Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women

  • Makoto Hirao
  • Jun Hashimoto
  • Wataru Ando
  • Takeshi Ono
  • Hideki Yoshikawa
Original Article


Alendronate decreases the risk of femoral neck fracture by suppressing bone turnover, and also decreases the serum total osteocalcin level. A low serum carboxylated osteocalcin level or high undercarboxylated osteocalcin level could be risk factors for femoral neck fracture. Vitamin K mediates the carboxylation of osteocalcin, but the effect of alendronate therapy with or without vitamin K2 supplementation remains unknown. Forty-eight postmenopausal women were enrolled in a 1-year prospective randomized trial and assigned to alendronate monotherapy (5 mg/day) (group A, n = 26) or vitamin K2 (45 mg/day) plus alendronate (5 mg/day) (group AK, n = 22). Bone mineral density was measured by dual-energy X-ray absorptiometry at 0 and 12 months; bone turnover parameters were measured at 0, 3, and 12 months. Four patients discontinued alendronate therapy, and we analyzed the remaining 44 patients (23 in group A and 21 in group AK) who completed 1 year of treatment. Alendronate decreased undercarboxylated osteocalcin; carboxylated osteocalcin was not affected. Addition of vitamin K2 enhanced the decrease of undercarboxylated osteocalcin levels and led to a greater increase of femoral neck bone mineral density. Alendronate monotherapy does not decrease carboxylation of osteocalcin, and combination of vitamin K2 and alendronate brings further benefits on both osteocalcin carboxylation and BMD of femoral neck in postmenopausal women with osteoporosis.

Key words

alendronate osteocalcin postmenopausal woman vitamin K2 


  1. 1.
    Ensrud KE, Black DM, Palermo L, Bauer DC, Barrett-Connor E, Quandt SA, Thompson DE, Karpf DB (1997) Treatment with alendronate prevents fractures in women at highest risk: results from the Fracture Intervention Trial. Arch Intern Med 157:2617–2624PubMedCrossRefGoogle Scholar
  2. 2.
    Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora AC II (1996) Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med 101:488–501PubMedCrossRefGoogle Scholar
  3. 3.
    Shiraki M, Kushida K, Fukunaga M, Kishimoto H, Kaneda K, Minaguchi H, Inoue T, Tomita A, Nagata Y, Nakashima M, Orimo H (1998) A placebo-controlled, single-blind study to determine the appropriate alendronate dosage in postmenopausal Japanese patients with osteoporosis. The Alendronate Research Group. Endocr J 45:191–201PubMedCrossRefGoogle Scholar
  4. 4.
    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
  5. 5.
    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 82:719–724PubMedCrossRefGoogle Scholar
  6. 6.
    Luukinen H, Kakonen SM, Pettersson K, Koski K, Laippala P, Lovgren T, Kivela SL, Vaananen HK (2000) Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin. J Bone Miner Res 15:2473–2478PubMedCrossRefGoogle Scholar
  7. 7.
    Suttie JW (1995) Vitamin K-dependent carboxylase. Annu Rev Biochem 54:459–477CrossRefGoogle Scholar
  8. 8.
    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
  9. 9.
    Miki T, Nakatsuka K, Naka H, Kitatani K, Saito S, Masaki H, Tomiyoshi Y, Morii H, Nishizawa Y (2003) Vitamin K (menaquinone 4) reduces serum undercarboxylated osteocalcin level as early as 2 weeks in elderly women with established osteoporosis. J Bone Miner Metab 21:161–165PubMedCrossRefGoogle Scholar
  10. 10.
    Ozuru R, Sugimoto T, Yamaguchi T, Chihara K (2002) Timedependent effects of vitamin K2 (menatetrenone) on bone metabolism in postmenopausal women. Endocr J 49:363–370PubMedCrossRefGoogle Scholar
  11. 11.
    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 15:515–521PubMedCrossRefGoogle Scholar
  12. 12.
    Iwamoto J, Takeda T, Ichihara S (2003) Combined treatment with vitamin K2 and bisphosphonate in postmenopausal women with osteoporosis. Yonsei Med J 44:751–756PubMedGoogle Scholar
  13. 13.
    Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG, Seeman E (2002) Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 87:985–992PubMedCrossRefGoogle Scholar
  14. 14.
    Frediani B, Allegri A, Bisogno S, Marcolongo R (1998) Effects of combined treatment with calcitriol plus alendronate on bone mass and bone turnover in postmenopausal osteoporosis. Two years of continuous treatment. Clin Drug Invest 15(3):235–244CrossRefGoogle Scholar
  15. 15.
    Greenspan SL, Resnik NM, Parker RA (2003) Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial. JAMA 289:2525–2533PubMedCrossRefGoogle Scholar
  16. 16.
    Vermeer C (1990) Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 266:625–636PubMedGoogle Scholar
  17. 17.
    Cowin SC, Moss-Salentijin L, Moss KL (1991) Candidates for the mechanosensory system in bone. J Biomed Eng 113:191–197Google Scholar
  18. 18.
    Aarden EM, Burger EH, Nijweide PJ (1994) Function of osteocytes in bone. J Cell Biochem 55:287–299PubMedCrossRefGoogle Scholar
  19. 19.
    Burger EH, Klein-Nulend J (1999) Mechanotransduction in bone: role of the lacunocanalicular network. FASEB J 13:S101–S112PubMedGoogle Scholar
  20. 20.
    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
  21. 21.
    Kameda T, Miyazawa K, Mori Y, Yuasa T, Shiokawa M, Nakamura Y, Mano H, Hakeda Y, Kameda A, Kumegawa M (1996) Vitamin K2 inhibits osteoclastic bone resorption by inducing osteoclast apoptosis. Biochem Biophys Res Commun 220:515–519PubMedCrossRefGoogle Scholar
  22. 22.
    Knapen MHJ, Hamulyák K, Vermeer C (1989) The effect of vitamin K supplementation on circulating osteocalcin (bone Gla-protein) and urinary calcium excretion. Ann Intern Med 111:1001–1005PubMedGoogle Scholar
  23. 23.
    Knapen MHJ, Jie KSG, Hamulyák K, Vermeer C (1993) Vitamin-K induced changes in markers for osteoblast activity and urinary calcium loss. Calcif Tissue Int 53:81–85PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2008

Authors and Affiliations

  • Makoto Hirao
    • 1
  • Jun Hashimoto
    • 1
  • Wataru Ando
    • 1
  • Takeshi Ono
    • 1
  • Hideki Yoshikawa
    • 1
  1. 1.Department of OrthopaedicsOsaka University Graduate School of MedicineOsakaJapan

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