Applied nutritional investigationJapanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk
Introduction
Vitamin K was discovered as an antihemorrhagic factor capable of curing a tendency for bleeding.1 It is now known to be an essential cofactor for posttranslational modification of glutamic acid (Glu) residues to γ-carboxyglutamic acid (Gla) residues.2, 3 Gla-containing protein and vitamin K-dependent carboxylase activity are located not only in the liver but also in various tissues including kidney, bone, spleen, placenta, and vascular tissue.4, 5 The conception of the biological role of vitamin K in humans has changed from that of a rather specific function in the synthesis of hepatic blood-coagulation proteins to the notion that vitamin K plays a more diverse role in extrahepatic tissues as well.6 Several lines of evidence indicate an important role for vitamin K in bone health.7, 8, 9 1) Three vitamin K-dependent proteins, osteocalcin (bone Gla protein), matrix Gla protein, and protein-S, have been identified as bone-matrix components produced by osteoblasts10, 11, 12; 2) The administration of vitamin K results in an increase in bone-mineral density and a reduction in bone resorption in humans13, 14, 15, 16, 17 and rodents18, 19, 20, 21, 22, 23, 24; 3) Treatment with oral anticoagulants, which inhibit vitamin K-dependent γ-carboxylation, are associated with a decrease in bone-mineral density,24, 25, 26, 27, 28 although there are some discrepancies in the literature with regard to the effects of anticoagulant-induced and diet-induced vitamin K deficiency on bone-mineral density and fracture risk29, 30, 31; and, 4) Low circulating levels of vitamin K are associated with high incidence of femoral neck and vertebral fractures32, 33, 34, 35 and low bone-mineral density.36, 37 The importance of vitamin K in bone metabolism is further supported by in vitro studies showing that vitamin K inhibits osteoclastic bone resorption and upregulates osteoblastic bone formation.38, 39, 40, 41
In the absence of aggravating factors such as antibiotic administration and parenteral feeding, vitamin K deficiency has been believed to be rare except in newborn babies. However, subclinical vitamin K deficiency in extrahepatic tissues, particularly in bone, has recently become an issue of investigation. Subclinical vitamin K deficiency in bone is characterized by undercarboxylated osteocalcin. High concentrations of circulating undercarboxylated osteocalcin are associated with low bone-mineral density42, 43 and increased risk of femoral neck fracture.44, 45, 46, 47 Elevated undercarboxylated osteocalcin was corrected or ameliorated by vitamin K supplementation.48, 49 Epidemiologic studies have also shown a higher risk of femoral neck fracture in women with low intake of vitamin K.50 This accumulated evidence indicates that a greater amount of vitamin K may be required for the prevention of vitamin K deficiency in bone tissue than is needed for blood coagulation.
In nature, there are two major forms of vitamin K: vitamin K1 (phylloquinone; PK), which is produced by plants and algae, and vitamin K2 (menaquinones; MKs), which is of microbial origin and comprises a family of molecules distinguished from PK by unsaturated side chains of isoprenoid units varying in length from 1 to 14 repeats.51 The major dietary form of vitamin K has been considered to be PK, whose major source is green and leafy vegetables.6, 52 In contrast, MKs are found in fermented food and in the colon, where they are synthesized by the intestinal microflora.53
However, little is known about vitamin K status in humans, in particular MKs. To our knowledge, only 10 studies have reported the circulating level of MKs in human adults.33, 34, 35, 36, 37, 54, 55, 56, 57, 58 There is a large interlaboratory difference in menaquinone-7 (MK-7) level in these studies; much higher MK-7 levels have been reported in studies done in eastern Japan than in western Japan and Europe (Table I). These discrepancies have received little scientific attention. Therefore, we measured samples from the geographically different areas at the same laboratory to rule out methodologic variations derived from tests carried out in different laboratories.
Fermented soybeans, referred to as natto, contain a large amount of MK-7 and is a traditional food in eastern Japan.59, 60 Natto is produced by growing Bacillus natto, a subspecies of Bacillus subtilis, on the surface of cooked soybean. During this process, MK-7 is synthesized and secreted by the bacteria.59, 60 Both natto and MK-7 prevent bone loss after ovariectomy in rats.24
Osteoporosis is characterized by reduced bone mass and microarchitectural damage. This disease is common in postmenopausal women. The first and second nationwide surveys of femoral neck fracture performed in 198761 and 1992,62 respectively, showed significant regional differences. A substantially higher incidence of fractures was found in women living in western Japan as opposed to eastern Japan. However, no hypothesis explaining this regional difference in fracture incidence has been proposed. The people of western Japan seldom eat natto, but natto is very popular in eastern Japan. This nutritional difference prompted us to investigate the influence of natto consumption on serum vitamin K levels and to analyze the relation between regional intake of natto and the incidence of hip fractures in Japanese women.
Section snippets
Subjects
The study population consisted of three groups of postmenopausal women who gave informed consent. The first group comprised 49 Japanese women living in Tokyo (aged 50–84 y). The second group comprised 25 Japanese women living in Hiroshima (aged 51–66 y). Tokyo and Hiroshima are located in the eastern and western parts of Japan, respectively. All Japanese women were asked about the frequency of natto intake. The third group consisted of 31 British women living in London or the Nottingham area
Circulating Levels of Vitamin K in Postmenopausal Women in Tokyo, Hiroshima, and the United Kingdom
As shown in Table II, a large difference was observed in serum MK-7 concentrations among these three areas. Serum MK-7 was the highest in Tokyo, followed by that in Hiroshima, and was the lowest in the United Kingdom. In contrast, serum PK concentration in the United Kingdom was slightly but significantly lower than that in Tokyo or in Hiroshima, whereas there was no difference between Tokyo and Hiroshima.
