in men and women. J Clin Endocrinol Metab 89(10):4904–4909. https://doi.org/10.1210/jc.2003-031673

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. Bmj 312(7041):1254–1259. https://doi.org/10.1136/bmj.312.7041.1254

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Hao G, Zhang B, Gu M, Chen C, Zhang Q, Zhang G, Cao X (2017) Vitamin K intake and the risk of fractures: a meta-analysis. Medicine (Baltimore) 96(17):e6725. https://doi.org/10.1097/MD.0000000000006725

    CAS  Article  Google Scholar 

  15. 15.

    Garner P, Hopewell S, Chandler J, MacLehose H, Schunemann HJ, Akl EA, Beyene J, Chang S, Churchill R, Dearness K, Guyatt G, Lefebvre C, Liles B, Marshall R, Martinez Garcia L, Mavergames C, Nasser M, Qaseem A, Sampson M, Soares-Weiser K, Takwoingi Y, Thabane L, Trivella M, Tugwell P, Welsh E, Wilson EC, Schunemann HJ, Panel for updating guidance for systematic r (2016) When and how to update systematic reviews: consensus and checklist. BMJ 354:i3507. https://doi.org/10.1136/bmj.i3507

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    RETRACTION: risedronate therapy for prevention of hip fracture after stroke in elderly women; risedronate therapy for prevention of hip fracture after stroke in elderly women. Reply from the Authors (2016). Neurology 87 (2):239. https://doi.org/10.1212/WNL.0000000000002788

  17. 17.

    Kupferschmidt K (2018) Researcher at the center of an epic fraud remains an enigma to those who exposed him. Science. https://doi.org/10.1126/science.aav1079

  18. 18.

    Poisot T (2011) The digitize package: extracting numerical data from scatterplots. R J 3(1):25–26

    Article  Google Scholar 

  19. 19.

    Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, Cochrane Bias Methods G, Cochrane Statistical Methods G (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928. https://doi.org/10.1136/bmj.d5928

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Hicks A, Fairhurst C, Torgerson DJ (2018) A simple technique investigating baseline heterogeneity helped to eliminate potential bias in meta-analyses. J Clin Epidemiol 95:55–62. https://doi.org/10.1016/j.jclinepi.2017.10.001

    Article  PubMed  Google Scholar 

  21. 21.

    Higgins JPT, Green S (2011) Cochrane handbook for systematic reviews of interventions, vol 5.1.0. https://doi.org/10.1002/9780470712184

  22. 22.

    Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, Carpenter J, Rucker G, Harbord RM, Schmid CH, Tetzlaff J, Deeks JJ, Peters J, Macaskill P, Schwarzer G, Duval S, Altman DG, Moher D, Higgins JP (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343:d4002. https://doi.org/10.1136/bmj.d4002

    Article  PubMed  Google Scholar 

  23. 23.

    Viechtbauer W (2010) Conducting meta-analyses in R with the metafor package. J Stat Softw 36(3). https://doi.org/10.18637/jss.v036.i03

  24. 24.

    R Development Core Team (2017) R: a language and environment for statistical computing. 3.4.0 edn. R Foundation for Statistical Computing, Vienna

    Google Scholar 

  25. 25.

    Booth SL, Dallal G, Shea MK, Gundberg C, Peterson JW, Dawson-Hughes B (2008) Effect of vitamin K supplementation on bone loss in elderly men and women. J Clin Endocrinol Metab 93(4):1217–1223. https://doi.org/10.1210/jc.2007-2490

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    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(4):509–519. https://doi.org/10.1359/jbmr.070116

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    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(6):983–991. https://doi.org/10.1359/jbmr.081254

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    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(6):889–895. https://doi.org/10.1177/03635465030310062601

    Article  PubMed  Google Scholar 

  29. 29.

    Braam LAJLM, Knapen MHJ, Geusens P, Brouns F, Hamulyk K, Gerichhausen MJW, Vermeer C (2003) Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int 73(1):21–26. https://doi.org/10.1007/s00223-002-2084-4

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    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(10):e196. https://doi.org/10.1371/journal.pmed.0050196

    CAS  Article  Google Scholar 

  31. 31.

