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Role of Vitamin K2-7 in Osteoporosis:Basic and Applied Aspects

  • Synergia Life Science, Mumbai, India
Role of Vitamin K2-7 in Osteoporosis: Basic and Applied
Dilip Mehta, Ph.D.*
AshokVaidya, M.D., Ph.D**
Chapter in “Post Menopause Osteoporosis book”,
Edited by Dr. Meeta Singh
Jaypee Publishers
* CEO, Viridis BioPharma Pvt Ltd. Mumbai, India, 400 022,
** Research Director, ICMR Advance Center of Reverse Pharmacology in
Traditional Medicine. Medical Research Center – Kasturba Health Society,
Mumbai, India, 400 050,
Role of Vitamin K2-7 in Osteoporosis: Basic
& Applied Aspects
Vitamin K
Vitamin K Analogues:
Mechanism of Action & Vitamin K Cycle:
Safety and Toxicity:
Choice of vitamin K analogue in osteoporosis:
1. Half-Lives:
2. Diet & BioAvailability:
3. Cofactor Activity:
4. Therapeutic Value:
The dosage schedule of vitamin K2-7:
Epidemiology of vitamin K2-7:
Relationship between vitamin k status to undercarboxylated
osteocalcin to bone health
Vitamin K reduces ucOC:
Lower ucOC and Reduced Fracture Rate:
Vitamin K2-7 – A missing link in management of osteoporosis
Role of Vitamin K2-7 in Osteoporosis : Basic and Applied Aspects
Osteoporosis is quite a challenging condition
because of its multifactorial etiology.
Reduced availability of calcium, vitamin D,
estrogen and several micronutrients play a
role in the deterioration of the skeletal bone
mass and its microarchitectural structure.
Several drugs, diseases and microgravity
have also been shown to play a pathogenic
role. Post menopausal osteoporosis is a
major subset due to lack of estrogens
affecting bone density and quality. The role
of vitamins in osteoporosis vis – a – vis
estrogen has been less explored.
From the time that Dam
vitamin K fifty years back attention for this
fat soluble vitamin remained confined to the
coagulation cascade with a thought that the
vitamin K story began and ended with blood
clotting. It is only recently that the role of
vitamin K, mostly vitamin K2-7, is
recognized as a significant prophylactic and
therapeutic agent in the maintenance and
improvement of bone mass and bone quality.
The scope of this review is to delineate the
role of vitamin K and its analogues in bone
health & osteoporosis. Factors that influence
the choice of an analogue will be reviewed.
Osteocalcin (OC), also called bone gla -
protein (BGP), expressed by osteoblasts,
osteocytes and odontoblasts, is a key protein
in building of the bones. OC belongs to a
class of proteins referred to as vitamin K-
dependent (VKD) proteins. It is biologically
inactive when expressed and is called
undercarboxylated osteocalcin (ucOC). Such
Proteins Induced by Vitamin K Absence
(PIVKAs) require vitamin K for their
activation to carboxylated osteocalcin
(cOC). Without vitamin K osteocalcin is not
carboxylated and thus is inactive and cannot
bind to the hydroxyapatite in the bone
[2, 3].
Many studies have reported a
high level of (30% - 40%) plasma ucOC
[4, 5]
in bone and cardiovascular disorders. This is
related to a high fracture rate. Indian
population’s ucOC percentages are not
known. However, these are likely to be
higher in this population as vitamin K2-7 is
low in the Indian dietary items.
Epidemiological studies have related high
vitamin K2-7 intake in the diet to a
significantly low rate of bone fractures and
cardiovascular events
[6, 7]
Matrix Gla Protein (MGP) is another
important VKD protein expressed in matrix
of the cartilage and of the vasculature. MGP
expressed is biologically inactive
uncarboxylated (ucMGP). Low levels of
vitamin K in plasma result in higher ucMGP
and consequently lead to an enhanced
calcification of vasa media and vasa intima.
This is known as calcium paradox wherein
calcium is deposited in the arterial walls
instead in the bones. The calcification of
arterial walls has become an independent
predictor of cardiovascular events and
biological Age
. MGP and OC are present
throughout the body and are accessed by
vitamin K2 present in the plasma. Hence
higher, intake of vitamin K2 activates MGP
in parallel with the activation of OC. The
role of vitamin K2-7 in osteoporosis and
coronary artery disease assumes greater
significance in menopause as estrogen
deficiency in menopause creates metabolic
dysfunction and cardiovascular risks.
Menopause is considered a type of
metabolic syndrome
Diets of most of the populations around the
world lack sufficient intakes of several
micronutrients in the ageing population and
particularly in postmenopausal women. It is
now becoming clear that supplementation of
vitamin K2 is emerging as equally important
to that of vitamin D. The notion that vitamin
K is a coagulation related micronutrient is
dispelled after discovering that vitamin K2
provides the ‘missing link’ between
osteoporosis and Coronary Artery Diseases
(CAD). Current research has emphasized the
need for different analogues of vitamin K in
the diet, or as supplements, because of the
organ specificity of different analogues.