The study population of Tokyo was significantly older than those in the United Kingdom
Discussion
This is the first report demonstrating a large geographic difference in circulating MK-7 levels, both internationally and domestically in Japan. Serum MK-7 levels were highest in Japanese postmenopausal women in Tokyo and lowest in British women (Table II). The result of the present study is similar to data from different laboratories shown in Table I.
The present study demonstrates that natto intake is one of the major contributors to the higher serum MK-7 concentration in Tokyo. Sustained
Summary
In conclusion, these data suggest that the large geographic difference in circulating MK-7 levels may be attributable to the intake of natto, a Japanese fermented soybean food, and support the proposal of a link between natto intake and low fracture risk in postmenopausal women in Japan.
References (69)
- et al.
Review articlemolecular basis of vitamin K-dependent g-carboxylation
Blood
(1990) Vitamin K metabolism and nutriture
Blood Rev
(1992)Improved functional endpoints for use in vitamin K assessmentimportant implications for bone disease
Am J Clin Nutr
(1997)Vitamin K-dependent formation of bone gla protein (osteocalcin) and its function
Vitam Horm
(1985)- et al.
Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients
Bone
(1998) - et al.
A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal womena comparative study with vitamin D3 and estrogen-progestin therapy
Maturitas
(1999) - et al.
Effects of menatetrenone on the decrease in calcium balance induced by vitamin K-deficient diet and sodium loading in rats
Jpn J Pharmacol
(1994) - et al.
Vitamin K and maintenance of skeletal integrity in adults
Am J Med
(1993) - et al.
Depressed levels of circulating menaquinones in patients with osteoporotic fractures of the spine and femoral neck
Bone
(1991) - et al.
Serum vitamin K level and bone mineral density in post-menopausal women
Int J Gynaecol Obstet
(1997)
Decreased circulating levels of vitamin K and 25-hydroxyvitamin D in osteopenic elderly men
Metabolism
Vitamin K2 inhibits osteoclastic bone resorption by inducing osteoclast apoptosis
Biochem Biophys Res Commun
Bone health of adult hemodialysis patients is related to vitamin K status
Kidney Int
Carboxylation of osteocalcin in post-menopausal osteoporotic women following vitamin K and D supplementation
Bone
Vitamin K intake and hip fractures in womena prospective study
Am J Clin Nutr
Vitamin K and human nutrition
J Am Diet Assoc
Distribution of K vitamins (phylloquinone and menaquinones) in human placenta and maternal and umbilical cord plasma
Am J Obstet Gynecol
Phylloquinone transport and its influence on g-carboxyglutamate residues of osteocalcin in patients on maintenance hemodialysis
Am J Clin Nutr
Quantification of genistein and genistin in soybeans and soybean products
Food Chem Toxicol
Role of soy protein with normal or reduced isoflavone content in reversing bone loss induced by ovarian hormone deficiency in rats
Am J Clin Nut
Antihaemorrhagic vitamin of the chic. Occurrence and chemical nature
Nature
Review articleg-carboxyglutamate-containing proteins and vitamin K-dependent carboxylase
Biochem J
Pathophysiology of vitamin K-deficiency and oral anticoagulants
Thromb Haemost
The roles of vitamins D and K in bone health and osteoporosis prevention
Proc Nutr Soc
Vitamin K and metabolic bone disease
J Clin Pathol
Osteocalcin and matrix gla proteinvitamin K-dependent proteins in bone
Physiol Rev
Protein-S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts
Endocrinology
Improved bone metabolism in female elite athletes after vitamin K supplementation
Int J Sports Med
Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide
J Clin Endocrinol Metab
Effects of menatetrenone on bone loss induced by ovariectomy in rats
Jpn J Pharmacol
Effects of menatetrenone on prednisolone-induced bone loss in rats
Bone
Effect of vitamin K2 (menaquinone-7) on bone metabolism in the femoral-metaphyseal tissues of normal and skeletal-unloaded rats: enhancement with zinc
Res Exp Med (Berl)
Cited by (198)
Fermented soybean foods: A review of their functional components, mechanism of action and factors influencing their health benefits
2022, Food Research InternationalVitamin K and cardiovascular complications in chronic kidney disease patients
2021, Kidney InternationalCitation Excerpt :More recently, a prospective study in Japanese women followed up for 3 to 4 years also confirmed an association between low vitamin K concentrations and increased incidence of vertebral fractures.95 Vice versa, in the Japanese diet, where natto is popular, MK7 is the predominantly ingested subform; and high natto consumption correlated with a lower fracture risk.96 Finally, a meta-analysis of 21 articles, including 222,592 participants, found that higher dietary vitamin K consumption was associated with a moderately lower risk of coronary heart disease.97
The impact of gut bacteria producing long chain homologs of vitamin K<inf>2</inf> on colorectal carcinogenesis
2023, Cancer Cell International