Vitamin K2 and Bone Quality

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Vitamins & Trace Elements
Sato, Vitam Trace Elem 2012, S6
DOI: 10.4172/2167-0390.S6-001
Rev iew Arti cle Open Access
Vitam Trace Elem Role of Vitamin and Trace Elements in Bone ISSN: 2167-0390 VTE, an open access journal
Vitamin K2 and Bone Quality
Toshiro Sato*
Fine Chemical Laboratory, Nakashinden, Fukuroi-city, Shizuoka, Japan
Abstract
Vitamin K is a cofactor required for post-translational gamma-carboxylation of vitamin K-dependent proteins,
including coagulation and anti-coagulation factors; osteocalcin (OC), essential for bone metabolism; and matrix
Gla proteins (MGP), an inhibitor of artery calcication. In addition to activation of OC, vitamin K2 induces collagen
accumulation in the bone matrix. The principle effects of vitamin K on bone health are not to increase bone mineral
density but to promote bone quality and bone strength. Vitamin K2, as menaquinone-7 (MK-7), is the only major vitamin
K homolog which can activate OC at nutritional doses. The higher efcacy of MK-7 is due to its better bioavailability
and longer half-life compared to other vitamin K homologs. Furthermore, a normal nutritional intake of MK-7 has been
shown to activate MGP, which inhibit artery calcication, and has been associated with prevention of cardiovascular
diseases. Thus, MK-7 is thought to contribute to calcium homeostasis in arteries as well as bones.
*Corresponding author: Toshiro Sato, Fine Chemical Laboratory, Nakashinden,
Fukuroi-city, Shizuoka, Japan, E-mail: toshiro.sato@j-oil.com
Received February 09, 2013; Accepted February 11, 2013; Published February
28, 2013
Citation: Sato T (2013) Vitamin K2 and Bone Quality. Vitam Trace Elem S6: 001.
doi:10.4172/2167-0390.S6-001
Copyright: © 2013 Sato T. This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Introduction
Vitamin K acts as a cofactor for the endoplasmic enzyme γ-glutamyl
carboxylase, during post-translational conversion of glutamic acid
residues to γ-carboxyglutamic acid (Gla) in specic proteins. ese
proteins are referred to as vitamin K-dependent proteins, and include
several blood coagulation factors and anti-coagulation factors, which
are synthesized in the liver; Osteocalcin(OC), a bone-specic protein
synthesized by osteoblasts; and Matrix Gla Protein (MGP), which is
synthesized in several organs. Recently, considerable attention has been
directed towards these vitamin K-dependent Gla proteins; their role
in bone metabolism; and their inhibitory eect on artery calcication.
e current average intake of vitamin K from a normal diet in healthy
adults is greater than that required for normal blood coagulation, but is
insucient for extra hepatic tissue requirements [1,2].
Vitamin K2 has been found to be highly eective in bone
metabolism compared to vitamin K1. In Japan, a high dose of vitamin
K2 (45 mg/day), as menaquinone-4 (MK-4), is used as therapeutic
treatment for osteoporosis. e principle eect of vitamin K2 on
osteoporosis is prevention of bone fracture by improving bone quality,
and not increasing bone mineral density. Recently, attention has been
directed towards another vitamin K2 homolog; menaquinone-7 (MK-
7) extracted from Bacillus subtilis natto. is has been found to be
highly eective in carboxylation of osteocalcin at nutritional doses. is
review focuses on the eects of vitamin K2 as MK-7 on bone quality.
Structure of Vitamin K and its Distribution in Foods
ere are two naturally occurring forms of vitamin K: vitamin
K1 (phylloquinone), derived from green plants; and vitamin
K2 (menaquinones, MK-n), which are a series of vitamers with
multi-isoprene units at position 3 of the common 2-methyl-1,4-
naphthoquinone ring structure.
In food, vitamin K1 is bound to the chloroplast membrane of
leafy green vegetables; whereas, MK-4 is found in animal products,
such as eggs, meat, and liver. MK-4 is derived from menadione (a
synthetic analog of vitamin K, consisting only of the 2-methyl-1,4-
naphthoquinone ring structure), which is given to animals as a feed
additive nutrient and converted to MK-4 in animal tissues. Long chain
menaquinones (e.g., MK-7, MK-8, and MK-9) are found in fermented
foods such as cheese, curd, and sauerkraut [3]. e Japanese fermented
food “natto” contains MK-7 at an exceptionally high concentration
[3]. Vitamin K1, MK-4, and MK-7 are currently used as nutritional
supplements and by the food industry (Figure 1).
