Advertisement

Osteoporosis International

, Volume 30, Issue 6, pp 1175–1186 | Cite as

The efficacy and safety of menatetrenone in the management of osteoporosis: a systematic review and meta-analysis of randomized controlled trials

  • S. Su
  • N. He
  • P. Men
  • C. Song
  • S. ZhaiEmail author
Review Article

Abstract

Summary

In our systematic review and meta-analysis, we comprehensively evaluated menatetrenone in the management of osteoporosis. We found that menatetrenone decreased the ratio of undercarboxylated osteocalcin to osteocalcin (ucOC/OC) and improved lumbar BMD compared with placebo based on the 18 studies assessed. However, its benefit in fracture risk control was uncertain.

Introduction

We performed a systematic review and meta-analysis of the efficacy and safety of menatetrenone in managing osteoporosis.

Methods

PubMed, Cochrane Library, Embase, ClinicalTrials.gov, and three Chinese literature databases (CNKI, CBM, Wanfang) were searched for relevant randomized controlled trials (RCTs) published before October 5, 2017, comparing menatetrenone with other anti-osteoporotic drugs or placebo in treating osteoporosis. The pooled risk ratio (RR) or mean difference (MD) and 95% confidence interval (CI) were calculated using fixed-effects or random-effects meta-analysis.

Results

Eighteen RCTs (8882 patients) were included. Pooled analyses showed that menatetrenone was more effective than placebo in improving lumbar bone mineral density (BMD) (five studies, N = 658, MD = 0.05 g/cm2, 95% CI 0.01 to 0.09 g/cm2) and decreasing ucOC/OC (two studies, N = 75, MD = − 21.78%, 95% CI − 33.68 to − 9.87%). Compared with placebo, menatetrenone was associated with a nonsignificantly decreased risk of vertebral fracture (five studies, N = 5508, RR = 0.87, 95% CI 0.64 to 1.20). Evidence on other anti-osteoporotic drugs as comparators was limited and revealed no significantly different effects of menatetrenone on BMD or fracture risks. Furthermore, compared with placebo, menatetrenone significantly increased the incidence of adverse events (AEs) (two studies, N = 1949, RR = 1.47, 95% CI 1.07 to 2.02) and adverse drug reactions (four studies, N = 6102, RR = 1.29, 95% CI 1.07 to 1.56). However, no significant difference in the incidence of serious AEs was found between menatetrenone and placebo.

Conclusions

Menatetrenone significantly decreases ucOC and might improve lumbar BMD in osteoporotic patients. However, its benefit in fracture risk control is uncertain.

Keywords

Menatetrenone Osteoporosis Efficacy Safety Meta-analysis 

Notes

Compliance with ethical standards

Conflicts of interest

None.

Supplementary material

198_2019_4853_MOESM1_ESM.pdf (72 kb)
ESM 1 (PDF 72 kb)
198_2019_4853_MOESM2_ESM.pdf (122 kb)
ESM 2 (PDF 122 kb)
198_2019_4853_MOESM3_ESM.pdf (147 kb)
ESM 3 (PDF 147 kb)
198_2019_4853_MOESM4_ESM.pdf (97 kb)
ESM 4 (PDF 97 kb)
198_2019_4853_MOESM5_ESM.pdf (148 kb)
ESM 5 (PDF 148 kb)
198_2019_4853_MOESM6_ESM.pdf (74 kb)
ESM 6 (PDF 73 kb)

