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Osteoporosis International

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01-06-2019 | Osteoporosis | Review Article

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

Authors: S. Su, N. He, P. Men, C. Song, S. Zhai

Published in: Osteoporosis International | Issue 6/2019

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.

Available only for authorised users

International Osteoporosis Foundation. https://www.iofbonehealth.org/what-osteoporosis-0. Accessed 1 May 2018

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/s00198-006-0172-4CrossRefPubMed

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

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.2017.06.015CrossRefPubMed

Mithal A, Kaur P (2012) Osteoporosis in Asia: a call to action. Curr Osteoporos Rep 10:245–247. https://doi.org/10.1007/s11914-012-0114-3CrossRefPubMed

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/gnw002CrossRefPubMed

Delmas PD (2002) Treatment of postmenopausal osteoporosis. N Engl J Med 359:736–746

Hauschka PV, Lian JB, Cole DE, Gundberg CM (1989) Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev 69:990–1047CrossRef

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 136:181–193CrossRef

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) 166:1256–1261CrossRef

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/s00774-011-0287-3CrossRefPubMed

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/s00198-014-2989-6CrossRefPubMed

13.

Iwamoto J (2014) Vitamin K(2) therapy for postmenopausal osteoporosis. Nutrients 6:1971–1980. https://doi.org/10.3390/nu6051971CrossRefPubMedPubMedCentral

14.

Iwamoto J, Sato Y (2013) Menatetrenone for the treatment of osteoporosis. Expert Opin Pharmacother 14:449–458. https://doi.org/10.1517/14656566.2013.763796CrossRefPubMed

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.2017.01.032CrossRefPubMed

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/hta13450CrossRefPubMed

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.

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–e34

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 318:2466–2482CrossRef

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.

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/s007740050034CrossRef

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 5:546–551CrossRef

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 20:45–100

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.2000.15.3.515CrossRefPubMed

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/s007760100002CrossRefPubMed

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 41:211–221CrossRef

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/s007740300025CrossRefPubMed

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.2004.05.019CrossRefPubMed

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/s00774-008-0008-8CrossRefPubMed

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/s00774-008-0034-6CrossRefPubMed

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/s00774-013-0490-5CrossRefPubMed

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/s00774-016-0768-5CrossRefPubMed

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.s54107CrossRefPubMedPubMedCentral

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.

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 23:643–646

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 21:1101–1105

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 651

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.xCrossRefPubMed

39.

Vermeer C, Jie KS, Knapen MH (1995) Role of vitamin K in bone metabolism. Annu Rev Nutr 15:1–22CrossRef

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)00037-3CrossRefPubMed

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/s00774-010-0167-2CrossRefPubMed

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–S17CrossRef

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.312.7041.1254CrossRefPubMedPubMedCentral

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/s00198-011-1594-1CrossRefPubMed

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.2010.02.010CrossRefPubMed

46.

Ahlborg HG, Johnell O, Turner CH, Rannevik G, Karlsson MK (2003) Bone loss and bone size after menopause. N Engl J Med 349:327–334CrossRef

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.2011.25CrossRefPubMedCentral

Title: The efficacy and safety of menatetrenone in the management of osteoporosis: a systematic review and meta-analysis of randomized controlled trials
Authors: S. Su
N. He
P. Men
C. Song
S. Zhai
Publication date: 01-06-2019
Publisher: Springer London
Keywords: Osteoporosis
Osteoporosis
Published in: Osteoporosis International / Issue 6/2019
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-019-04853-7

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

Abstract

Summary

Introduction

Methods

Results

Conclusions

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