Research & Case History Support

Blood 2007 Apr 15;109(8):3279-83. Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.
Schugers LJ, et alM
Vita K & Cardiovascular Research Institute Maastricht, University of Maastricht, 6200 MD Maastricht, The Netherlands.
Vitamin K is a cofactor in the production of osteocalcin (in bone), and matrix Gla protein (cartilage and vessel wall). Accumulating evidence suggests that for optimal bone and vascular health, relatively high intakes of vitamin K are needed. The synthetic vitamin K(1) is commonly used in food supplements, but recently the natural long-chain menaquinone-7 (MK-7) has become available as an over-the-counter (OTC) supplement. The purpose of this paper was to compare the absorption and efficacy of K(1) and MK-7 in healthy volunteers.
A major difference between the 2 vitamin K species is the very long half-life time of MK-7, resulting in much more stable blood levels, and accumulation of MK-7 to higher levels (7- to 8-fold) during prolonged intake. MK-7 induced more complete carboxylation of osteocalcin.
PMID: 17158229

Clin Calcium 2006 Sep;16(9):1526-34.
Protective effects of vitamin K against osteoporosis and its pleiotropic actions
Kaneki M.
Harvard Medical School, Massachusetts General Hospital, Department of Anesthesia & Critical Care.MBR< Recently, vitamin K has emerged as a potential protector against osteoporosis and liver cancer (hepatocarcinoma). Accumulated evidence indicates that subclinical vitamin K deficiency, particularly in bone, exists widely in the otherwise healthy adult population. Both vitamin K(1) and K(2) have been shown to exert protective effects against osteoporosis. Most of the new biological functions of vitamin K in bone cells are considered to be attributable to promotion of gamma-carboxylation of glutamic acid residues in vitamin K-dependent proteins, which is shared by both vitamins K(1) and K(2). In contrast, vitamin K(2)-specific, gamma-carboxylation-unrelated functions have also been demonstrated. These functions include stimulation of steroid and xenobiotic receptor (SXR)-mediated transcription and anti-oxidant property. Thus, biological differences between vitamins K(1) and K(2), and a potential involvement of gamma-carboxylation-independent actions in the new roles of vitamin K remain open issues.
PMID: 16951479 [PubMed - indexed for MEDLINE]

Nippon Rinsho 2006 Sep;64(9):1639-43
Active vitamin D and vitamin K as therapeutic agents for osteoporosis
Katagiri H.
Department of Orthopaedic Surgery, Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University.
Active vitamin D has been most widely used in Japan for the treatment of osteoporosis. Recent reports suggest that active vitamin D may prevent fracture not only through enhancement of intestinal calcium absorption but also by improving bone quality and/or strength independently of bone mass and by improving neuromuscular function to reduce the number of falls. Low serum concentrations of vitamin K have been reported in patients with osteoporosis, and serum osteocalcin appears to be undercarboxylated in these individuals, a process dependent on vitamin K.
PMID: 16972672

Gynecol Endrocrinol 2006 Aug;22(8):455-9.
Effect of vitamin K2 treatment on carboxylation of osteocalcin in early postmenopausal women.
Yasui T, et al
Department of Obstetrics and Gynecology, School of Medicine, University of Tokushima, Tokushima, Japan. yasui@clin.med.tokushima-u.ac.jp
OBJECTIVE: We examined the serum level of undercarboxylated osteocalcin (uc OC), which is a sensitive marker of vitamin K status, and levels of bone turnover markers in early postmenopausal women receiving vitamin K2 treatment with or without vitamin D3. METHODS: Thirty-four postmenopausal women with a mean age of 53 years whose bone mineral density (BMD) was less than 0.809 g/cm2 (osteopenia and osteoporosis) were treated with vitamin K2 or with a combination of vitamin K2 and vitamin D3. Seventeen women received daily oral administration of 45 mg vitamin K2 and 17 women received daily oral administration of 45 mg vitamin K2 plus 0.75 microg 1alpha-hydroxyvitamin D3. Serum levels of uc OC, intact osteocalcin (OC) and bone alkaline phosphatase (BAP), urinary deoxypyridinoline (DPD) levels and BMD at the lumbar spine were measured before and at 1 and 2 years after the start of treatment. RESULTS: Serum undercoboxylated osteocalcin levels in women treated with vitamin K2 alone and with both vitamin K2 and vitamin D3 decreased significantly. Serum levels of intact osteocalcin and bone alkaline phosphatase (BAP) in women treated with vitamin K2 did not show significant changes, while those in women who received vitamin K2 and vitamin D3 together decreased significantly . On the other hand, urinary DPD level in women treated with vitamin K2 did not change, while that in women who received the combined treatment tended to decrease (p < 0.1). CONCLUSION: Serum uc OC levels in early postmenopausal women who received vitamin K2 decreased due to carboxylation of uc OC. Combined treatment with vitamin K2 and vitamin D3 may be effective for sustaining BMD in early postmenopausal women whose bone turnovers are highly activated.
PMID: 17012108