    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(10):1731–1740. https://doi.org/10.1007/s00198-009-1126-4

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    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(4):458–464. https://doi.org/10.1097/TP.0b013e3181c46b69

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Fulton RL, McMurdo ME, Hill A, Abboud RJ, Arnold GP, Struthers AD, Khan F, Vermeer C, Knapen MH, Drummen NE, Witham MD (2016) Effect of vitamin K on vascular health and physical function in older people with vascular disease—a randomised controlled trial. J Nutr Health Aging 20(3):325–333. https://doi.org/10.1007/s12603-015-0619-4

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Gleeson D, Hodges S, Rigney E, Blumsohn A, Hannon R, Peel N, Eastell R (2003) 740 placebo-controlled trial of vitamin K supplementation on bone mineral density in primary biliary cirrhosis (PBC). Hepatology 38:516–516. https://doi.org/10.1016/s0270-9139(03)80782-6

    Article  Google Scholar 

  35. 35.

    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(3):260–264. https://doi.org/10.1007/s00774-007-0823-3

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Hozuki T, Imai T, Tsuda E, Matsumura A, Yamamoto D, Toyoshima T, Suzuki S, Yamauchi R, Hayashi T, Hisahara S, Shimohama S (2010) Response of serum carboxylated and undercarboxylated osteocalcin to risedronate monotherapy and combined therapy with vitamin K2 in corticosteroid-treated patients: a pilot study. Intern Med 49(5):371–376. https://doi.org/10.2169/internalmedicine.49.2551

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Inoue K, Hamano T, Nango N, Matsui I, Tomida K, Mikami S, Fujii N, Nakano C, Obi Y, Shimomura A, Kusunoki Y, Rakugi H, Isaka Y, Tsubakihara Y (2014) Multidetector-row computed tomography is useful to evaluate the therapeutic effects of bisphosphonates in glucocorticoid-induced osteoporosis. J Bone Miner Metab 32(3):271–280. https://doi.org/10.1007/s00774-013-0485-2

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    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(1):66–75. https://doi.org/10.1007/s00774-008-0008-8

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    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(8):549–555. https://doi.org/10.1016/j.amjmed.2004.05.019

    CAS  Article  Google Scholar 

  40. 40.

    Iwamoto I, Kosha S, Noguchi S-i, 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(2):161–164. https://doi.org/10.1016/s0378-5122(98)00114-5

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Je SH, Joo NS, Choi BH, Kim KM, Kim BT, Park SB, Cho DY, Kim KN, Lee DJ (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(8):1093–1098. https://doi.org/10.3346/jkms.2011.26.8.1093

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Jiang Y, Zhang ZL, Zhang ZL, Zhu HM, Wu YY, Cheng Q, Wu FL, Xing XP, Liu JL, Yu W, Meng XW (2014) Menatetrenone versus alfacalcidol in the treatment of Chinese postmenopausal women with osteoporosis: a multicenter, randomized, double-blinded, double-dummy, positive drug-controlled clinical trial. Clin Interv Aging 9:121–127. https://doi.org/10.2147/CIA.S54107

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Jokar M, Mirfeizi Z, Esmaili HMK (2016) Effect of vitamin K and alendronate combination treatment on bone mineral density of postmenopausal osteoporosis patients: a pilot study. Patient Saf Qual Improv 4(1):320–333. https://doi.org/10.22038/psj.2016.6288

    Article  Google Scholar 

  44. 44.

    Retraction blues (2013) Nat Med 19(12):1547–1548. https://doi.org/10.1038/nm.3426

    CAS  Article  Google Scholar 

  45. 45.

