|
 |
 |
| |
| Vitamin K2 – The Essential Bone Ingredient |
|
| Fragility fractures are an important source of morbidity, mortality, and cost to society. Osteoporosis (Low mineral bone mass density) ultimately leading to fracture is a major health concern in modern societies. |
|
| Sub-optimal vitamin K status is associated with increased risk of fracture. Low vitamin K consumption or impaired vitamin K status is associated with a higher risk of hip fracture among older women and men, lower bone mass in older women and men, and increased bone turnover. The relationship between dietary vitamin K intake and bone status has been investigated in several epidemiologic studies. |
|
| Normal |
 |
|
| |
| Osteoporosis |
 |
|
|
|
| Mechanism of Action: |
|
| Vitamin K is a cofactor in a number of biochemical pathways. The most common of these reactions is the vitamin K dependent carboxylation reaction. Osteocalcin is a bone protein synthesized mainly by osteoblasts; when carboxylated, osteocalcin has the ability to bind calcium to bone thereby promoting mineralization. Gamma- carboxylation of the glutamic acid in Osteocalcin is vitamin K dependent and involves the conversion of glutamic acid residues (Glu) to gamma carboxy glutamic acid residues (Gla). Osteocalcin, when under carboxylated, cannot bind to hydroxyapitate in bone and is thus inactive. Serum levels of osteocalcin are a good biochemical marker of the metabolic turnover of bone; a number of clinical studies have been conducted to investigate the effect of vitamin K administration on the carboxylation of osteocalcin, BMD, and thus fracture rates. Various dosages of both phylloquinone (K1) and menaquinone (K2) used in these clinical trials showed that under carboxylated osteocalcin levels declined significantly with Vitamin K supplementation. |
|
|
|
| Epidemiology |
|
| The Japanese natto (soy) fermented food contains approximately 998 μg of vitamin K2-7 per 100 gms [1]. Typical intake of fermented natto in Japan is approximately 80 gms per day. Kaneki et al [2] report that serum MK-7 concentrations were 5.26 ±6.13 ng/mL (mean ± SD) in the Japanese women in Tokyo, 1.22 ± 1.85 ng/mL in the Japanese women in Hiroshima and 0.37 ± 0.20 ng/mL in the British women. Natto is eaten more frequently in Eastern Japan, Tokyo, but less frequently in Hiroshima and is not at all a food item in Britain. Kaneki et al [2] discovered a statistically significant inverse correlation between incidence of hip fracture, natto consumption and serum MK-7 levels between the three groups. |
|
| In a study of 72,327 women, vitamin K intake was inversely related to the risk of hip fractures [4]. |
|
| Undercarboxylated Osteocalcin(ucOC) vs Carboxylated Osteocalcin(cOC) vs Fracture Rate: |
|
| As mentioned above, epidemiologically, MK-7 concentrations in the serum correlate inversely to the incidence of hip fracture. Tskamoto et al [3], in a prospective study, administered 50 gms of natto per day to three groups. The concentration of MK-7 was either 865, 1295 or 1730 μg of MK-7 per 100 g. General population in Eastern Japan has 100 gms of natto for breakfast at a time. Tsakamoto [3] found that the serum MK-7 concentration and γ-carboxylated osteocalcin concentration were both elevated parallel to the administered level of MK-7. This now with the above epidemiological finding relates MK-7 administered level to hip fracture. |
|
 |
|
|
| Human Studies |
|
| There are several studies relating high prevalence of disease and drug specific osteopenia and osteoporosis relating to vitamin K status. |
|
| Schoon et al [5], in a 32 patient Crohn’s disease study, conclude ucOC inversely associated with bone mineral density. |
|
| Tamatani et al [6] concluded that vitamin K1 and MK-7 were significantly, positively correlated with bone mineral density. |
|
| Kanai et al [7] observed low BMD in women with lower serum vitamin K1 and K2. |
|
| Hodges et al [8] sites that vitamin K2 may be up to 25 times more active than vitamin K1. His study of 29 patients with fracture, 17 controls, concluded that vitamin K1 and K2 were significantly lower in the fracture group than in the control group. |
|
| Takahashi et al [9] carried out a study to determine effect of vitamin K vs. that of vitamin D. They concluded that ucOC decreased significantly in the groups receiving vitamin K (vitamin K only and vitamin K+D); whereas in the vitamin D-only group ucOC did not change significantly. |
|
| Why bone loss is predisposed in microgravity is unknown but the ucOC lowering in the cosmonauts is controlled by vitamin K supplementation [10]. |
|
