Vitamin K2 for bone health Vitamin K2-A key factor for optimal bone health at all ages

Abstract

Vitamin K is important for optimal bone health throughout life as vitamin K is crucial for calcium regulation in the body. Osteocalcin, an important vitamin K-dependent protein, found in bone tissue binds calcium and ensures calcium is incorporated into bone. Vitamin K comprises a group of closely related fat-soluble vitamins. The most important naturally occurring forms of vitamin K are phylloquinone and menaquinones, also known as vitamin K1 and vitamin K2 (consisting of a group of menaquinones), respectively. Recent studies suggest that there is a vitamin K2 deficiency in the general population and that supplemental doses of menaquinone-7 (MK-7) (microgram doses), may result in improved bone health.

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KEYWORDS: Vitamin K2, menaquinone-7, bone health, osteoporosis, osteocalcin, calcium.
Abstract Vitamin K is important for optimal bone health throughout life as vitamin K is crucial for calcium regulation
in the body. Osteocalcin, an important vitamin K-dependent protein, found in bone tissue binds calcium
and ensures calcium is incorporated into bone. Vitamin K comprises a group of closely related fat-soluble vitamins. The most
important naturally occurring forms of vitamin K are phylloquinone and menaquinones, also known as vitamin K1 and vitamin K2
(consisting of a group of menaquinones), respectively. Recent studies suggest that there is a vitamin K2 deficiency in the general
population and that supplemental doses of menaquinone-7 (MK-7) (microgram doses), may result in improved bone health.
Vitamin K2 for bone health
Vitamin K2 – A key factor for optimal bone health at all ages
INTRODUCTION
Bone diseases present
large challenges for
society
Bone health is critically
important to overall
health and quality of
life. Healthy bones
provide the body with
the framework that
allows for mobility
and for protection
against injury. Bones
stores minerals such
as calcium which are
vital to the functioning
of for instance muscle
contraction, nerve
signaling and many
enzymatic reactions.
A major health challenge is the increasing number of people
with weak bones caused by osteopenia (lower than normal
bone mineral density (BMD)) and osteoporosis (a disease
state with low BMD). An estimated 75 million people in Europe,
USA and Japan have osteoporosis and three times as many
women are affected (1, 2) compared to men. TThere is a
clear, worldwide correlation between osteoporosis and
fractures, with lifetime risk of osteoporotic fractures in women
and men 30-50% and 15-30%, respectively (3). It has been
estimated that the fracture incidence is more than 2.3 million
cases annually in Europe and the US
alone (1).
Brittle bones and osteoporosis result in
a huge economic burden worldwide
with large implications for the individual
as well as for society.
The economic burden in the EU is
estimated to be € 37 billion, and this is
projected to increase, on an average,
by 25% in 2025 (4).
As such, just a small improvement in
bone health may have large positive
implications on public health budgets
and increase the longevity and quality
of life of individuals. The importance of
vitamin K for bone health, particularly
vitamin K1 and vitamin K2 (MK-4), has
been summarized in several review
papers (5-7). K2 MK-4 is approved
as a drug in Japan for treatment of
osteoporosis (dose; 45 mg/day, 3 X 15
mg/ day).This paper focuses speci cally on the documented
role of vitamin K2 MK-7, in supplement doses, in relation to
bone health and the bone building process.
BONES ARE LIVING TISSUE, CONSTANTLY RENEWED ALL
THROUGH LIFE
The skeleton consists of bone (hydroxyapatite)
supplemented by ligaments, tendons, muscles and
MONA E. MØLLER
Kappa Bioscience AS
Gaustadalléen 21, 0349 Oslo, Norway
Mona E. Møller
Figure 1. Osteopenia and osteoporosis are common in elderly
people. Bones are getting porous and brittle as we get older; the risk
of fractures increases with age (Zoaring 2014, © Kappa Bioscience).