References

  1. 1.
    International Osteoporosis Foundation. https://www.iofbonehealth.org/what-osteoporosis-0. Accessed 1 May 2018
  2. 2.
    Johnell O, Kanis JA (2006) An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 17:1726–1733.  https://doi.org/10.1007/s00198-006-0172-4 CrossRefPubMedGoogle Scholar
  3. 3.
    Keene GS, Parker MJ, Pryor GA (1993) Mortality and morbidity after hip fractures. BMJ 307:1248–1250.  https://doi.org/10.1136/bmj.307.6914.1248
  4. 4.
    Baim S (2017) The future of fracture risk assessment in the management of osteoporosis. J Clin Densitom 20:451–457.  https://doi.org/10.1016/j.jocd.2017.06.015 CrossRefPubMedGoogle Scholar
  5. 5.
    Mithal A, Kaur P (2012) Osteoporosis in Asia: a call to action. Curr Osteoporos Rep 10:245–247.  https://doi.org/10.1007/s11914-012-0114-3 CrossRefPubMedGoogle Scholar
  6. 6.
    Briggs AM, Cross MJ, Hoy DG, Sànchez-Riera L, Blyth FM, Woolf AD, March L (2016) Musculoskeletal health conditions represent a global threat to healthy aging: a report for the 2015 World Health Organization world report on aging and health. Gerontologist 56(Suppl 2):S243–S255.  https://doi.org/10.1093/geront/gnw002 CrossRefPubMedGoogle Scholar
  7. 7.
    Delmas PD (2002) Treatment of postmenopausal osteoporosis. N Engl J Med 359:736–746Google Scholar
  8. 8.
    Hauschka PV, Lian JB, Cole DE, Gundberg CM (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69:990–1047CrossRefPubMedGoogle Scholar
  9. 9.
    Urayama S, Kawakami A, Nakashima T, Tsuboi M, Yamasaki S, Hida A, Ichinose Y, Nakamura H, Ejima E, Aoyagi T (2000) Effect of vitamin K 2 on osteoblast apoptosis: vitamin K 2 inhibits apoptotic cell death of human osteoblasts induced by Fas, proteasome inhibitor, etoposide, and staurosporine. J Lab Clin Med 136:181–193CrossRefPubMedGoogle Scholar
  10. 10.
    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 (Structured abstract) 166:1256–1261CrossRefPubMedGoogle Scholar
  11. 11.
    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 30:60–68.  https://doi.org/10.1007/s00774-011-0287-3 CrossRefPubMedGoogle Scholar
  12. 12.
    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 26:1175–1186.  https://doi.org/10.1007/s00198-014-2989-6 CrossRefPubMedGoogle Scholar
  13. 13.
    Iwamoto J (2014) Vitamin K(2) therapy for postmenopausal osteoporosis. Nutrients 6:1971–1980.  https://doi.org/10.3390/nu6051971 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Iwamoto J, Sato Y (2013) Menatetrenone for the treatment of osteoporosis. Expert Opin Pharmacother 14:449–458.  https://doi.org/10.1517/14656566.2013.763796 CrossRefPubMedGoogle Scholar
  15. 15.
    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? Metabolism 70:57–71.  https://doi.org/10.1016/j.metabol.2017.01.032 CrossRefPubMedGoogle Scholar
  16. 16.
    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(iii-xi):1–134.  https://doi.org/10.3310/hta13450 CrossRefPubMedGoogle Scholar
  17. 17.
    Higgins J, Green SE (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0. http://handbook-5-1.cochrane.org/ Accessed 22 November 2017
  18. 18.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Epidemiol Biostat Public Health 6:e1–e34Google Scholar
  19. 19.
    Zhao JG, Zeng XT, Wang J, Liu L (2017) Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis. Jama 318:2466–2482CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Steichen T (2001) METANINF: Stata module to evaluate influence of a single study in meta-analysis estimation. Stat Softw Components. http://ideas.repec.org/c/boc/bocode/s419201.html Accessed 4 Sept 2018
  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 16:106–112.  https://doi.org/10.1007/s007740050034 CrossRefGoogle Scholar
  22. 22.
    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
  23. 23.
    Orimo H, Fujita T, Onomura T, Inoue T, Kushida K, Shiraki M (1992) Clinical evaluation of Ea-0167 (menatetrenone) in the treatment of osteoporosis. Phase III double-blind multicenter comparative study with alfacalcidol. Clin Eval 20:45–100Google Scholar
  24. 24.
    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.  https://doi.org/10.1359/jbmr.2000.15.3.515 CrossRefPubMedGoogle Scholar
  25. 25.
    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 6:487–492.  https://doi.org/10.1007/s007760100002 CrossRefPubMedGoogle Scholar
  26. 26.