| Females having strenuous life style are prone to hypoestrogenism and amenorrhoea. As a consequence a low peak bone mass and rapid bone loss is often seen in relatively young athletes. Craciun et al [11] working with 8 female marathon runners observed in all subjects increased vitamin K was associated with an increased calcium-binding capacity of osteocalcin. In the low-estrogen group vitamin K supplementation induced a 15-20% increase of bone formation markers and a parallel 20- 25% decrease of bone resorption markers. This shift is suggestive for an improved balance between bone formation and resorption. |
|
| Sokoll et al [12] show a significant reduction in ucOC with vitamin K supplementation. |
|
| Recent studies (2008) of Tsugawa et al [13] relate a significantly higher incidence of vertebral fracture of 14.4% in the low vitamin K group to 4.2 % in the high vitamin K group. This study involved a cohort of 379 healthy women aged 30-88 years. |
|
| Lucas et al [14] (2006) conclude that premenopausal women show reduced BMD despite normal estrogen profiles. %ucOC may be a specific bone marker of the early postmenopause in healthy women. |
|
| In a randomized, open-label study [15], 241 osteoporotic women were given either 45 mg/day vitamin K2 or 150 mg elemental calcium (treatment group; n=120) or 150 mg elemental calcium (control group; n=121). After two years, vitamin K2 was shown to maintain lumbar BMD. Patients receiving K2 also experienced significantly lower fracture incidence (10% versus 30%, in the treatment and control groups, respectively. |
|
| References |
|
| 1) Schurgers LJ, Vermeer C: Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis 2000, 30(6):298-307. |
|
| 2) Kaneki M, Hedges SJ, Hosoi T, Fujiwara S, Lyons A, Crean SJ, Ishida N, Nakagawa M, Takechi M, Sano Y et al: Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk. Nutrition 2001, 17(4):315-321. |
|
| 3) Tsukamoto Y, Ichise H, Yamaguchi M: Prolonged Intake of Dietary Fermented Soybeans (Natto) with the Reinforced Vitamin K2 (Menaquinone-7) Enhances Circulating ? - Carboxylated Osteocalcin Concentration in Normal Individuals. Journal of Health Science 2000, 46(4):317-321. |
|
| 4) Feskanish D, Weber P, Willet WC et al. Vitamin K intake and hip fractures in women: a prospective study. Am J Clin Nutr. 1999; 69:74-9.
|
|
| 5) Schoon EJ, Muller MC, Vermeer C, Schurgers LJ, Brummer RJ, Stockbrugger RW: Low serum and bone vitamin K status in patients with longstanding Crohn's disease: another pathogenetic factor of osteoporosis in Crohn's disease? Gut 2001, 48(4):473-477. |
|
| 6) Tamatani M, Morimoto S, Nakajima M, Fukuo K, Onishi T, Kitano S, Niinobu T, Ogihara T: Decreased circulating levels of vitamin K and 25-hydroxyvitamin D in osteopenic elderly men. Metabolism 1998, 47(2):195-199. |
|
| 7) Kanai T, Takagi T, Masuhiro K, Nakamura M, Iwata M, Saji F: Serum vitamin K level and bone mineral density in post-menopausal women. Int J Gynaecol Obstet 1997, 56(1):25-30. |
|
| 8) Hodges SJ, Pilkington MJ, Stamp TC, Catterall A, Shearer MJ, Bitensky L, Chayen J: Depressed levels of circulating menaquinones in patients with osteoporotic fractures of the spine and femoral neck. Bone 1991, 12(6):387-389. |
|
| 9) Takahashi M, Naitou K, Ohishi T, Kushida K, Miura M: Effect of vitamin K and/or D on undercarboxylated and intact osteocalcin in osteoporotic patients with vertebral or hip fractures. Clin Endocrinol (Oxf) 2001, 54(2):219-224. |
|
| 10) Caillot-Augusseau A, Vico L, Heer M, Voroviev D, Souberbielle JC, Zitterman A, Alexandre C, Lafage-Proust MH: Space flight is associated with rapid decreases of undercarboxylated osteocalcin and increases of markers of bone resorption without changes in their circadian variation: observations in two cosmonauts. Clin Chem 2000, 46(8 Pt 1):1136-1143. |
|
| 11) Craciun AM, Wolf J, Knapen MH, Brouns F, Vermeer C: Improved bone metabolism in female elite athletes after vitamin K supplementation [In Process Citation]. Int J Sports Med 1998, 19(7):479-484. |
|
| 12) Sokoll LJ, Booth SL, O'Brien ME, Davidson KW, Tsaioun KI, Sadowski JA: Changes in serum osteocalcin, plasma phylloquinone, and urinary gamma- carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects. Am J Clin Nutr 1997, 65(3):779-784. |
|
| 13) Tsugawa N, Shiraki M, Suhara Y, Kamao M, Ozaki R, Tanaka K, Okano T: Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women. J Bone Miner Metab 2008, 26(1):79-85. |
|
| 14) Lukacs JL, Booth S, Kleerekoper M, Ansbacher R, Rock CL, Reame NE: Differential associations for menopause and age in measures of vitamin K, osteocalcin, and bone density: a cross-sectional exploratory study in healthy volunteers. Menopause 2006, 13(5):799-808. |
|
| 15) Shiraki M, Shiraki Y, Aoki C, Miura M. Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res 2000; 15:515-521. |
|
|
|
|