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Japan is one of the
countries with ow
frequencies of bone-
and cardiovascular
diseases, especially
in certain regions
in the North (10). In
these Northern regions
the Japanese eat a
dish called natto -
fermented soybeans
which contain high
amounts of vitamin
K2, menaquinones-7
(MK-7). This food has
been used for hundreds of years and is approved as a
Health Food in Japan. Many Japanese epidemiological
studies have pointed to benecial effects of vitamin K2,
MK-7 for bone health (11, 12). In a large three-year study in
Japanese women it was demonstrated that intake of natto
resulted in increased BMD at the femoral neck (13). These
effects were attributed to intake of MK-7 in the natto food.
When the incidence of hip fractures in twelve regions in
Japan were an analysed and correlated to intake of the
key nutrients calcium, magnesium, vitamin D and vitamin
K, the strongest inverse correlation to fractures was found
to be intake of vitamin K, in particularly vitamin K2, MK-7,
both in men and women (10). Intake of natto food was
also inversely correlated with hip fractures in women (14).
Furthermore, natto intake was associated with improved
BMD in elderly men (15). Thus, several Japanese studies
demonstrate the benecial effects of MK-7 on bone
strength and for prevention of fractures. Furthermore, these
studies show that MK-7 is safe without any side effects.
THE IMPORTANCE
OF COMBINING
CALCIUM,
VITAMIN D3 AND
VITAMIN K2 – “THE
TRI-ESSENTIALS”
The most widely
used supplements
to support bone
health are
calcium and
vitamin D3. Vitamin D3 increases the intestinal uptake of
calcium into the blood stream. To secure an optimal bone
building process, however, vitamin K is needed to activate
osteocalcin, allowing osteocalcin to bind calcium and
transport calcium from blood into the bone. Vitamin K,
vitamin D3 and calcium work in concert for building strong
bones: the “tri-essentials” for bone health (Figure 3).
The importance of vitamin K2 for bone health in healthy
subjects has been recently documented. In a large three
year placebo-controlled study of 244 postmenopausal
women with daily intake of 180 µg of MK-7, a statistically
signicant difference in bone quality parameters was
found between the MK-7 group and the control (16). It was
concluded that MK-7 preserves bone at Lumbar spine L1-L4
(both BMC and BMD).
cartilage. Calcium is an important building block in the
bone matrix. Bone building processes constantly ongoing
- in fact the entire skeleton is regenerated every seven
years. Bone build-up cells (osteoblasts) and break-
down cells (osteoclasts) regulate the strength of bones,
and when break-down cell activity dominates, the
skeleton becomes increasingly fragile. This may result in
development of osteoporosis.
In the cycle of bone remodeling, the osteoclasts remove
old or damaged bone (this removal is called bone
resorption. The removed bone constituents, including
calcium, are released into circulating blood. At the same
time the osteoblasts produce new bone (bone formation).
In this process, osteoblasts produce osteocalcin (OC), a
protein that, in its activated form, can bind calcium and
incorporate calcium into bones (8).
It is important throughout life to secure sufficient calcium
to maintain a healthy skeleton. Bone mass increases from
childhood until the early twenties, before beginning to
decline (Figure 2). From 30-40 years onwards, bone mass
gradually decreases in both men and women. This implies
that sufficient calcium intake is particularly important in
childhood/puberty and from age 35 onwards. Further,
the risk of broken bones increases with age and the
ability to recover decreases. Post-menopausal women
are particularly vulnerable for development of brittle
bones, leading to fractures.
HOW CAN WE IMPROVE BONE HEALTH – LOOK TO JAPAN!
Osteoporosis is to a large extent a preventable disease.
Several environmental factors, such as physical exercise
and diet (considered mainly to be attributed to sufficient
intake of calcium and vitamin D3), can strongly influence
our bone quality. Worldwide, the risk of osteoporotic
fracture can vary up to 10-fold, depending on country
of origin, with Caucasians having the greatest reported
risk (9). The fact that major risk factors for osteoporosis
are well known, but incidences are increasing worldwide,
suggests that important factor) for a good bone health
are being overlooked.
Figure 2. Bone mass as a function of age. During puberty: a large
increase in bone mass. From 50 years onwards: a strong decrease in
bone mass, particularly in females (© Kappa Bioscience).
Figure 3.
The “three
essentials” for
bone health:
calcium,
vitamin D3 and
vitamin K. See
Knapen et al.
(© Kappa
Bioscience).