    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(4):251–262. https://doi.org/10.1007/s00223-012-9571-z

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Kasukawa Y, Miyakoshi N, Ebina T, Aizawa T, Hongo M, Nozaka K, Ishikawa Y, Saito H, Chida S, Shimada Y (2014) Effects of risedronate alone or combined with vitamin K2 on serum undercarboxylated osteocalcin and osteocalcin levels in postmenopausal osteoporosis. J Bone Miner Metab 32(3):290–297. https://doi.org/10.1007/s00774-013-0490-5

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    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(9):2499–2507. https://doi.org/10.1007/s00198-013-2325-6

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Knapen MH, Schurgers LJ, Vermeer C (2007) Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int 18(7):963–972. https://doi.org/10.1007/s00198-007-0337-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Koitaya N, Sekiguchi M, Tousen Y, Nishide Y, Morita A, Yamauchi J, Gando Y, Miyachi M, Aoki M, Komatsu M, Watanabe F, Morishita K, Ishimi Y (2014) Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. J Bone Miner Metab 32(2):142–150. https://doi.org/10.1007/s00774-013-0472-7

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    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(4):501–506. https://doi.org/10.1007/s00774-010-0256-2

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Nishiguchi S, Shimoi S, Kurooka H, Tamori A, Habu D, Takeda T, Ochi H (2001) Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis. J Hepatol 35(4):543–545. https://doi.org/10.1016/s0168-8278(01)00133-7

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    O'Connor EM, Grealy G, McCarthy J, Desmond A, Craig O, Shanahan F, Cashman KD (2014) Effect of phylloquinone (vitamin K1) supplementation for 12 months on the indices of vitamin K status and bone health in adult patients with Crohn’s disease. Br J Nutr 112(7):1163–1174. https://doi.org/10.1017/S0007114514001913

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Ronn SH, Harslof T, Pedersen SB, Langdahl BL (2016) Vitamin K2 (menaquinone-7) prevents age-related deterioration of trabecular bone microarchitecture at the tibia in postmenopausal women. Eur J Endocrinol 175(6):541–549. https://doi.org/10.1530/EJE-16-0498

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Purwosunu Y, Muharram RIA, Reksoprodjo S, Sekizawa A (2006) Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia. J Obstet Gynaecol Res 32(2):230–234. https://doi.org/10.1111/j.1447-0756.2006.00386.x

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    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(1):41–47. https://doi.org/10.1007/s00774-004-0539-6

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    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(4):978–981. https://doi.org/10.1111/j.1572-0241.2002.05618.x

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    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(3):333–340. https://doi.org/10.1007/s00774-008-0034-6

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    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(3):515–521. https://doi.org/10.1359/jbmr.2000.15.3.515

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    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(8):2700–2704. https://doi.org/10.1210/jcem.84.8.5920

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Tanaka S, Miyazaki T, Uemura Y, Miyakawa N, Gorai I, Nakamura T, Fukunaga M, Ohashi Y, Ohta H, Mori S, Hagino H, Hosoi T, Sugimoto T, Itoi E, Orimo H, Shiraki M (2017) Comparison of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis: Japanese Osteoporosis Intervention Trial-03. J Bone Miner Metab 35(4):385–395. https://doi.org/10.1007/s00774-016-0768-5

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Ushiroyama T, Ikeda A, Ueki M (2002) Effect of continuous combined therapy with vitamin K2 and vitamin D3 on bone mineral density and coagulofibrinolysis function in postmenopausal women. Maturitas 41(3):211–221. https://doi.org/10.1016/s0378-5122(01)00275-4

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    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(9):577–582. https://doi.org/10.1016/j.nutres.2008.06.006

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Yuko M, Hitoshi S, Masao K, Hiromitsu F, Satoshi M, Takashi K, Yasuhiko K, Tatsuya A, Teruo H, Katsuhiko A, Yasuhiko T (2014) Poster session-PS3-036 risedronate combined with menatetrenone may prevent glucocorticoid-induced osteoporosis in patients with chronic glomerulonephritis. Nephrology 19:77–202. https://doi.org/10.1111/nep.12237

    Article  Google Scholar 

  64. 65.

    Holden RM, Booth SL, Day AG, Clase CM, Zimmerman D, Moist L, Shea MK, McCabe KM, Jamal SA, Tobe S, Weinstein J, Madhumathi R, Adams MA, Heyland DK (2015) Inhibiting the progression of arterial calcification with vitamin K in HemoDialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease. Can J Kidney Health Dis 2:17. https://doi.org/10.1186/s40697-015-0053-x

    Article  PubMed  PubMed Central  Google Scholar 

  65. 66.