Osteocalcin and Vitamin K
OC is produced by osteoblasts and forms bone matrix. Fully-
carboxylated OC binds to calcium and shows anity for hydroxyl
apatite in bone [4]. e exact function of OC in bone is unclear, but
is thought to be involved in calcium modulation. e rst study using
OC-knockout mice found that bone formation was accelerated in the
knockout mice [5]; in contrast, bone structure turned fragile in OC-
knockout mice aer ovariectomy treatment [6]. is suggested that OC
is important for bone maturation and bone quality.
OC has been used as a biomarker for bone metabolism: deciency
in vitamin K, elevates serum undercarboxylated OC (ucOC) levels;
and high serum ucOC has been associated with hip fracture [7,8], and
has been recognized as independent risk factor of fracture. In Japan,
serum ucOC has been used as diagnostic marker to evaluate vitamin K
deciency in bone, since 2007.
Bone Quality and Vitamin K2
Murasawa et al. [9] conducted a study on ovariectomized rats
fed with MK-7 (30 mg/kg bw per day) for 5 months. ey observed
O
O
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
K1
O
O
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
MK-4
MK-７
O
O
CH3
CH3CH3CH3CH3CH3CH3
CH3
CH3
Figure 1: Structure of vitamin K1, menaquinone-4, and menaquinone-7.

Citation: Sato T (2013) Vitamin K2 and Bone Quality. Vitam Trace Elem S6: 001. doi:10.4172/2167-0390.S6-001
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Vitam Trace Elem Role of Vitamin and Trace Elements in Bone ISSN: 2167-0390 VTE, an open access journal
a signicant reduction in the bone mineral density of femurs in
ovariectomized rats compared to sham-operated rats. MK-7 was
modestly protective against this decrease (Figure 2); but markedly
improved bone strength. erefore, the benets of MK-7 on bone
strength were thought to be by maintaining and improving bone
quality, and not by increasing bone mineral density.
A clinical study on post-menopausal women treated with MK-4
(45 mg/day) for 3 years, exhibited no eect on bone mineral density; in
contrast, its eects on the maintenance of bone mass and bone quality
indices of the femur were signicant over the 3 year period [10]. Other
intervention studies on vitamin K1 (5 mg/day; duration: 2 or 4 years)
also found that vitamin K1 had no eect on bone mineral density, but
signicantly decreased the fracture rates [11].
Another possible mechanism by which vitamin K maintains and
improves bone quality has been suggested. In addition to carboxylation
and activation of OC, MK-4 may also increase collagen accumulation
[12]. We conrmed this nding by showing that MK-7 increased
collagen production through osteoblastic cells (Figure 3). Collagen
occupies more than half the volume of bone and makes the foundations
on which calcium and other minerals accumulate; and collagen
accumulation contributes to bone exibility and elasticity. erefore,
along with calcium and other minerals, collagen accumulation is
critically important for high quality bone formation.
MK-7 has been reported to activate bone formation by osteoblastic
cells [13], and suppress bone resorption [14]. e mechanism
was recently demonstrated, and showed that MK-7 stimulates
osteoblastogenesis and suppresses osteoclastogenesis by inhibiting NF-
κB activation [15].
In addition to OC, many vitamin K-dependent proteins, such as
MGP; protein S [16]; and periostin [17], are contained within the bone
matrix; therefore, vitamin K-dependent proteins are thought to have,
unknown functions in bone until now.
Observational studies of vitamin K intake and many observational
studies on the relationship between bone metabolism, bone fracture,
and vitamin K intake have been reported: MK-7 intakes from natto
were inversely associated with bone fracture rates in Japan [18,19];
high serum ucOC was associated with hip fracture [7,8]; and serum
vitamin K levels were inversely associated with hip fracture rates [20].
Furthermore, serum vitamin K levels and ucOC levels were inversely
associated [21]. ese ndings clearly showed the close correlation
between carboxylation of OC by vitamin K and fracture rates.
erefore, it is believed that an increased nutritional intake of vitamin
K could reduce the risk of osteoporosis.