Osteocalcin and MGP, which are extra
hepatic, have a significant percentage
undercarboxylated and they are biologically
. This indicates that there may be
a wide spread deficiency of vitamin K2.
Epidemiological studies have correlated
vitamin K2 intake to osteoporosis and CAD
[7, 11-15]
. A number of studies have shown
direct correlation between vitamin K, ucOC
and the fracture rate
. These are reasons
for an active consideration of
supplementation with vitamin K. Several
fundamental scientific studies reinforce the
aforesaid role of vitamin K in calcium
[5, 8, 30-35]
Vitamin K1 may be considered liver specific
where coagulation cascade VKD proteins
are expressed. Vitamin K1 in the diet may
be sufficient for activating VKD proteins
expressed in the liver but could be
inadequate for the carboxylation needs in
other extra - hepatic tissues. Vitamin K2
transported to the rest of the body, is
essential for carboxylation of the extra
hepatic expression of osteocalcin and matrix
gla protein (MGP).
Dam discovered vitamin K in 1930s with the
observation that chickens on a fat free diet
developed haemorrhages
. He eventually
isolated the active component from alfalfa
and named it vitamin K, from the first letter
of the German word ‘Koagulation’. It was
research group that
characterized it as 2-methyl-3-phytyl-1,4-
naphthoquinone (Fig. 1), with the scientific
name of Phylloquinone or vitamin K1. Both
were awarded, in 1945, Noble Prize for their
work on vitamin K. Deficiency of vitamin
K1 was related to the decreased activity of
prothrombin in plasma leading to
coagulation defect and bleeding.
Administration of vitamin K was shown to
cure bleeding complications in patients with
malabsorption hepatic and biliary diseases
. Later it was discovered that clotting
factors VII, IX and X were also VKD
proteins and called for post-translational
activation. Proteins C, S and Z are part of
the coagulation cascade and are VKD
Vitamin K Analogues: Vitamin K refers to
molecules with vitamin K activity i.e.
Phylloquinone (vitamin K1) and
Menaquinones (vitamin K2). Menaquinones
are also 2-methyl-1,4-naphthaquinones just
as is Phylloquinones but with the side chain
at position 3 composed of a variable number
of unsaturated isoprenyl residues (Fig. 1).
Menaquinones are denoted by MK-n, where
n stands for the number of isoprenoid
residues. Both MK-n and K2-n
nomenclature are interchangeably used in
literature. In other words, MK-4 is also
referred to as K2-4 and in this particular
case in Japan, where it was introduced as a
drug nearly two decades ago, it is called
menatetranone also.
Sources: Vitamin K1is found in the
membranes of the chloroplasts of green
leafy vegetables. Source of K2-4 in diet is
through animal products (meat, dairy, eggs).
Food studies have shown natural occurrence
of K2-4 to K2-10 in fermented foods with
K2-7 to 9 being most common. Table 1
summarizes vitamin K content of common
foods. Eastern Japanese practice of
fermenting soy beans for breakfast yields the
highest level of K2-7 known in any food.
Cheese, soft and hard, is also a good source
of vitamin K2-7 but with the associated
disadvantage of higher lipid consumption.
The mammalian intestinal flora is known to
produce vitamin K2 but there are doubts if it
contributes to the daily need
. However, it
is worthwhile to conduct more critical
studies on the colonic microflora and
vitamin K absorption.
Table 1: Mean of K vitamins (µg/100 g or µg/100 ml) in various foods
Performed, -- : Not Detectable
# Ref
* Unpublished data from Viridis BioPharma lab.
Sr. No. Item K1 K2-4 K2-7
1 Chicken Legs
-- 8.5 (5.8–10.5) --
2 Beef
0.6 (0.6–0.7) 1.1 (0.7–1.3) --
3 Prawn
0.1 (0.0–0.1) -- --
4 Spinach
387 (299–429) -- --
5 Green peas# 36.0 (31.2–39.4) -- --
6 Banana
0.3 (0.2–0.4) -- --
7 Whole milk
0.5 (0.4–0.6) 0.8 (0.7–0.9) --
8 Chocolate
6.6 (6.4–6.7) 1.5 (1.4–1.6) --
9 Hard cheeses
10.4 (9.4–12.1) 4.7 (4.2–6.6) 1.3 (1.1–1.5)
10 Soft cheeses
2.6 (2.4–2.9) 3.7 (3.3–3.9) 1.0 (0.9–1.1)
11 Curd cheese
0.3 (0.2–0.4) 0.4 (0.3–0.6) 0.3 (0.2–0.5)
12 Egg yolk
2.1 (1.9–2.3) 31.4 (29.1–33.5) --
13 Butter
14.9 (13.2–15.9) 15.0 (13.5–15.9) --
14 Natto 34.7 (31.2–36.7) -- 998 (882–1,034)
15 Dosa* -- NP --
16 Dhokla* -- NP --
17 Whole yoghurt*
-- NP --
Mechanism of Action & Vitamin K Cycle:
Vitamin K acts as a cofactor to activate Glu
proteins.VKD proteins mentioned earlier
have in common clusters of glutamic acid
(Glu) residues.