    Hampson G (2015) Vitamin K as additive treatment in osteoporosis. https://ClinicalTrials.gov/show/NCT01232647

  66. 67.

    Genant HK, Li J, Wu CY, JA S (2000) Vertebral fractures in osteoporosis: a new method for clinical assessment. J Clin Densitom 3:281–290

    CAS  Article  Google Scholar 

  67. 68.

    Fukunaga M, Nakamura T, Shiraki M, Kuroda T, Ohta H, Hosoi T, Orimo H (2004) Absolute height reduction and percent height ratio of the vertebral body in incident fracture in Japanese women. J Bone Miner Metab 22(2):104–110. https://doi.org/10.1007/s00774-003-0457-z

    Article  PubMed  Google Scholar 

  68. 69.

    Tai V, Leung W, Grey A, Reid IR, Bolland MJ (2015) Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ 351:h4183. https://doi.org/10.1136/bmj.h4183

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 70.

    Veronese N, Bano G, Bertozzo G, Granziera S, Solmi M, Manzato E, Sergi G, Cohen AT, Correll CU (2015) Vitamin K antagonists’ use and fracture risk: results from a systematic review and meta-analysis. J Thromb Haemost 13(9):1665–1675. https://doi.org/10.1111/jth.13052

    CAS  Article  PubMed  Google Scholar 

  70. 71.

    Bach AU, Anderson SA, Foley AL, Williams EC, Suttie JW (1996) Assessment of vitamin K status in human subjects administered “minidose” warfarin. Am J Clin Nutr 64(6):894–902. https://doi.org/10.1093/ajcn/64.6.894

    CAS  Article  PubMed  Google Scholar 

  71. 72.

    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(3):1175–1186. https://doi.org/10.1007/s00198-014-2989-6

    CAS  Article  PubMed  Google Scholar 

  72. 73.

    Su S, He N, Men P, Song C, Zhai S (2019) The efficacy and safety of menatetrenone in the management of osteoporosis: a systematic review and meta-analysis of randomized controlled trials. Osteoporos Int. https://doi.org/10.1007/s00198-019-04853-7

  73. 74.

    Newman P, Shearer MJ (2008) Metabolism and cell biology of vitamin K. Thromb Haemost 100(10):530–547. https://doi.org/10.1160/th08-03-0147

    Article  PubMed  Google Scholar 

  74. 75.

    Ballane G, Cauley JA, Luckey MM, El-Hajj Fuleihan G (2017) Worldwide prevalence and incidence of osteoporotic vertebral fractures. Osteoporos Int 28(5):1531–1542. https://doi.org/10.1007/s00198-017-3909-3

    CAS  Article  PubMed  Google Scholar 

  75. 76.

    Shea MK, Booth SL (2016) Concepts and controversies in evaluating vitamin K status in population-based studies. Nutrients 8(1). https://doi.org/10.3390/nu8010008

Download references

Funding

There was no funding for this systematic review.

Author information

Affiliations

Authors

Corresponding author

Correspondence to A. Mott.

Ethics declarations

Conflicts of interest

None.

Additional information

Data

Data and R code are available at https://doi.org/10.6084/m9.figshare.7315040 and https://doi.org/10.6084/m9.figshare.7315064.v1.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 382 kb)

ESM 2

(DOCX 18 kb)

ESM 3

(DOCX 14 kb)

ESM 4

(DOCX 15 kb)

ESM 5

(DOCX 17 kb)

ESM 6

(PDF 154 kb)

ESM 7

(PDF 33 kb)

ESM 8

(PDF 33 kb)

ESM 9

(PDF 96 kb)

ESM 10

(PDF 104 kb)

ESM 11

(PDF 109 kb)

ESM 12

(PDF 87 kb)

ESM 13

(DOCX 13 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mott, A., Bradley, T., Wright, K. et al. Effect of vitamin K on bone mineral density and fractures in adults: an updated systematic review and meta-analysis of randomised controlled trials. Osteoporos Int 30, 1543–1559 (2019). https://doi.org/10.1007/s00198-019-04949-0

Download citation

Keywords

  • Bone health
  • Bone mineral density
  • Fracture
  • Osteoporosis
  • Systematic review
  • Vitamin K