Vitamin K2 for Children
It is widely recognized that increasing peak bone mass before 20-30
years of age is very important for the prevention of osteoporosis, since
bone mass gradually decreases with age. However, decreasing bone
mass in children has been reported [22]. Bone metabolism is highly
active in children, serum OC and ucOC levels are also extremely high
compared to adults [23]. Furthermore, serum ucOC levels in children
and bone health indices are inversely correlated [24,25]; and 45 μg of
MK-7 has been shown to activate OC in children [26]. erefore, it is
expected that a sucient intake of vitamin K may contribute children’s
bone health.
Calcium Paradox and Vitamin K2
Ectopic artery calcication is frequently accompanied by
osteoporosis in patients. is contradictory association is known
as the “Calcium Paradox” or “Calcication Paradox” [27]. Vascular
calcication is associated with increased cardiovascular mortality
and morbidity [28,29], and is recognized as an independent risk
factor for cardiovascular death [30]. A vitamin K-dependent protein,
MGP, is a strong inhibitor of vascular calcication [31,32], and
an intake of vitamin K, sucient to fully activate MGP, is thought
to prevent ectopic artery calcication. Two large epidemiological
studies have shown inverse associations between vitamin K2 intake
and cardiovascular death and/or disease [33,34]. Long chain vitamin
K2 such as MK-7 mainly contributed to the result, while vitamin K1
showed no associations. Another study has also shown an inverse
relationship between vitamin K2 intake and artery calcication [35].
e dierence between vitamin K1 and K2 are due to dierences in
their bioavailability and cofactor activity. Recently, nutritional intake
of MK-7 has been found to activate MGP [36,37]. us, it is expected
that MK-7 may have therapeutic functions that contribute to both
artery health and bone metabolism, and may solve the symptoms of
“Calcium Paradox” [27].
Recent studies indicated that calcium supplements may increase
cardiovascular rates [38,39]; it was concluded that this potentially
detrimental eect on cardiovascular health needs to be balanced
against the probable benets of calcium on bone health [38]. It
is widely recognized that calcium alone is not sucient for bone
health; therefore, other minerals, such as magnesium and vitamin D,
are normally added. Vitamin K, through two vitamin K-dependent
proteins; OC and MGP, has an essential role in modulating calcium
骨密度 骨強度
300
400
500
600
700
Sham O VX O VX + MK -7
骨密度 (m g/cm3
）
p
< 0.05
100
79 82
p
< 0.00 1
5
6
7
8
9
10
11
12
13
14
Sham O VX O VX + MK -7
骨強度 (kgf）
p
< 0.00 1
100
94
107
Bone mineral density (mg/cm3)
Bone strength ( kgf )
Bone mineral density Bone strength
Figure 2: Effect of menaquinone-7 on the femurs of ovariectomized rats.
MK-7 (30 mg/kg bw) was fed to rats for 5 months. Data is expressed as mean
± SEM; n=10 rats. Sham: sham-operated group; OVX: ovariectomized rats
control group; OVX+MK-7: ovariectomized rats fed with MK-7 [9].
*
35.0
36.0
37.0
38.0
39.0
40.0
41.0
42.0
43.0
44.0
45.0
control MK4（10μM）MK7（10μM）
Collagen content (μg/well)
*: Signicantly different (P<0.05).
Figure 3: Effect of vitamin K2 on collagen accumulation in vitro. MK-4 (10
μM) or MK-7 (10 μM) was added to osteoblastic MG63 cells. The cells were
cultured for 10 days; and collagen levels in culture were determined by ELISA.
Data is expressed as mean ± SEM; n=4 cultures.

Citation: Sato T (2013) Vitamin K2 and Bone Quality. Vitam Trace Elem S6: 001. doi:10.4172/2167-0390.S6-001
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Vitam Trace Elem Role of Vitamin and Trace Elements in Bone ISSN: 2167-0390 VTE, an open access journal
homeostasis. As such, vitamin K2 should be recommended as an
addition to calcium supplements.
Nutritional Features of Menaquinone-7
e eect of long chain vitamin K2, such as MK-7, on normal
blood coagulation in rats was found to be higher and long lasting,
than vitamin K1 and MK-4 [40,41]. A human study demonstrated that
MK-7 derived from natto has a very long half-life time in the serum,
and induced more complete carboxylation of OC compared to vitamin
K1 [2]. It was also demonstrated that a high dose of MK-4 has a very
short-half life in humans [42]. Our study found that a nutritional dose
of MK-4 (420 μg) was not absorbed; whereas, MK-7 was absorbed well
in healthy women (Figure 4) [43]. e minimum dose of 1500 μg/day
of MK-4 is required to activate OC in healthy subjects [44]; in contrast,
45-150 μg MK-7 was able to activate OC in healthy subjects [2,26,45].