These proteins can participate in the calcium
metabolism if the glutamic acid residues are
carboxylated in the gamma position to
gamma-carboxyglutamic (Gla) acid.
Vitamin K is a cofactor for gamma-glutamyl
carboxylase (GGCX), which is an essential
enzyme for the gamma-carboxylation of
vitamin K-dependent proteins. The activated
form of VKD proteins can now participate in
the homeostasis of the calcium metabolism
(Fig. 3). Carboxylation of VKD proteins by
vitamin K requires the presence of the
reduced form of vitamin K (KH
), molecular
oxygen and carbon dioxide.
This reduced form of vitamin K is a cofactor
in a reaction, catalyzed by a vitamin K-
dependent carboxylase, in which Glu are
modified to Gla. During this reaction KH
converted to K epoxide. The vitamin K
epoxide is cycled back to vitamin K by the
vitamin K epoxide reductase, an enzyme
sensitive to inhibition by coumarin based
anticoagulants. This set of sequential
reactions, recycling vitamin K, is known as
vitamin K cycle. This cycle is highly
conserved in evolution.
Safety and Toxicity: Even with high doses,
such as ~800 mcg of K2-7 in natto breakfast,
the natural forms of vitamin K have not
produced any signs and symptoms of
toxicity in healthy humans. The Institute of
Medicine at the National Academy of
Sciences chose not to set a Tolerable Upper
Limit (UL) for vitamin K when it revised its
public health recommendations for this
vitamin in the year 2000 AD
Vitamin K has generally been
contraindicated for anyone under
anticoagulation treatment. This view is
changing as one moves to a much higher
half-life K2-7 providing a stable serum level
and acting as a buffer to increase the
stability of oral anticoagulation therapy
Many factors play a role in the choice of
vitamin K analogue as a prophylactic and
therapeutic agent for osteoporosis. It is
important to note that K1, K2-4 and K2-7
are the ones found biologically significant,
commercially available and will be
considered here.
1. Half-Lives: Vitamin K’s side chain
influences its half life. The half-life
increases due to increased hydrophobicity
due to the longer side chain. Investigator
have determined the half-life of K1 as 1.5
[39, 43, 44]
, K2-4 as 1 hr
and a half-life
of K2-7 as around 72 hrs
[45, 46]
. Vitamin K1
and K2-4 with shorter half-lives will show a
substantial circulating and tissue
fluctuations. Vitamin K2-7 with a long half-
life of ~3 days will show more stable plasma
and tissue level
2. Diet & Bioavailability: Booth et al
studied the bioavailability (BA) of pure
phylloquinone versus equivalent amount in
crude spinach(1mg). The BA for spinach
was 4% of that with pure phylloquinone.
Adding butter to the spinach increased BA
to 13%. Schurgers et al
, experimentally
studied absorption of K1 from spinach and
absorption of K2-7 from Natto (from
Japanese fermented Soy), one week apart to
exclude mutual interference of absorption,
and also broccoli as source for K1 and curd
cheese and egg yolk as sources for higher
menaquinones (K2-8 and K2-9) and K2-4
respectively. They conclude “In all cases it
was found that K1 absorption from
vegetables was very poor (5–10% without
concomitant fat intake and 10–15% if taken
together with 30 g fat), whereas
menaquinone absorption from dairy
products and natto was much better,
probably almost complete.”
In absolute amounts K1 forms well over
80% of the total amount of vitamin K in the
western diet. However, it must be noted that
due to the difference in bioavailability
absolute absorption of K2 in the system will
be higher. Considering 20% bioavailability
for K1 and 80% bioavailability for K2, the
ratio of K1/K2 absorbed by the body is 1 to
2. This advantage in bioavailability can
impact positively the supply of vitamin K2
towards extra-hepatic tissues.
The absorption curve of vitamin K2-7 in the
human plasma is biphasic. This suggests the
incorporation of vitamin K2 in the
lipoproteins and release by liver after initial
redistribution and deep compartmental
uptake. Hence vitamin K2-7 is steadily
available for carboxylation needs of
osteocalcin and MGP.
3. Cofactor Activity: Experiments, in vitro,
by Buitenhuis et al
have studied the
kinetics of various vitamin K’s cofactor
activity and determined the half-maximal
reaction velocity viz Km. Schurgers
(unpublished data)
has provided in vitro data
of the carboxylation rate for vitamins K1
and K2-7 (Fig. 4). These two studies
demonstrate that at low concentrations
vitamin K2-7 binds stronger to the
carboxylase and drives the reaction of Glu to
Gla more efficiently. Vitamin K2-7 has a
steep and sudden rise in carboxylation rate
and reaches a plateau at around 8µm viz
18µmol/hr. The curve having carboxylation
rate with K1 is much flatter and reaches a
plateau only at 28 µmol.
