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Effect of Low-Dose Vitamin K2 Supplementation on Bone Mineral Density in Middle-Aged and Elderly Chinese: A Randomized Controlled Study

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Abstract

Previous studies indicated a positive effect of vitamin K2 (VK2) supplementation on bone turnover biomarkers and bone mineral density (BMD), but the doses varied, and few studies have focused on the difference between VK2 supplementation alone and in combination with calcium and vitamin D3. The aim of this study was to explore a low and effective dose of VK2 for improving BMD, and to examine whether the co-supplementation of VK2, calcium and vitamin D3 would bring greater effects. In this trial, a total of 311 community-dwelling men and postmenopausal women aged 50 and 75 years were randomly assigned to four groups, receiving placebo, 50 µg/day, 90 µg/day or co-supplementation with calcium (500 mg/day) and vitamin D3 (10 µg/day) for 1 year. At the endpoint, the bone loss of femoral neck was significantly lower in postmenopausal women in the two 90 µg groups (treatment × time, p = 0.006) compared with placebo, but no effects in men. Serum biomarkers cOC/ucOC ratio increased in the intervention groups (treatment × time, p < 0.001). VK2 supplementation in dose of 90 µg/day performed a significant effect on reducing bone loss in postmenopausal women, but in combination with calcium and vitamin D3 brought no additional effects.

Trial registration This trial was registered at http://www.chictr.org.cn as chiCTR1800019240.

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References

  1. Rachner TD, Khosla S, Hofbauer LC (2011) Osteoporosis: now and the future. Lancet 377(9773):1276–1287. https://doi.org/10.1016/S0140-6736(10)62349-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Prince RL, Devine A, Dhaliwal SS, Dick IM (2006) Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. JAMA Internal Med 166(8):869–875. https://doi.org/10.1001/archinte.166.8.869

    Article  CAS  Google Scholar 

  3. Larsen ER, Mosekilde L, Foldspang A (2004) Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study. J Bone Miner Res 19(3):370–378. https://doi.org/10.1359/JBMR.0301240

    Article  CAS  PubMed  Google Scholar 

  4. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE (1997) Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 337(10):670–676. https://doi.org/10.1056/NEJM199709043371003

    Article  CAS  PubMed  Google Scholar 

  5. Kahwati LC, Weber RP, Pan H, Gourlay M, LeBlanc E, Coker-Schwimmer M, Viswanathan M (2018) Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA 319(15):1600–1612. https://doi.org/10.1001/jama.2017.21640

    Article  PubMed  Google Scholar 

  6. Xiao Q, Murphy RA, Houston DK, Harris TB, Chow WH, Park Y (2013) Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP diet and health study. JAMA Internal Med 173(8):639–646. https://doi.org/10.1001/jamainternmed.2013.3283

    Article  CAS  Google Scholar 

  7. Shearer MJ, Fu X, Booth SL (2012) Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr 3(2):182–195. https://doi.org/10.3945/an.111.001800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Atkins GJ, Welldon KJ, Wijenayaka AR, Bonewald LF, Findlay DM (2009) Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by {gamma}-carboxylation-dependent and -independent mechanisms. Am J Physiol Cell Physiol 297(6):C1358–1367. https://doi.org/10.1152/ajpcell.00216.2009

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Willems BA, Vermeer C, Reutelingsperger CP, Schurgers LJ (2014) The realm of vitamin K dependent proteins: shifting from coagulation toward calcification. Mol Nutr Food Res 58(8):1620–1635. https://doi.org/10.1002/mnfr.201300743

    Article  CAS  PubMed  Google Scholar 

  11. Gijsbers BL, Jie KS, Vermeer C (1996) Effect of food composition on vitamin K absorption in human volunteers. Br J Nutr 76(2):223–229. https://doi.org/10.1079/bjn19960027

    Article  CAS  PubMed  Google Scholar 

  12. Schurgers LJ, Teunissen KJ, Hamulyak K, Knapen MH, Vik H, Vermeer C (2007) Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood 109(8):3279–3283. https://doi.org/10.1182/blood-2006-08-040709

    Article  CAS  PubMed  Google Scholar 

  13. Shearer MJ, Bach A, Kohlmeier M (1186S) Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. J Nutr 126(4 Suppl):1181S–1186S. https://doi.org/10.1093/jn/126.suppl_4.1181S