Clin Calcium 2005 Jul;15(7):57-61.
The interplay of magnesium and vitamin K2 on bone mineralization
Amikuka N, et al
Divisions of Oral Anatomy, Niigata University Graduate School of Medical and Dental Sciences Center for Transdisciplinary Research, Niigata University, Niigata, Japan.
Magnesium (Mg) is most likely restored in bone matrix, implicating a pivotal role in bone mineralization. Mg-insufficient bone reveals fragility to mechanical loading despite normal or higher levels of bone mineral content, permitting stimulated osteoclastic bone resorption. In contrast, vitamin K(2) inhibited osteoclastic bone resorption stimulated by the Mg-insufficiency, thereby normalizing bone remodeling. The Mg-insufficiency caused an increased concentration of calcium, which resulted in an extremely-high purity of hydroxyapatite (HA) crystal and accelerated mineralization in bone. In contrast, Vitamin K2 did not affect the calcium-concentration nor HA-purity, but repressed mineralization accelerated by Mg-insufficiency. Thus, vitamin K2 appears to recover the "bone quality" lessened by the Mg-insufficiency by two mechanisms:controlling bone turnover and mineralization.
PMID: 15995297

Intl J Mol Med 2005 Feb;15(2):231-6.
Menaquinone-7 regulates the expressions of osteocalcin, OPG, RANKL and RANK in osteoblastic MC3T3E1 cells.
Department of Public Health, Kawasaki Medical School, Kurashiki 701-0192, Japan. katsu@med.kawasaki-m.ac.jp
Epidemiological studies show that dietary intake of natto, which contains significant amount of vitamin K(2), reduces the risk of bone formation loss. However, many confounding factors, such as calcium and isoflavone, are found in natto, because it is made from soybeans. In this study, the direct effects of MK-7, a vitamin K(2) analogue, were assessed in osteoblasts. Osteoblastic MC3T3E1 cells were cultured with or without MK-7 for 10 days and the number of cells was calculated. The cell count was not different between MK-7 treated cells and control cells for 1, 2, and 4 days. However, it was significantly suppressed in MK-7 treated cells at 10 days, suggesting that MK-7 suppressed cell proliferation. Real-time PCR analysis showed that mRNAs of osteocalcin (OC), osteoprotegerin (OPG), and the receptor activator of the NFkappaB ligand (RANKL) were induced after MK-7 administration to the culture medium. RANK mRNA expression was also enhanced by MK-7 administration. Immunocytochemical analysis showed that MK-7 increased the protein levels of OC and RANKL. These observations suggest that MK-7 may directly affect MC3T3E1 cells and stimulate osteoblastic differentiation, not proliferation.
PMID: 15647836

Biofactors 2004;22(1-4):5-19. Studies on action of menaquinone-7 in regulation of bone metabolism and its preventive role of osteoporosis.
Tsukamoto Y..
Central Research Institute, Mizkan Group Corporation, 2-6 Nakamura-Cho, Handa-Shi, Aichi, Japan. ytsukamoto@mizkan.co.jp
The effect of menaquinone-7 (MK-7) on bone components and bone resorbing factors induced-bone resorption using the femoral-diaphyseal and - metaphyseal tissues obtained from elderly female rats in vitro were examined. Calcium content, alkaline phosphatase activity and deoxyribonucleic acid (DNA) in the diaphyseal and metaphyseal tissues in elderly females rats were significantly decreased as compared with that of young rats, indicating that aging causes a deterioration of bone formation. The presence of MK-7 (10(-6)-10(-5) M) caused a significant prevention of reduction of biochemical components. On the other hand, the bone-resorbing factor, parathyroid hormone (1-34) (PTH; 10(-7) M) and prostaglandin E(2) (PGE(2); 10(-5) M) caused a significant decrease in calcium content in the diaphyseal and metaphyseal tissues. This decreases was completely inhibited in the presence of MK-7 (10(-7)-10(-5) M). In addition, MK-7 (10(-7)-10(-5) M) completely prevented the PTH (10(-7) M) or PGE(2) (10(-5) M) induced increases in medium glucose consumption and lactic acid production by bone tissues, Furthermore, the effect of the prolonged intake of dietary MK-7 on bone loss in ovariectomized rats was investigated. As a result, it was found that the intake of experimental diets containing the fermented soybean (natto) with supplemental MK-7 caused significant elevations of MK-7 and gamma-carboxylated osteocalcin concentration, a bio marker of bone formation, in the serum of both ovariectomized rats and normal subjects, suggesting that MK-7 may play an important role in the prevention of age-related bone loss.
PMID: 15630245