4. Therapeutic Value: The quantum of
conversion from Glu to Gla defines the
therapeutic value of vitamin K. The value
varies amongst the vitamin K group
analogues. The value is defined by the
complex and less understood interactions of
absorption, distribution compartments,
metabolism and excretion of the diverse
vitamin K forms. Number of vitamin K
cycles can be a measure of therapeutic
value. Current knowledge of therapeutic
value of various vitamin K analogues clearly
point to values as K2-7 > K2-4 > K1. It is
important to note that the therapeutic value
for specific indications will vary based on
the organ availability, putative carboxylation
kinetics and specific needs.
A longer half life of K2-7 (72 hours)
coupled with higher potency on Glu to Gla
conversion could indicate a potential for
higher therapeutic activity; higher than K1
and K2-4. This is actually confirmed in the
Rotterdam study
(n = 4473) by
demonstration of 50% reduction in cardio
mortality and similar reduction in
calcification with a dose of 45 mcg K2 -7/
day for 10 years, whereas there was no
correlation between cardiomortality and
vitamin K1. The University of Masstricht
researchers have clearly demonstrated that
vitamin K2-7 is much more effective in
carboxylation than analogues, vitamins K1
or K2-4
[46, 49]
Hodges et al
cites that vitamin K2 may
be up to 25 times more active than vitamin
K1 the choice with current knowledge is of
vitamin K2-7 for supplementation in post
menopausal osteoporosis and as well as
general for bone building.
Currently the vitamin K2-7 dose is
traditionally at 45 micro gram (mcg) per day
in marketed products whereas vitamin K2-4,
which is used as a drug in Japan, uses as
high a dose of 45, 000 mcg per day. K2-7 as
an ingredient is available in 1000 ppm (parts
per million) format and therefore 45 mg of
K2-7 will provide a dose of 45 mcg of pure
K2-7. This should not be confused with the
45 mg of K2-4.
The practice of 45 mcg daily dose of K2-7
was a consequence of impressive results of
the Rotterdam study where the mortality and
the calcification were found to be 50% less
in the population consuming this dose of
K2-7 daily as opposed to those having 12.5
mcg in their diet. Secondly this dose was
also found to be convenient from the
regulatory perspective of current RDA
(Recommended Dietary Allowances) norms.
Despite that the daily dose of 45 mcg of K2-
7 may still be inadequate in high prevailing
levels of ucOC or ucMGP
The Japanese natto(soy fermented food) 100
gm contains approximately 998 mcg of
vitamin K2-7
. Typical intake of
fermented natto in Japan is approximately
80 gms per day. Kaneki et al
report that
serum K2-7 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 the eastern Japan, viz Tokyo,
but less frequently in Hiroshima and is not at
all a food item in Britain. Kaneki et al
discovered a statistically significant inverse
correlation between incidence of hip
fracture, natto consumption and serum MK-
7 levels amongst the three groups.
Epidemiological population-based
Rotterdam study
examined the correlation
between dietary intakes of vitamin K and
aortic calcification and Coronary Heart
Disease (CHD). Their follow-up of 4473
subjects, with no history of Myocardial
infarction, over a period of 10 years showed
a significant 50% reduction in CHD
mortality and aortic calcification and 25%
reduction in all cause mortality for those
who were in the 45 mcg per day of dietary
intake of vitamin K2-7 in the upper tertile
and 25% reduction in 24 mcg per day mid
tertile compared to the 12.5 mcg per day
lower tertile (Table 2). Such dose-response
relationship in a population was impressive
for the new role of vitamin K2-7. Their
findings did not show any correlation
between vitamin K1 intakes to the CHD
Table 2: Vitamin K2 – 7 vs CHD – Rotterdam Study
Mortality All cause mortality
Average Vitamin
K2-7 daily intake
45 mcg/day
24 mcg/day
12.5 mcg/day
50% reduction 25% reduction
25% reduction Marginal Reduction
Base Base
Average Vitamin
K1 (250 mcg/day)
No Co-relation No Co-relation
Gast study
with a cohort of 16,057
women, aged 49-70 years, free of CHD at
baseline, who were followed for a period of
8.1 years, conclude a 9% reduction in risk of
developing CHD for every 10 mcg of natural
vitamin K2 consumed. The highest average
consumption was >36 mcg K2/day. This
study could not confirm a protective effect
of vitamin K1 for coronary calcification and
CHD similar to the conclusions of
Rotterdam study
, Health Professionals’
Follow-up Study
and Gast groups earlier
. The need for a higher dose of
vitamin K2-7 was obvious.