    Article  CAS  PubMed  Google Scholar 

  14. Booth SL, Pennington JA, Sadowski JA (1996) Food sources and dietary intakes of vitamin K-1 (phylloquinone) in the American diet: data from the FDA Total Diet Study. J Am Diet Assoc 96(2):149–154. https://doi.org/10.1016/s0002-8223(96)00044-2

    Article  CAS  PubMed  Google Scholar 

  15. Schurgers LJ, Vermeer C (2000) Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis 30(6):298–307. https://doi.org/10.1159/000054147

    Article  CAS  PubMed  Google Scholar 

  16. Schurgers LJ, Vermeer C (2002) Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta 1570(1):27–32. https://doi.org/10.1016/s0304-4165(02)00147-2

    Article  CAS  PubMed  Google Scholar 

  17. Wu WJ, Gao H, Jin JS, Ahn BY (2019) A comparatively study of menaquinone-7 isolated from Cheonggukjang with vitamin K1 and menaquinone-4 on osteoblastic cells differentiation and mineralization. Food Chem Toxicol 131:110540. https://doi.org/10.1016/j.fct.2019.05.048

    Article  CAS  PubMed  Google Scholar 

  18. Sato T, Schurgers LJ, Uenishi K (2012) Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Nutr J 11:93. https://doi.org/10.1186/1475-2891-11-93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Marles RJ, Roe AL, Oketch-Rabah HA (2017) US pharmacopeial convention safety evaluation of menaquinone-7, a form of vitamin K. Nutr Rev 75(7):553–578. https://doi.org/10.1093/nutrit/nux022

    Article  PubMed  Google Scholar 

  20. Palermo A, Tuccinardi D, D'Onofrio L, Watanabe M, Maggi D, Maurizi AR, Greto V, Buzzetti R, Napoli N, Pozzilli P, Manfrini S (2017) Vitamin K and osteoporosis: myth or reality? Metab Clin Exp 70:57–71. https://doi.org/10.1016/j.metabol.2017.01.032

    Article  CAS  PubMed  Google Scholar 

  21. 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(2):380–386. https://doi.org/10.1093/ajcn/83.2.380

    Article  CAS  PubMed  Google Scholar 

  22. Theuwissen E, Magdeleyns EJ, Braam LA, Teunissen KJ, Knapen MH, Binnekamp IA, van Summeren MJ, Vermeer C (2014) Vitamin K status in healthy volunteers. Food Funct 5(2):229–234. https://doi.org/10.1039/c3fo60464k

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. 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. Osteoporosis Int 24(9):2499–2507. https://doi.org/10.1007/s00198-013-2325-6

    Article  CAS  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. Na L, Wu X, Feng R, Li J, Han T, Lin L, Lan L, Yang C, Li Y, Sun C (2015) The harbin cohort study on diet, nutrition and chronic non-communicable diseases: study design and baseline characteristics. PLoS ONE 10(4):e0122598. https://doi.org/10.1371/journal.pone.0122598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Knapen MH, Braam LA, Teunissen KJ, Van't Hoofd CM, Zwijsen RM, van den Heuvel EG, Vermeer C (2016) Steady-state vitamin K2 (menaquinone-7) plasma concentrations after intake of dairy products and soft gel capsules. Eur J Clin Nutr 70(7):831–836. https://doi.org/10.1038/ejcn.2016.3

    Article  CAS  PubMed  Google Scholar 

  29. Theuwissen E, Cranenburg EC, Knapen MH, Magdeleyns EJ, Teunissen KJ, Schurgers LJ, Smit E, Vermeer C (2012) Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects. Br J Nutr 108(9):1652–1657. https://doi.org/10.1017/S0007114511007185

    Article  CAS  PubMed  Google Scholar 

  30. Bruge F, Bacchetti T, Principi F, Littarru GP, Tiano L (2011) Olive oil supplemented with menaquinone-7 significantly affects osteocalcin carboxylation. Br J Nutr 106(7):1058–1062. https://doi.org/10.1017/S0007114511001425

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  32. Burt LA, Billington EO, Rose MS, Raymond DA, Hanley DA, Boyd SK (2019) Effect of high-dose vitamin D supplementation on volumetric bone density and bone strength: a randomized clinical trial. JAMA 322(8):736–745. https://doi.org/10.1001/jama.2019.11889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gigante A, Bruge F, Cecconi S, Manzotti S, Littarru GP, Tiano L (2015) Vitamin MK-7 enhances vitamin D3-induced osteogenesis in hMSCs: modulation of key effectors in mineralization and vascularization. J Tissue Eng Regen Med 9(6):691–701. https://doi.org/10.1002/term.1627