Because all vitamin K homologs are converted to MK-4 in
organs, MK-4 has been thought to have specic functions, other than
γ-carboxylation of vitamin K-dependent proteins [46,47]. However,
our previous rat study [48] found that an adequate nutritional intake of
MK-4 did not increase the MK-4 levels in extrahepatic organs; whereas,
MK-7 increased MK-4 signicantly in organs, such as the femur, brain,
testis, kidney, and pancreas, indicating that MK-7 is better than MK-4
as an MK-4 precursor in vivo (Figure 5).
0
2
4
6
8
10
12
0 24 48 72
h after administration
Serum vitamin K2level (ng/ml)
Figure 4: Change in serum vitamin K2 levels following a single oral dose (420 μg) of MK-4 or MK-7. Each point represents the mean ± SEM of 5 subjects, at 0, 2, 4,
6, 10, 24, 48, and 72 h. ■=MK-4; ○=MK-7 [43].
0
40
80
120
160
K-
deficient
MK-4 diet MK-7 diet M K-4 diet MK-7 diet
MK-4 level （pmol/g）
1.11nmol/g diet
a
b
a
ab
c
3.33nmol/g diet
0
30
60
90
120
150
K-
deficient
MK-4 diet MK-7 diet MK-4 diet MK-7diet
MK-4 level（pmol/g）
1.1 nmol/g diet 3.3 nmol/g diet
ab
bc
c
d
a
0
20
40
60
80
K-
deficient
MK-4 diet MK-7 diet MK-4 diet MK -7diet
MK-4 level（pmol/g)
1.11nmol/g diet 3.33nmol/g diet
a
a
bb
c
0
60
120
180
240
300
K-
deficient
MK-4diet MK-7 diet MK-4 diet MK-7 diet
MK-4 level（pmol/g）
1.11nmol/g diet 3.33nmol/g diet
aaa
b
c
Figure 5: Menaquinone-4 levels in extrahepatic tissues after administration of menaquinone-4 or menaquinone-7 in rats. Rats were fed with an adequate vitamin
K diet (1.1 nmol/kg; required dose for normal coagulation for rats); or a high vitamin K diet (3.3 nmol/kg), for 21 days. Menaquinone-4 levels were determined in (A)
brain; (B) kidney; (C) femur; and (D) testis. Data is expressed as mean ± SEM; n=5 rats. Values with different superscript letters are signicantly different (P<0.05) [48].

Citation: Sato T (2013) Vitamin K2 and Bone Quality. Vitam Trace Elem S6: 001. doi:10.4172/2167-0390.S6-001
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Vitam Trace Elem Role of Vitamin and Trace Elements in Bone ISSN: 2167-0390 VTE, an open access journal
MK-4 appears to be the logical choice for the pharmacological use of
vitamin K (at high dose; 45 mg/day) for the treatment for osteoporosis.
e long half-life and better bioavailability of MK-7 would mean that
a regular intake of physiological or nutritional doses of MK-7 (50-150
μg/day) would lead to the accumulation of vitamin K2 in extrahepatic
tissues, at levels that could only be achieved by MK-4 at much higher
doses.
Conclusion
e principle eects of vitamin K on bone health are to maintain
and promote bone quality, and not to increase bone mineral density.
Possibly the mechanisms may be activating osteocalcin, increasing
collagen matrix, and regulating dierentiation of osteoblasts and
osteoclasts. Among the vitamin K homologs, MK-7 shows highest
activity and bioavailability in humans. erefore, it is believed
that MK-7 at nutritional doses will promote bone health. A larger
intervention trial for MK-7 is justied.
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Thisarticlewasoriginallypublishedinaspecialissue,Role of Vitamin and
Trace Elements in BonehandledbyEditor(s).Prof.MasayoshiYamaguchi,
BaylorCollegeofMedicine,USA
Citation: Sato T (2013) Vitamin K2 and Bone Quality. Vitam Trace Elem S6:
001. doi:10.4172/2167-0390.S6-001