In a population-based osteoporosis study
(JPOS Study) at the department of public
health in Osaka, Japan, intake of fermented
soybean containing a high level of vitamin
K2-7 was correlated to reduced bone loss in
the postmenopausal women
. The study
cohort was of 944 women over a period of 3
years. It was concluded that the fermented
soybean helps to prevent postmenopausal
bone loss through the bone building effects
of vitamin K2-7. Particularly it was noted
that there was significant positive
association between the intake and in BMD
(Bone Mineral Density) at the femoral neck
and at the distal third of the radius in the
post menopausal women.
There are a number of other studies
supporting the above findings
[11, 13, 14]
Vitamin K is known to maintain bone health
via the gamma-carboxylation of osteocalcin
and similarly suppresses calcification via
gamma-carboxylation of matrix gla protein.
A number of researchers have studied
relation between vitamin K status and the
magnitude of osteocalcin carboxylation,
vitamin K status and fracture rate or
osteopenia and osteoporosis
[19, 21-29, 54-61]
Their findings are that vitamin K status in
serum is inversely related to the presence of
ucOC. These are directly related to the
fracture rate in peri and postmenopausal
Vitamin K reduces ucOC: Sokoll
assessed effect of vitamin K on osteocalcin
by varying amounts of vitamin K in the diet.
He measured the effect of a variable dose of
vitamin K on ucOC with subjects in a
metabolic ward. Though there was no
change in the total serum osteocalcin
concentration, ucOC concentration increases
by 28% in vitamin K unsupplemented diet
and decrease by 44% with supplemented
diet. Findings of similar inverse relationship
between vitamin K and ucOC have been
reported for the patients with 1. osteoporotic
patients with vertebral or hip fractures
in elderly women with established
3. in early postmenopausal
4. in postmenopausal women
receiving hormone therapy daily and on
alternate days
5. serum ucOC
concentration in perimenopausal women
where ucOC is significantly higher than that
in premenopausal women
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
with 8 female marathon runners observed
that 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
in favor of between bone formations
compared to bone resorption.
Takahashi et al
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
Lower ucOC Levels and Reduced
Fracture Rates: There are several studies
relating high prevalence of osteoporosis,
postmenopausal osteoporosis and drug
specific osteopenia and osteoporosis relating
to reduced vitamin K status and a higher
Szulc et al , in a three year follow-up study
with elderly women
, confirm their
previous findings
[25, 58]
that elderly women
with an increased serum ucOC level have an
increased risk of sustaining a hip fracture as
compared to those with normal serum ucOC.
Szulc’s studies were with a small group of
elderly institutionalized women. Vergnaud
et al
reconfirms Szulc’s findings in an
EPIDOS prospective study of 7598 healthy
independently living women over 75 years
of age. He further finds that it is the ucOC
but not total OC that predicts hip fracture
risk independently of femoral neck BMD in
elderly women. In women over 60 years,
age-related bone remodeling increases total
OC but the rise in ucOC has more to do with
the fall in vitamin K status
. This same
relates reduced ucOC more to
better bone quality than so much to just
Recent studies (2008) of Tsugawa et al
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. Lukacs et al
(2006) conclude that
premenopausal women show reduced BMD
despite normal estrogen profiles. The
percent ucOC may be a specific bone marker
of the early postmenopause in healthy
A study of Thai women finds that the ucOC
level of urbanized elderly women was
higher than that of rural elderly. Higher
ucOC in Thai women was related to the
risks of osteoporosis
. Schoon et al
, in
a study with 32 patients with Crohn’s
disease conclude that ucOC is inversely
associated with the bone mineral density.
There is an urgent need, in India, for such
epidemiological studies in vitamin K2-7 and
Calcium, vitamin D, a well-rounded diet and
weight bearing exercise are integral
elements in any osteoporosis management
strategy. In the standard of care for
osteoporosis prevention and treatment
common recommendations are to have
intake of 1000 to 1200 mg elemental
calcium per day
and for vitamin
D(Calciferol), for females, 5,10 and 15 mcg
per day respectively for 31-50 yrs, 50-70 yrs
and greater than 70 years age groups
However, in a meta-analysis of prospective
cohort studies and randomized controlled
trial, Bischoff-Ferrari et al
concluded that
fracture risk in men or women is not
significantly associated with calcium intake.
The question then is where does that leave
It was early on recognized that vitamin D is
important to bone health, and must be
supplemented along with calcium, as it
promotes calcium absorption from the bowel
and is also central to osteocalcin expression
by osteoblasts. Even then the combination of
calcium and vitamin D hasn’t been able to
give a satisfactory answer to the problem of
bone quality and loss. Only recently it has
become clear that the missing link in the
calcium metabolism is the need to
supplement vitamin K2-7 along with
calcium and vitamin D (Fig.5).