    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
  27. 27.
    Miki T, Nakatsuka K, Naka H, Kitatani K, Saito S, Masaki H, Tomiyoshi Y, Morii H, Nishizawa Y (2003) Vitamin K(2) (menaquinone 4) reduces serum undercarboxylated osteocalcin level as early as 2 weeks in elderly women with established osteoporosis. J Bone Miner Metab 21:161–165.  https://doi.org/10.1007/s007740300025 CrossRefPubMedGoogle Scholar
  28. 28.
    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.  https://doi.org/10.1016/j.amjmed.2004.05.019 CrossRefPubMedGoogle Scholar
  29. 29.
    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.  https://doi.org/10.1007/s00774-008-0008-8 CrossRefPubMedGoogle Scholar
  30. 30.
    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 27:333–340.  https://doi.org/10.1007/s00774-008-0034-6 CrossRefPubMedGoogle Scholar
  31. 31.
    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 32:290–297.  https://doi.org/10.1007/s00774-013-0490-5 CrossRefPubMedGoogle Scholar
  32. 32.
    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 35:385–395.  https://doi.org/10.1007/s00774-016-0768-5 CrossRefPubMedGoogle Scholar
  33. 33.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Liu L (2015) The efficacy of vitamin K2 in treating osteoporotic patients and its effects on patients’ coagulation function. Master thesis. Jilin University. http://cdmd.cnki.com.cn/Article/CDMD-10183-1015591169.htm. Accessed 20 October 2017
  35. 35.
    Hu H, You M, Ran J (2017) The efficacy and safety of menatetrenone soft capsules combined with Salmon calcitonin in the treatment of elderly osteoporosis. Chin J Osteoporos 23:643–646Google Scholar
  36. 36.
    Luo J, Nie G, Huang X, Yang S, Xin J (2017) The effect of menatetrenone soft capsules with Caltrate Din the treatment of osteoporosis and femoral intertrochanteric fracture and its effect on bone metabolism index. Anhui Med Pharm J 21:1101–1105Google Scholar
  37. 37.
    Zhuang H, Chen D, Xu M, Su Q, Dong T (2017) The effect of vitamin K2 on the prevention and treatment of postmenopausal osteoporosis and serum cathepsin K. Chin J Osteoporosis 23:627–630 and 651Google Scholar
  38. 38.
    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.  https://doi.org/10.1111/j.1447-0756.2006.00386.x CrossRefPubMedGoogle Scholar
  39. 39.
    Vermeer C, Jie KS, Knapen MH (1995) Role of vitamin K in bone metabolism. Annu Rev Nutr 15:1–22CrossRefPubMedGoogle Scholar
  40. 40.
    Szulc P, Chapuy MC, Meunier PJ, Delmas PD (1996) Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: a three year follow-up study. Bone 18:487–488.  https://doi.org/10.1016/8756-3282(96)00037-3 CrossRefPubMedGoogle Scholar
  41. 41.
    Shiraki M, Yamazaki Y, Shiraki Y, Hosoi T, Tsugawa N, Okano T (2010) High level of serum undercarboxylated osteocalcin in patients with incident fractures during bisphosphonate treatment. J Bone Miner Metab 28:578–584.  https://doi.org/10.1007/s00774-010-0167-2 CrossRefPubMedGoogle Scholar
  42. 42.
    Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J (2000) The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporos Int 11(Suppl 6):S2–S17CrossRefPubMedGoogle Scholar
  43. 43.
    Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. Bmj 312:1254–1259.  https://doi.org/10.1136/bmj.312.7041.1254 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    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 23:705–714.  https://doi.org/10.1007/s00198-011-1594-1 CrossRefPubMedGoogle Scholar
  45. 45.
    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 29:761–765.  https://doi.org/10.1016/j.clnu.2010.02.010 CrossRefPubMedGoogle Scholar
  46. 46.
    Ahlborg HG, Johnell O, Turner CH, Rannevik G, Karlsson MK (2003) Bone loss and bone size after menopause. N Engl J Med 349:327–334CrossRefPubMedGoogle Scholar
  47. 47.
    Confavreux CB (2011) Bone: from a reservoir of minerals to a regulator of energy metabolism. Kidney Int Suppl 79:S14–S19.  https://doi.org/10.1038/ki.2011.25 CrossRefPubMedCentralGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2019

Authors and Affiliations

  1. 1.Department of PharmacyPeking University Third HospitalBeijingChina
  2. 2.Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical SciencePeking UniversityBeijingChina
  3. 3.Department of OrthopaedicsPeking University Third HospitalBeijingChina

Personalised recommendations