Journal of Bone and Mineral Metabolism

, Volume 27, Issue 1, pp 66–75 | Cite as

Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules

  • Tetsuo Inoue
  • Toshiharu Fujita
  • Hideaki Kishimoto
  • Toshitaka Makino
  • Tetsuro Nakamura
  • Toshitaka Nakamura
  • Tosiya Sato
  • Kaoru Yamazaki
Original article

Abstract

An open-label study with blinded evaluation was performed to compare the preventive effect of a calcium supplement alone (monotherapy) or calcium supplement plus menatetrenone (combined therapy) on fracture in osteoporotic postmenopausal women aged 50 years or older. Patients were randomized to receive monotherapy (n = 2,193) or combined therapy (n = 2,185). Before randomization, the subjects were stratified into a subgroup without vertebral fractures (n = 2,986; no-fracture subgroup) and a subgroup with at least one vertebral fracture (n = 1,392; fracture subgroup). The incidence rate of new vertebral fractures during 36 months of treatment (primary endpoint) did not differ significantly between either subgroup of the two treatment groups. Although the cumulative 48-month incidence rate of new clinical fractures (secondary endpoint) was lower in the combined therapy group, the difference was not significant. There was a lower risk of new vertebral fractures in patients with at least five baseline fractures who received combined therapy. Also, the loss of height was less with combined therapy than with monotherapy among patients 75 years of age or older at enrollment, those whose last menstrual period occurred 30 years or more before enrollment, and those with at least five vertebral fractures at enrollment. Adverse events and adverse reactions were more frequent in the combined therapy group. In conclusion, menatetrenone therapy was not effective for preventing vertebral fractures in the full analysis set of this study, but the results suggested that it may prevent vertebral fractures in patients with more advanced osteoporosis.

Keywords

Osteoporosis Fractures Menatetrenone Controlled study ADL 

Notes

Acknowledgments

Research funds were provided by the Japanese Ministry of Health, Labor and Welfare for the first 2 years of the study, and thereafter the study was funded by Eisai Co. Ltd. (Tokyo, Japan). We thank all the study participants, physicians, and co-medical staff.