High levels of ucOC have been correlated to
higher fracture rate. There is a need of
sufficient vitamin K2-7 in diet or through
supplementation to reduced ucOC for
improved calcium metabolism and bone
Nutritional and endocrine influences are
involved in multifactorial etiology of
osteoporosis. The role of calcium bank,
vitamin D and estradiol has been
significantly investigated. Vitamin K group,
esp vitamin K2-7 is only recently being
recognized for its role in skeletal and
cardiovascular health. One reason for this
delay was almost a total identification of
vitamin K with the coagulation cascade. In
1971 prothrombin and osteocalcin was
identified as ‘Glu’ proteins needing vitamin
K. The need was due to the functional
conversion of Glu (uncarboxylated) to Gla
(carboxylated) form of these proteins.
However the therapeutic application of
vitamin K was significantly procrastinated.
Many studies reported a high level of plasma
uncarboxylated oteocalcin in bone disorders
with high vascular calcium index. These
suggested vitamin K deficiency. Several
recent and ongoing studies with vitamin K2-
7 in osteoporosis have shown positive
directionality. This is enhanced by the
benefits of reduced calcium index in
coronary vasculature. As menopause, by
estrogen deprivation, leads to both
osteoporosis and cardiovascular events,
vitamin K2-7 would offer a complimentality
in its current management. In the Rotterdam
study (n = 4473) the cardiovascular
mortality was reduced by 50%. This
reduction in mortality was ascribed to intake
of vitamin K2-7. In Japan too natto
(fermented Soy) intake has shown similar
benefits in health. In view of the ongoing
increase in cardiovascular risk factor in
south Asians, vitamin K2-7 needs attention,
further investigation and interventional
studies. Pragmatic clinicians, taking hints
from the western studies, have already
started using products with vitamin K2-7*.
* Products containing vitamin K2-7:
Minosta ® (Aristo Pharmaceuticals), Filcal
(Fortes India (Ltd)), Kvion® (J.B.
Chemical & Pharmaceuticals Ltd.),
Calcimax K2® (Meyer Organics Pvt. Ltd.),
Ostium K2® (Medley Ltd.), Kardivin®
(Themis Medicare Ltd.),
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Nature 1935, 135:652-653.
2. Hauschka PV, Carr SA: Calcium-dependent alpha-helical structure in osteocalcin.
Biochemistry 1982, 21(10):2538-2547.
3. Price PA: Vitamin K-dependent formation of bone Gla protein (osteocalcin) and its
function. Vitam Horm 1985, 42:65-108.
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Figure 1
Vitamin K Analogues
Phylloquinone (K1)
Menaquinone (K2)
K1 + K2
rich lipoprotein
Small Intestine
K1 carboxylate blood
coagulating proteins
in Liver
K2 = most of K2
travels to other
Figure 2
Vitamin K Sources, Transport, Distribution
Vitamin K including vitamin K1, K2-4 & K2-7, is absorbed from small intestine. K1 comprises of 80%
western diet, has very low bioavailability of 20%, where as K2-7 forms the 20 % of diet bit has higher
bioavailability of 80%. From small intestine vitamin K is transported to liver via chylomicrons and
triacylglycerol rich lipoprotein. In the liver majority of vitamin K1 is utilize by blood coagulation protein
and only small amount travels out. Most of vitamin K2-7 is travel to other organs like bone and arteries.
Figure 3:
Vitamin K Cycle : VKD Carboxylase catalyzes Glu to Gla in the presence of cofactor
which cycles to vitamin K epoxide and then to vitamin K which is reduced again to
. This is vitamin K cycle. KH
= Vitamin K hydroquinone, KH
R = KH
Reductase , KO = Vitamin K epoxide, VKOR = KO Reductase.
Figure 4
Comparison of K1 and K2 as cofactor
(Schurgers, LJ Unpublished data)
Figure 5
Machanism of Bone
Vitamin K
Vitamin D
Vitamin K
Figure 5
Mechanism of Bone
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We attempted to investigate whether vitamin K2 (menatetrenone) treatment effectively prevents the incidence of new fractures in osteoporosis. A total of 241 osteoporotic patients were enrolled in a 24-month randomized open label study. The control group (without treatment; n = 121) and the vitamin K2–treated group (n = 120), which received 45 mg/day orally vitamin K2, were followed for lumbar bone mineral density (LBMD; measured by dual-energy X-ray absorptiometry [DXA]) and occurrence of new clinical fractures. Serum level of Glu-osteocalcin (Glu-OC) and menaquinone-4 levels were measured at the end of the follow-up period. Serum level of OC and urinary excretion of deoxypyridinoline (DPD) were measured before and after the treatment. The background data of these two groups were identical. The incidence of clinical fractures during the 2 years of treatment in the control was higher than the vitamin K2–treated group (χ2 = 10.935; p = 0.0273). The percentages of change from the initial value of LBMD at 6, 12, and 24 months after the initiation of the study were −1.8 ± 0.6%, −2.4 ± 0.7%, and −3.3 ± 0.8% for the control group, and 1.4 ± 0.7%, −0.1 ± 0.6%, and −0.5 ± 1.0% for the vitamin K2–treated group, respectively. The changes in LBMD at each time point were significantly different between the control and the treated group (p = 0.0010 for 6 months, p = 0.0153 for 12 months, and p = 0.0339 for 24 months). The serum levels of Glu-OC at the end of the observation period in the control and the treated group were 3.0 ± 0.3 ng/ml and 1.6 ± 0.1 ng/ml, respectively (p < 0.0001), while the serum level of OC measured by the conventional radioimmunoassay (RIA) showed a significant rise (42.4 ± 6.9% from the basal value) in the treated group at 24 months (18.2 ± 6.1% for the controls; p = 0.0081). There was no significant change in urinary DPD excretion in the treated group. These findings suggest that vitamin K2 treatment effectively prevents the occurrence of new fractures, although the vitamin K2–treated group failed to increase in LBMD. Furthermore, vitamin K2 treatment enhances γ-carboxylation of the OC molecule.
