Effect of continuous combined therapy with vitamin K2 and vitamin D3 on bone mineral density and coagulofibrinolysis function in postmenopausal women


      Objectives: To investigate the therapeutic effect of combined use of vitamin K2 and D3 on vertebral bone mineral density in postmenopausal women with osteopenia and osteoporosis. Subjects and methods: We enrolled 172 women with vertebral bone mineral density <0.98 g/cm2 (osteopenia and osteoporosis) as measured by dual-energy X-ray absorptiometry. In this study, we employed the criteria for diagnosis of osteopenia and osteoporosis using dual energy X-ray absorptiometry proposed by the Japan Society of Bone Metabolism in 1996. Subjects were randomized into four groups (each having 43 subjects in vitamin K2 therapy group, vitamin D3 therapy group, vitamin K2 and D3 combined therapy group, or a control group receiving dietary therapy alone) and treated with respective agents for 2 years, with bone mineral density was measured prior to therapy and after 6, 12, 18, and 24 months of treatment. The bone metabolism markers analyzed were serum type 1 collagen carboxyterminal propeptide (P1CP), serum intact osteocalcin, and urinary pyridinoline. Tests of blood coagulation function consisted of measurement of activated partial thromboplastin time (APTT) and analysis of concentrations of antithrombin III (AT III), fibrinogen, and plasminogen. Results: Combined therapy with vitamin K2 and D3 for 24 months markedly increased bone mineral density (4.92±7.89%), while vitamin K2 alone increased it only 0.135±5.44%. The bone markers measured, revealed stimulation of both bone formation and resorption activity. We observed an increase in coagulation and fibrinolytic activity that was within the normal range, suggesting that balance was maintained in the fibrinolysis–coagulation system. Conclusions: Continuous combination therapy with vitamin K2 and D3 may be useful for increasing vertebral bone mass in postmenopausal women. Furthermore, the increase in coagulation function observed during this therapy was within the physiological range, and no adverse reactions were observed.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Maturitas
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kanis J.A
        Risk factors in osteoporosis.
        Maturitas. 1998; 30: 229-233
        • Ushiroyama T
        • Okamura S
        • Ikeda A
        • Ueki M
        Efficacy of ipriflavone and 1α vitamin D therapy for the cessation of vertebral bone loss.
        Int. J. Gynecol. Obstet. 1995; 48: 283-288
        • Netelenbos C
        Osteoporosis: intervention options.
        Maturitas. 1998; 30: 235-239
        • Watts N.B
        • Becker P
        Alendronate increases spine and hip bone mineral density in women with postmenopausal osteoporosis who failed to respond to intermittent cyclical etidronate.
        Bone. 1999; 24: 65-68
        • Rozenberg S
        • Vandromme J
        • Ayata N.B
        • Filippidis M
        • Kroll M
        Osteoporosis management.
        Int. J. Fertil. Womens Med. 1999; 44: 241-249
        • Watts N.B
        Postmenipausal osteoporosis.
        Obstet. Gynecol. Surv. 1999; 54: 532-538
        • Celotti F
        • Bignamini A
        Dietary calcium and mineral/vitamin supplementation: a controversial problem.
        J. Int. Med. Res. 1999; 27: 1-14
        • New S.A
        Bone health: the role of micronutrients.
        Br. Med. Bull. 1999; 55: 619-633
        • Meunier P.J
        Calcium, vitamin D and vitamin K in the prevention of fractures due to osteoporosis.
        Osteoporosis Int. 1999; 2: S48-S52
        • Matsunaga S
        • Ito H
        • Sakou T
        The effect of vitamin K and D supplementation on ovariectomy-induced bone loss.
        Calcif. Tissue Int. 1999; 65: 285-289
        • Shearer M.J
        The roles of vitamins D and K in bone health and osteoporosis prevention.
        Proc. Nutr. Soc. 1997; 56: 915-937
        • Orimo H
        • Fujita T
        • Onomura T
        • Inoue T
        • Kushida K
        • Shiraki M
        Clinical evaluation of Ea-0167 (Menatetrenone) in the treatment of osteoporosis.
        Clin. Eval. (In Japanese). 1992; 20: 45-100
        • Sato Y
        • Honda Y
        • Kuno H
        • Oizumi K
        Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients.
        Bone. 1998; 23: 291-296
        • Feskanich D
        • Weber P
        • Willett W.C
        • Rockett H
        • Booth S.L
        • Colditz G.A
        Vitamin K intake and hip fractures in women: a prospective study.