References

  1. 1.
    Bouckaert JH, Said AH (1960) Fracture healing by vitamin K. Nature (Lond) 185:849CrossRefGoogle Scholar
  2. 2.
    Stenflo J, Fernlund P, Egan W, Roepstorff P (1974) Vitamin K dependent modification of glutamic acid residues in prothrombin. Proc Natl Acad Sci USA 71:2730–2733PubMedCrossRefGoogle Scholar
  3. 3.
    Hauschka PV, Lian JB, Gallop PM (1975) Direct identification of the calcium-binding amino acid, γ-carboxyglutamate, in mineralized tissue. Proc Natl Acad Sci USA 72:3925–3929PubMedCrossRefGoogle Scholar
  4. 4.
    Price PA, Otsuka AS, Poser JW, Kristaponis J, Raman N (1976) Characterization of a γ-carboxyglutamic acid-containing protein from bone. Proc Natl Acad Sci USA 73:1447–1451PubMedCrossRefGoogle Scholar
  5. 5.
    Hara K, Akiyama Y, Nakamura T, Murota S, Morita I (1995) The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain. Bone (NY) 16:179–184Google Scholar
  6. 6.
    Koshihara Y, Hoshi K (1997) Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro. J Bone Miner Res 12:431–438PubMedCrossRefGoogle Scholar
  7. 7.
    Hart JP, Shearer MJ, Klenerman L, Catterall A, Reeve J et al (1985) Electrochemical detection of depressed circulating levels of vitamin K1 in osteoporosis. J Clin Endocrinol Metab 60:268–1269CrossRefGoogle Scholar
  8. 8.
    Bitensky L, Hart JP, Catterall A, Hodges SJ, Pilkington MJ et al (1988) Circulating vitamin K levels in patients with fractures. J Bone Joint Surg 70:663–664Google Scholar
  9. 9.
    Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD (1993) Circulating levels of vitamin K1 and K2 decreased in elderly women with hip fracture. J Bone Miner Res 10:1241–1245CrossRefGoogle Scholar
  10. 10.
    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 91:1769–1774PubMedCrossRefGoogle Scholar
  11. 11.
    Orimo H, Hayashi Y, Fukunaga M, Sone T, Fujiwara S et al (2001) Diagnostic criteria for primary osteoporosis: year 2000 revision. J Bone Miner Metab 19:331–337PubMedCrossRefGoogle Scholar
  12. 12.
    Inoue T, Kushida K, Miyamoto S, Sumi Y, Orimo H et al (1983) Quantitative assessment of bone density on X-ray picture. J Jpn Orthop Assoc 57:1923–1936Google Scholar
  13. 13.
    Orimo H, Fujita T, Onomura T, Inoue T, Kushida K et al (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
  14. 14.
    Rothman KJ, Greenland S (1998) Modern epidemiology, 2nd edn. Lippincott-Raven, PhiladelphiaGoogle Scholar
  15. 15.
    Orimo H, Shiraki M, Hasyashi Y, Hoshino T, Onaya T et al (1994) Effects of 1α-hydroxyvitamin D3 on lumbar bone mineral density and vertebral fractures in patients with postmenopausal osteoporosis. Calcif Tissue Int 54:370–376PubMedCrossRefGoogle Scholar
  16. 16.
    Tilyard MW, Spears GFS, Thomson J, Dovey S (1992) Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med 326:357–362PubMedGoogle Scholar
  17. 17.
    Aloia JF, Vaswani A, Yeh JK, Ellis K, Yasumura S et al (1988) Calcitriol in the treatment of postmenopausal osteoporosis. Am J Med 84:401–408PubMedCrossRefGoogle Scholar
  18. 18.
    Gallagher JC, Riggs BL, Recker RR, Goldgar D (1989) The effect of calcitriol on patients with postmenopausal osteoporosis with special reference to fracture frequency (42922). Proc Soc Exp Biol 191:287–292Google Scholar
  19. 19.
    The European Prospective Osteoporosis Study (EPOS) Group (2002) Incidence of vertebral fracture in Europe: results from the European prospective osteoporosis study (EPOS). J Bone Miner Res 17:716–724CrossRefGoogle Scholar
  20. 20.
    Fujiwara S, Kasagi F, Masunari N, Naito K, Suzuki G et al (2003) Fracture prediction from bone mineral density in Japanese men and women. J Bone Miner Res 18:1547–1553PubMedCrossRefGoogle Scholar
  21. 21.
    Hayashi Y, Fujita T, Inoue T (1992) Decrease of vertebral fracture in osteoporotics by administration of 1α-hydroxy-vitamin D3. J Bone Miner Metab 10:184–188CrossRefGoogle Scholar
  22. 22.
    Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T et al (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 282:1344–1352PubMedCrossRefGoogle Scholar
  23. 23.
    Reginster J-Y, Minne HW, Sorensen OH, Hooper M, Roux C et al (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 11:83–91PubMedCrossRefGoogle Scholar
  24. 24.
    Cockayne S, Adamson J, Lanham-New S, Shearer M, Gilbody S et al (2006) Vitamin K and the prevention of fractures. Arch Intern Med 166:1256–1261PubMedCrossRefGoogle Scholar
  25. 25.
    Knapen MHJ, Schurgers LJ, Vermeer C (2007) Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int 18:963–972PubMedCrossRefGoogle Scholar
  26. 26.
    Kushida K, Fukunaga M, Kishimoto H, Shiraki M, Itabashi A et al (2004) A comparison of incidences of vertebral fracture in Japanese patients with involutional osteoporosis treated with risedronate and etidronate: a randomized, double-masked trial. J Bone Miner Metab 22:469–478PubMedGoogle Scholar
  27. 27.
    Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD (1991) Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women. J Bone Miner Res 6:1211–1216PubMedGoogle Scholar
  28. 28.
    Tsugawa N, Shiraki M, Suhara Y, Kamao M, Tanaka K et al (2006) Vitamin K status of healthy Japanese women: age-related vitamin K requirement for γ-carboxylation of osteocalcin. Am J Clin Nutr 83:380–386PubMedGoogle Scholar
  29. 29.
    Ross PD, Fujiwara S, Huang C, Davis JW, Epstein RS et al (1995) Vertebral fracture prevalence in women in Hiroshima compared to Caucasians or Japanese in the US. Int J Epidemiol 24:1171–1177PubMedCrossRefGoogle Scholar
  30. 30.
    Jinbayashi H, Aoyagi K, Ross PD, Ito M, Shindo H et al (2002) Prevalence of vertebral deformity and its associations with physical impairment among Japanese women: the Hizen-Oshima study. Osteoporos Int 13:723–730PubMedCrossRefGoogle Scholar
  31. 31.
    Lipid Research Clinical Program (1984) The lipid research clinical coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA 251:351–364CrossRefGoogle Scholar
  32. 32.
    Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y et al (2006) Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomized controlled trial. Lancet 368:1155–1163PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2008

Authors and Affiliations

  • Tetsuo Inoue
    • 1
  • Toshiharu Fujita
    • 2
  • Hideaki Kishimoto
    • 3
  • Toshitaka Makino
    • 4
  • Tetsuro Nakamura
    • 5
  • Toshitaka Nakamura
    • 6
  • Tosiya Sato
    • 7
  • Kaoru Yamazaki
    • 8
  1. 1.Aoyama General HospitalKosakaiJapan
  2. 2.Department of Data ScienceInstitute of Statistical MathematicsMinato-kuJapan
  3. 3.Department of OrthopedicsSan-in Rosai HospitalYonagoJapan
  4. 4.Japan Cosmetic Industry AssociationTokyoJapan
  5. 5.Institute for Medical Science of AgingTokyoJapan
  6. 6.Department of Orthopedic SurgeryUniversity of Occupational and Environmental HealthKitakyushuJapan
  7. 7.Department of BiostatisticsKyoto University School of Public HealthKyotoJapan
  8. 8.Department of Orthopaedic SurgeryHamamatsu University School of MedicineHamamatsuJapan

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