Full-text available
Vitamin K-dependent proteins, including matrix Gla-protein, have been shown to inhibit vascular calcification. Activation of these proteins via carboxylation depends on the availability of vitamin K. We examined whether dietary intake of phylloquinone (vitamin K-1) and menaquinone (vitamin K-2) were related to aortic calcification and coronary heart disease (CHD) in the population-based Rotterdam Study. The analysis included 4807 subjects with dietary data and no history of myocardial infarction at baseline (1990-1993) who were followed until January 1, 2000. The risk of incident CHD, all-cause mortality, and aortic atherosclerosis was studied in tertiles of energy-adjusted vitamin K intake after adjustment for age, gender, BMI, smoking, diabetes, education, and dietary factors. The relative risk (RR) of CHD mortality was reduced in the mid and upper tertiles of dietary menaquinone compared to the lower tertile [RR = 0.73 (95% CI: 0.45, 1.17) and 0.43 (0.24, 0.77), respectively]. Intake of menaquinone was also inversely related to all-cause mortality [RR = 0.91 (0.75, 1.09) and 0.74 (0.59, 0.92), respectively] and severe aortic calcification [odds ratio of 0.71 (0.50, 1.00) and 0.48 (0.32, 0.71), respectively]. Phylloquinone intake was not related to any of the outcomes. These findings suggest that an adequate intake of menaquinone could be important for CHD prevention.
Full-text available
This randomized, controlled study evaluated the bioavailability of phylloquinone from an intravenous lipid emulsion. A mild vitamin K deficiency was induced in 12 healthy adult men and women by dietary restriction of phylloquinone (40 microg/d, days 1-11) and by administration of warfarin (1.0 mg/d, days 5-11). On day 11, subjects received a 500-mL intravenous solution of either lipid or saline, both of which contained 154 microg phylloquinone. Bioavailability was assessed by serial measurements of plasma phylloquinone, vitamin K1-2,3-epoxide. PIVKA-II (proteins induced by vitamin K absence or antagonists-II), and percentage undercarboxylated osteocalcin. As a result of vitamin K deficiency and minidose warfarin, vitamin K1-2,3-epoxide, PIVKA-II, and percentage undercarboxylated osteocalcin increased significantly between days 1 and 11 (P = 0.05, 0.016, and 0.001, respectively). With the infusions, plasma phylloquinone increased in both groups (P = 0.001). After the infusions vitamin K,-2,3-epoxide decreased in both groups (P = 0.002). Changes in plasma phylloquinone and vitamin K1-2,3-epoxide were no different in the two groups (mean areas under the curves +/- SEM: 116+/-13 nmol x h/L for the saline group and 102+/-20 nmol x h/L for the lipid group for phylloquinone; 38.6+/-7.5 nmol x h/L for the saline group and 31.3+/-9.0 nmol x h/L for the lipid group for vitamin K1-2,3-epoxide). PIVKA-II decreased significantly from baseline values (P = 0.005) in both groups after the infusions. Intravenous lipid reversed the effects of minidose warfarin and of dietary restriction of phylloquinone on hemostasis and vitamin K nutritional status. This reversal was no different from that seen with the infusion of phylloquinone in a saline solution.
IN earlier papers1,2 a new deficiency disease in chicks has been described which is characterised by a tendency to large hæmorrhages. It has been ascribed to the lack of a specific antihæmorrhagic factor which is different from vitamin C. More recent work has demonstrated that the factor in question is a fat-soluble vitamin occurring in hog liver fat, in hemp seed and certain vegetables, such as tomatoes and kale, and-to a less degree-in many cereals. Beef muscle, calf brain and beef lungs desiccated at low temperature are ineffective when they form 20 per cent of the diet, but 20 per cent of dried hog liver will prevent the disease.