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VITAMIN K IN FOOD – IS THERE A DEFICIENCY IN THE
GENERAL POPULATION?
Vitamin K is a fat-soluble vitamin. Vitamin K comprises a
number of structurally related compounds including
phylloquinone (vitamin K1) and menaquinones (vitamin K2s).
Menaquinones are classied according to the length
of their side chains; menaquinone-4 (MK-4) and
menaquinone-7 (MK-7) being the most important.
Phylloquinone is found in green/leafy vegetables such
as green salads, broccoli and spinach. Vitamin K1 is
considered as the major dietary source of vitamin K,
accounting for approximately 90% of total vitamin K
intake (23). Based on different studies of content in food
worldwide, Suttie has estimated the intake of vitamin K in
the general population to be between 70 - 250 µg/day (24).
However, the bioavailability of vitamin K1 from food is low;
less than 20% is absorbed (25).
Vitamin K2, menaquinones, are found in animal products
such as meat, dairy, eggs (mainly MK-4) and fermented
food, e.g. cheese, yoghurt, and fermented soybean
products/natto (mainly MK-7).
( 23,26,27). In the Netherlands the
average intake of MK-4 and long-chain
menaquinones from eggs and cheese
has been reported to be in the range
of 7µg/day and 22µg/day, respectively
(28). Limited knowledge exists regarding
intake of longer menaquinones from
food in other European countries or the
US, though fermented cheeses may
be the most important source (23, 29).
However, the most efcacious vitamin
K, specically MK-7, is found to a very
low extent in these fermented products
(23). These factors likely lead to a
deciency of vitamin K2 intake in most
countries.
VITAMIN K DEFICIENCY RESULTS IN LOW
BMD AND HIGH RISK OF FRACTURES IN
SOME DISEASES
Several medical conditions and drug
treatments may result in vitamin K
deciency. For instance, treatment with
anti-coagulants (warfarin/coumarins)
that block the re-use of vitamin K in the so-called vitamin
K cycle result in low serum concentration of vitamin K. This
has been shown to affect bone health in both adults and
children.
In young people aged 8.6 to 18.8 years that received
warfarin for more than 12 months, signicant reduction in
bone mineral density was observed. In another study, more
than 50% of pediatric patients on warfarin/coumarin were
reported to have osteopenia (30). Long–term treatment
with anti-inammatory drugs (corticosteroids) is another
example of drugs that have detrimental effects on bone
quality (31).
People with various diseases affecting intestinal absorption
of vitamin K (and other vitamins and minerals) such as
Furthermore, measured bone strength was preserved in the
treatment group.
This study demonstrates that benecial effects on bone
health can be obtained with supplement doses of vitamin
K2, MK-7 (180µg). Vitamin K1 and MK-4 are also used, but
this is documented to be sub-optimal, due to the very high
doses of vitamin K1 (1-5 mg) or MK-4 (45 mg) required.
(Reviews 5, 6, 7). Such dosages exceed the nutritional
vitamin guidelines, and the amount typically available in
dietary supplement tablets of 50 -100µg - far below what
is needed for vitamin K1 or MK-4 to have benecial effects
on bone parameters. Vitamins in high (mg) doses are often
classied as drugs; for example, MK-4 is registered as a drug
for treatment of osteoporosis in Japan and administered at
45mg/daily dose.
OSTEOCALCIN, A VITAMIN K-DEPENDENT PROTEIN
IMPORTANT FOR BONE BUILDING
Osteocalcin (OC) is a non-collagenous protein primarily
expressed in osteoblasts involved in bone metabolism
and calcium binding. OC
is dependent on vitamin
K in order to carry out its
function of building calcium
into bone and is important
for bone mineralization and
calcium homeostasis (7).
Vitamin K is a co-factor for
the enzyme that activates
OC by carboxylation of the
protein at certain sites. In the
activated (carboxylated)
form, OC can bind calcium
and transport calcium into the
bone matrix (Figure 4). OC is a
so-called Gla-protein which is
dependent on vitamin K for its
function (all Gla-proteins use
vitamin K as cofactor for the
carboxylation step).
From bone, OC partly goes
into blood circulation and the
fraction of undercaboxylated-
osteocalcin (ucOC, inactive)
and carboxylated osteocalcin
(cOC) can be measured as
surrogate markers for vitamin
K status (17).
Individuals with low vitamin K2 intake have a larger fraction
of non-activated osteocalcin, resulting in reduced capacity
for calcium binding. High serum concentration of ucOC
is thus correlated with low BMD and is a predictor of hip
fracture risk (18-20). Since high ucOC concentration also is
a marker of vitamin K deciency, studies demonstrate the
pivotal role of sufcient intake of vitamin K for optimal bone
health. As may be expected, low serum concentration of
vitamin K, in particular vitamin K2, menaquinone-7 (MK-7), is
correlated with increased fracture incidence (21-22, 10).
In conclusion, ucOC is an important biomarker for bone
health; a high concentration of ucOC is a strong indicator
of vitamin K deciency and relates to low BMD and risk of
hip fractures.
Figure 4. Osteocalcin, OC, is activated by a vitamin
K-dependent step. After activation OC binds calcium
and brings it to bone
(© Kappa Bioscience).