        Am. J. Clin. Nutr. 1999; 69: 74-79
        • Sato Y
        • Tsuru T
        • Oizumi K
        • Kaji M
        Vitamin K deficiency and osteopenia in disuse-affected limbs of vitamin D-deficient elderly stroke patients.
        Am. J. Physiol. Med. Rehabil. 1999; 78: 317-322
        • Lian J.B
        • Gundberg C.M
        Osteocalcin—biochemical considerations and clinical applications.
        Chin. Orthopaed. 1988; 226: 267-291
        • Orishige H
        Clinical evaluation of menaquinone versus alfacalcidol in the treatment of osteoporosis: a double-blind, controlled Phase III clinical trial.
        Clin. Eval. 1992; 20: 45-100
        • Akiyama Y
        Research on the mechanism of inhibitory action of vitamin K2 on bone resorption in cultured organ culture.
        J. Jpn. Soc. Bone Min. Metab. 1991; 9: 239
        • Koshihara Y
        Establishment of human osteoblastic cells derived from periosteum in culture.
        In Vitro Cell Dev. Biol. 1989; 25: 37-43
        • Anderson J.J
        • Rondano P
        • Holmes A
        Roles of diet and physical activity in the prevention of osteoporosis.
        Scand. J. Rheumatol. Suppl. 1996; 103: 65-74
        • Feskanich D
        • Weber P
        • Willett W.C
        • Rockett H
        • Booth S.L
        • Colditz G.A
        Vitamin K intake and hip fractures in women: a prospective study.
        Am. J. Clin. Nutr. 1999; 69: 74-79
        • Kamezawa K
        Inhibitory effects of combined treatment with vitamin K and D on bone loss of ovariectomized rats: a microradiographic study.
        Fukuoka Igaku Zasshi. 1999; 90: 71-78
        • Douglas A.S
        • Robins S.P
        • Hutchinson J.D
        • Porter R.W
        • Stewart A
        • Reid D.M
        Carboxylation of osteocalcin in postmenopausal osteoporotic women following vitamin K and D supplementation.
        Bone. 1995; 17: 15-20
        • Orimo H
        • Sugioka Y
        • Fukunaga M
        • Muto Y
        • Hokokebuchi T
        • Gorai I
        • Nakamura T
        • Kushida K
        • Tanaka H
        • Ikai T
        • Oh-hashi Y
        Diagnostic criteria of primary osteoporosis.
        J. Bone Miner. Metab. 1998; 16: 139-150
        • Eyre D.R
        • Dickson I.R
        • Van Ness K.P
        Collagen cross-linking in human bone and articular cartilage. Age-related changes in the content of mature hydroxypyridinium residues.
        Biochem. J. 1988; 252: 495-500
        • Kuwada M
        • Katayama K
        A high-performance liquid chromatographic method for the simultaneous determination of γ-carboxyglutamic acid and glutamic acid in proteins, bone, and urine.
        Anal. Biochem. 1981; 117: 259-265
        • Koshihara Y
        Current topics in vitamin K research: promotion of bone formation.
        Vitamin. 1998; 72: 641-644
        • Iwamoto I
        • Kosha S
        • Noguchi S
        • Murakami M
        • Fujino T
        • Douchi T
        • Nagata Y
        A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women: a comparative study with vitamin D3 and estrogen–progestin therapy.
        Maturitas. 1999; 31: 161-164
        • Somekawa Y
        • Chigugi M
        • Harada M
        • Ishibashi T
        Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide.
        J. Clin. Endocrinol. Metab. 1999; 84: 2700-2704
        • Akedo Y
        • Hosoi T
        • Inoue S
        Vitamin K2 modulates proliferation and function of osteoblastic cells in vitro.
        Biochem. Biophys. Res. Commun. 1992; 187: 814-820
        • Mehta A.B
        • Mclntyre N
        Haematological disorders in liver disease.
        Forum Genova. 1998; 8: 8-25
        • Andrew M
        The relevance of developmental hemostasis to hemorrhagic disorders of newborns.
        Semin. Perinatol. 1997; 21: 70-85
        • Ronden J.E
        • Groenen van Dooren M.M
        • Hornstra G
        • Vermeer C
        Modulation of arterial thrombosis tendency in rats by vitamin K and its side chains.
        Atherosclerosis. 1997; 11: 61-67