The vitamins phylloquinone (K1), menadione (K3) and various menaquinones (K2) were compared for their ability to serve as a cofactor for the hepatic vitamin K-dependent carboxylase. It was found that the cofactor activity of the menaquinones varied with the length of the aliphatic side-chain and showed an optimum at MK-3. Menadione was not active at all. The concentration required for half-maximal reaction velocity () was determined for the various menaquinones and decreased at increasing chain length. The value for MK-4 was 3-times lower than that for vitamin K1. Under our in vitro conditions both vitamin K1 and the K2 vitamins were rapidly metabolized into a mixture of the quinone, the hydroquinone and the epoxide form. The fact that at equilibrium the level of these three metabolites was independent of the starting material shows that the vitamin K cycle is operational for vitamin K1 as well as for K2.
The effect of the degree of carboxylation of osteocalcin (OC) on the properties of bone is unclear. The aim of this study was to relate serum concentrations of total OC (tOC) and undercarboxylated OC (ucOC), measured with a two-site immunoassay, to bone mineral density (BMD) at the femoral neck and ultrasonic transmitted velocity (UTV) at the os calcis in 257 women aged 60-99 years, 22 of whom had sustained a hip fracture. There was an increase in tOC (r = 0.19, P = 0.003) and ucOC (r = 0.20, P = 0.002) with age. No significant difference in tOC or ucOC between subjects with and without hip fracture was found. Serum tOC was negatively correlated with femoral neck BMD (r = -0.23, P = 0.0001) and os calcis UTV (r = -0.29, P = 0.0001) and partial correlations indicated that these relationships were independent of age. Serum ucOC also correlated negatively with os calcis UTV (r = -0.21, P = 0.001) and less strongly with femoral neck BMD (r = -0.13, P = 0.052). After adjusting for age, only the relationship between ucOC and os calcis UTV remained significant (r = -0.16, P = 0.017). It is concluded that in women over 60 years, the increase in tOC reflects an age-related rise in bone remodeling, whereas the increase in ucOC reflects an age-related fall in vitamin K status. The stronger relationship of ucOC with UTV than BMD suggests that the rise in ucOC may perhaps relate more to changes in bone quality than mineral content. Higher serum ucOC concentrations in subjects with a history of hip fracture could not be confirmed.
The present study sought to identify dietary nutrients associated with the prevalence of radiographic knee osteoarthritis (OA) in the Japanese elderly of a population-based cohort of the Research on Osteoarthritis Against Disability (ROAD) study. From the baseline survey of the ROAD study, 719 participants >or=60 years of age (270 men, 449 women) of a rural cohort were analyzed. Dietary nutrient intakes for the previous 1 month were assessed by a self-administered brief diet history questionnaire. The radiographic severity at both knees was determined by the Kellgren/Lawrence (KL) system. The prevalence of knee OA of KL >or=2 was 70.8%. Age, body mass index, and female sex were positively associated with the prevalence. Among the dietary factors, only vitamin K intake was shown to be inversely associated with the prevalence of radiographic knee OA by multivariate logistic regression analysis. The presence of joint space narrowing of the knee was also inversely associated with vitamin K intake. The prevalence of radiographic knee OA for each dietary vitamin K intake quartile decreased with the increased intake. The present cross-sectional study using a population-based cohort supports the hypothesis that low dietary vitamin K intake is a risk factor for knee OA. Vitamin K may have a protective role against knee OA and might lead to a disease-modifying treatment.
The objective of the present review of the literature was to evaluate the effect of vitamin K supplementation on the skeleton of postmenopausal women. PubMed was used to search the reliable literature for randomized controlled trials (RCTs) by using the inclusion criteria: >or= approximately 50 subjects per group and study period of >or= 2 years. The results of 7 RCTs that met the inclusion criteria showed that vitamin K (K(1) and K(2)) supplementation reduced serum undercarboxylated osteocalcin levels regardless of dose, but that it had inconsistent effects on serum total osteocalcin levels and no effect on bone resorption. Despite the lack of a significant change or the occurrence of only a modest increase in bone mineral density, high-dose vitamin K supplementation improved indices of bone strength in the femoral neck and reduced the incidence of clinical fractures. Furthermore, a post hoc analysis in a large RCT in Japan showed that high-dose vitamin K(2) supplementation decreased the subsequent incidence of vertebral fractures in osteoporotic postmenopausal women with a history of at least 5 vertebral fractures. The review of the reliable literature showed the effect of high-dose vitamin K supplementation on the skeleton of postmenopausal women mediated by mechanisms other than bone mineral density and bone turnover.
Post-transcriptional maturation with the presence of vitamin K(2) promotes gamma-carboxylation of osteocalcin, enabling further binding to hydroxyapatite, from which one could infer that vitamin K(2) increased the quality of bone matrix. For instance, vitamin K(2) rescued the impaired collagen mineralization caused by Mg insufficiency, by promoting a re-association of the process of collagen mineralization with mineralized nodules. Sodium warfarin, which antagonizes the function of vitamin K(2), reduced the binding of osteocalcin to bone matrices, and consequently resulted in crystalline particles being dispersed throughout the osteoid without forming mineralized nodules. Therefore, gamma-carboxylated Gla proteins mediated by vitamin K(2) appear to play a pivotal role in normal mineralization in bone.