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effect on bone health in young people with
cystic  brosis (34).
VITAMIN K2, MK-7 - THE VITAMIN K OF CHOICE
The major difference between vitamin K1 and
vitamin K2 as MK-7 are their respective half-
lives. All fat-soluble vitamins are absorbed well
in the presence of fat. Vitamin K1 however,
quickly disappears from circulation (half-life
approx. 1- 2 hours). MK-7 in contrast, has a
very long half-life (approx. 2- 3 days) (35). This
considerable difference in half-lives is due
to the MK-7 molecular structure, resulting in
a difference in uptake, transport in blood,
distribution and breakdown in the body. This
leads to the large difference in the steady
state concentration. Serum concentration of
MK-7 is substantially higher than for vitamin K1
when subjects are given equimolar amounts
(same number of molecules) (Figure 5). As a result, MK-7
remains in serum and is far more accessible for extra-
hepatic organs such as bone and vessel walls, resulting in
more ef cacious carboxylation of osteocalcin and MGP
(36). In the EU the recommended daily allowance (RDA)
celiac disease and cystic  brosis are reported to have
poor bone health (32, 33). The correlation of poor bone
health associated with cystic  brosis and vitamin K
de ciency (increased ucOC) is well established (32) and
supplementation with vitamin K is known to have bene cial
Figure 5. Concentration of vitamin K in serum after intake of vitamin K1 and vitamin K2
(MK-7), including natto food in various amounts. Only intake of MK-7 in dietary doses
gives a serum concentration above 1ng/ml. DS = dietary supplement (modi ed from ref
42, 29, 46, own data, unpublished), (© Kappa Bioscience).

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Osteoporosis Int, 2012, 23, 2239-56
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or vitamin K2 for postmenopausal osteoporosis, Keio J Med. 2003;
52(3):147-50
12. Ushiroyama T, Ikeda A, Ueki M. Effect of continuous combined
therapy with vitamin K(2) and vitamin D(3) on bone mineral
density and coagulofibrinolysis function in postmenopausal
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Natto, Is Associated wiht Reduced Bone Loss in Postmenopausal
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vitamins K1 and K2 decreased in elderly women with hip
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24. Suttie JS ed, Vitamin K in health and disease, CRC Press, 2009
25. Garber AK, Binkley NC, Krueger DC, et al., Comparison of
Phylloquinone Bioavailability from Food Sources or a Supplement
in Human Subjects, J Nutr , 1999, 129,1201-1203
26. Kaneki M, Hodges SJ, Hosoi T, 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; 17:315-21
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formation by fermented soybean (Natto) intake in
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Readers interested in a full list of references are invited to visit our
website at www.teknoscienze.com
of vitamin K is 75 µg/day and is based on requirements for
activation of clotting factors in the blood (37). In healthy
individuals the intake of vitamin K from food is sufcient
to fully activate clotting factors in the liver (meaning the
clotting factors are always 100% activated) (35, 38). In
contrast to the coagulation factors, several studies have
demonstrated that both OC and matrix Gla-protein in
serum are far from fully activated in the general population
(10-40%) and that supplementation with vitamin K increases
the degree of activation (38-43).
In a recent study of healthy volunteers it as documented
that the concentration of undercarboxylated OC (ucOC)
was high, pointing to an extra-hepatic vitamin K deciency
(44). Interestingly, both children and adults above age 40
year had high concentrations of circulating ucOC. The
authors concluded that by increasing the extra-hepatic
carboxylation of Gla-proteins (i.e. supplementation with
vitamin K2) one can contribute to better bone health (44).
Recent published data supports that doses of vitamin K2 in
the range of 90-120 µg/day (US RDA) can to a great extent
reduce circulating ucOC (40, 43).
CONCLUSIONS
Vitamin K2 deciencies seem to be quite common in
the general population, except for people eating natto.
Dietary supplement tablets typically contain 50 -100 µg
vitamin K . Based on data from the literature, only vitamin
K2, as MK-7, seems to be efcacious with respect to
benecial effects on bone health in supplement doses.
Vitamin K2 is also documented to be safe with no side
effects even in very high doses. Increased intake of vitamin
K2 in the general population to faciillitate healthy bones
may have substantial benecial effects for the individual
and huge positive implications on the public health and
health budgets worldwide.
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