    Article  CAS  PubMed  Google Scholar 

  34. Li Y, Lin J, Cai S, Yan L, Pan Y, Yao X, Zhuang H, Wang P, Zeng Y (2016) Influence of bone mineral density and hip geometry on the different types of hip fracture. Bosn J Basic Med Sci 16(1):35–38. https://doi.org/10.17305/bjbms.2016.638

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mayhew PM, Thomas CD, Clement JG, Loveridge N, Beck TJ, Bonfield W, Burgoyne CJ, Reeve J (2005) Relation between age, femoral neck cortical stability, and hip fracture risk. Lancet 366(9480):129–135. https://doi.org/10.1016/S0140-6736(05)66870-5

    Article  PubMed  Google Scholar 

  36. Oden A, McCloskey EV, Johansson H, Kanis JA (2013) Assessing the impact of osteoporosis on the burden of hip fractures. Calcifi Tissue Int 92(1):42–49. https://doi.org/10.1007/s00223-012-9666-6

    Article  CAS  Google Scholar 

  37. Langdahl B, Ferrari S, Dempster DW (2016) Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskelet Dis 8(6):225–235. https://doi.org/10.1177/1759720X16670154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Urayama S, Kawakami A, Nakashima T, Tsuboi M, Yamasaki S, Hida A, Ichinose Y, Nakamura H, Ejima E, Aoyagi T, Nakamura T, Migita K, Kawabe Y, Eguchi K (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(3):181–193. https://doi.org/10.1067/mlc.2000.108754

    Article  CAS  PubMed  Google Scholar 

  39. Koshihara Y, Hoshi K, Okawara R, Ishibashi H, Yamamoto S (2003) Vitamin K stimulates osteoblastogenesis and inhibits osteoclastogenesis in human bone marrow cell culture. J Endocrinol 176(3):339–348. https://doi.org/10.1677/joe.0.1760339

    Article  CAS  PubMed  Google Scholar 

  40. Yamaguchi M, Weitzmann MN (2011) Vitamin K2 stimulates osteoblastogenesis and suppresses osteoclastogenesis by suppressing NF-kappaB activation. Int J Mol Med 27(1):3–14. https://doi.org/10.3892/ijmm.2010.562

    Article  CAS  PubMed  Google Scholar 

  41. Fujita Y, Iki M, Tamaki J, Kouda K, Yura A, Kadowaki E, Sato Y, Moon JS, Tomioka K, Okamoto N, Kurumatani N (2012) Association between vitamin K intake from fermented soybeans, natto, and bone mineral density in elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study. Osteoporos Int 23(2):705–714. https://doi.org/10.1007/s00198-011-1594-1

    Article  CAS  PubMed  Google Scholar 

  42. 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(2):512–516. https://doi.org/10.1093/ajcn/77.2.512

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank all the volunteers from the HDNNCDS for their participation in this study, and also thank all the colleagues who have taken part in the works for setting up, maintaining and following up this HDNNCDS cohort.

Funding

This study was funded by the Applied Technology Research and Development Plan of Heilongjiang Province (GA18C005).

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Contributions

Author YL designed the study. She is guarantor. Author YZ prepared the first draft of the paper. Authors YZ, ZL, LD, YY, SY, YZ and HL contributed to the study investigation and experimental work. Authors YW and PW were responsible for statistical analysis of the data. All authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

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Correspondence to Jiepeng Chen or Ying Li.

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Yingfeng Zhang, Zhipeng Liu, Lili Duan, Yeyu Ji, Sen Yang, Yuan Zhang, Hongyin Li, Yu Wang, Peng Wang, Jiepeng Chen, and Ying Li declare that they have no conflicts of interest.

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The study has been approved by the Ethical Committee of Harbin Medical University and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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All participants gave written informed consent before entering the study.

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Zhang, Y., Liu, Z., Duan, L. et al. Effect of Low-Dose Vitamin K2 Supplementation on Bone Mineral Density in Middle-Aged and Elderly Chinese: A Randomized Controlled Study. Calcif Tissue Int 106, 476–485 (2020). https://doi.org/10.1007/s00223-020-00669-4

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