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BEYOND DEFICIENCY: NEW ROLES FOR VITAMINS
Vitamin K and Bone Health
Peter Weber, MD, PhD
From F. Hoffmann-La Roche Ltd, Vitamins and Fine Chemicals Division, Human
Nutrition & Health, Basel, Switzerland
In the past decade it has become evident that vitamin K has a significant role to play in human health that
is beyond its well-established function in blood clotting. There is a consistent line of evidence in human
epidemiologic and intervention studies that clearly demonstrates that vitamin K can improve bone health.
The human intervention studies have demonstrated that vitamin K can not only increase bone mineral
density in osteoporotic people but also actually reduce fracture rates. Further, there is evidence in human
intervention studies that vitamins K and D, a classic in bone metabolism, works synergistically on bone
density. Most of these studies employed vitamin K2 at rather high doses, a fact that has been criticized
as a shortcoming of these studies. However, there is emerging evidence in human intervention studies that
vitamin K1 at a much lower dose may also benefit bone health, in particular when coadministered with
vitamin D. Several mechanisms are suggested by which vitamin K can modulate bone metabolism.
Besides the ␥-carboxylation of osteocalcin, a protein believed to be involved in bone mineralization, there
is increasing evidence that vitamin K also positively affects calcium balance, a key mineral in bone
metabolism. The Institute of Medicine recently has increased the dietary reference intakes of vitamin K
to 90 ␮g/d for females and 120 ␮g/d for males, which is an increase of approximately 50% from previous
recommendations. Nutrition 2001;17:880 – 887. ©Elsevier Science Inc. 2001
KEY WORDS: vitamin K, bone health, osteocalcin, bone mineral density, fracture, osteoporosis
DEDICATION
When I met Larry for the first time, he was “officially” already
retired. I say “officially” because he never did really retire from
science. I got to know Larry as a person who loved to talk science.
Actually, I was the person to succeed him in the Human Nutrition
Group at the Roche Office in Nutley, New Jersey, which to me was
a great honor and even more of a challenge. Although retired,
Larry continued to come to our offices quite often. Actually, he
was one of those wonderful people who introduced me, a European
fellow, to many things of “American life” related to science and
non-science. I really treasure the conversations with Larry on
vitamins and science in general and I am very grateful for the way
he liked to share his great scientific expertise on vitamin E. I very
much enjoyed hearing Larry’s thoughts on the effects essential
nutrients such as vitamins may have “beyond merely preventing
deficiency,” a concept I was impressed with. However, the really
great thing about Larry was his unfailing optimism, forward thinking, and openness to novel ideas. This is the way he embraced life.
Often we used to talk about vacation trips, going West, fishing,
hiking, bird watching, and an endless list of many trivial things of
daily life. I always will remember Larry as a great scientific leader
in vitamin research and an individual whose company I enjoyed.
INTRODUCTION
Osteoporosis, a major, worldwide, public health problem, is a
systemic skeletal disease characterized by decreased bone mass
and a microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures.1
Correspondence to: Peter Weber, MD, PhD, Roche Vitamins Ltd, Human
Nutrition & Health, CH-4070 Basel, Switzerland. E-mail: [email protected]
roche.com
Date accepted: June 10, 2001.
Nutrition 17:880 – 887, 2001
©Elsevier Science Inc., 2001. Printed in the United States. All rights reserved.
The World Health Organization (WHO) criteria for the diagnosis
of osteoporosis are based on comparisons with peak adult bone
mass, as measured by bone densitometry. Osteoporosis is characterized by a bone mineral density (BMD) of more than 2.5 standard
deviations (SD) below the mean value of peak bone mass in young
normal women. A moderate decrease of BMD in the range of at
least ⫺1 SD and to no more than ⫺2.5 SD of the mean value of
peak bone mass in young normal women is called osteopenia.2
Based on the WHO diagnostic categories, it is estimated that 54%
of postmenopausal white women in the United States have osteopenia and another 30% have osteoporosis.3 Thus, in the United
States, more than 25 million people4 have significantly decreased
BMDs, which predisposes them to more than 1.5 million fractures
per year.5 This puts a significant burden on the US health care
system. The annual cost of osteoporosis is estimated to be more
than $10 billion per year4 and is expected to reach $240 billion by
2040 as the life expectancy of people in the Western world is
anticipated to drastically increase.6
Some of the many factors that influence an individual’s risk of
osteoporosis are genetic predisposition, age, sex, race, general
health, exercise, cigarette smoking, alcohol abuse, hormone replacement therapy, and nutritional factors.7 In fact, current research is emphasizing the role of nutrition in the development of
this disease. Much of this work has focused on the roles of
calcium, magnesium, vitamin D, and macronutrients such as protein as reviewed by several researchers.8 –14 The aim of the present
paper is to review the human studies concerning vitamin K and
bone health.
DIETARY SOURCES OF VITAMIN K
Naturally occurring K vitamins can be classified into two groups:
K1 (phylloquinone), the major form occurring in plants, and K2,
which is synthesized by bacteria. Vitamin K2 is a family of
compounds called menaquinones (based on the number of the
repeating prenyl units of the side chain, this number is given as a
suffix, i.e., menaquinone-n). Natural sources of vitamin K1 are
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Nutrition Volume 17, Number 10, 2001
Vitamin K and Bone
TABLE I.
DIETARY SOURCES OF VITAMIN K ACCORDING TO
SCHURGERS ET AL.16
Food source
Meat
Fish
Fruit
Green vegetables
Grains
Natto
Cheese
Other milk products
Eggs
Margarine and plant oils
Vitamin K1 content
(␮g/100 g)
Vitamin K2 content
(␮g/100 g)
0.5–5
0.1–1
0.1–3
100–700
0.5–3
20–40
0.5–10
0.5–15
0.5–2.5
50–200
1–30
0.2–4
—
—
—
900–1200
40–90
0.2–50
10–25
—
green leafy vegetables.15 Dairy products such as cheese are a major
source of vitamin K2 (Table I). It is noteworthy that natto, a
product derived from fermented soy and very popular in Asia, is a
rich source of vitamin K2.16 Intestinal bacteria also produce vitamin K2, but it has become obvious in recent years that the contribution of intestinal-derived vitamin K2 to overall vitamin K status
was greatly overestimated in the past.17,18
MECHANISMS
Vitamin K is required for the biological activity of several coagulation factors such as factors II, VII, and IX and proteins C and
S.19 This is considered the classic metabolic role of vitamin K.
881
More precisely, vitamin K functions as a cofactor for the vitamin
K– dependent carboxylase, a microsomal enzyme that facilitates
the posttranslational conversion of glutamyl to ␥-carboxyglutamyl
residues.20 –23
In addition to the hepatic tissue, in which the synthesis of
clotting factors occurs, ␥-carboxyglutamyl– containing proteins
are abundantly available in bone tissue.24 Osteocalcin accounts for
up to 80% of the total ␥-carboxyglutamyl content of mature bone.
Human osteocalcin is synthesized mainly in the bone-forming
cells, the so-called osteoblasts.25 Human carboxylated osteocalcin
contains three ␥-carboxyglutamyl residues that confer a highly
specific affinity to the calcium ion of the hydroxyapatite molecule.26 Although the exact role of osteocalcin in bone metabolism
remains to be clarified, the available mechanistic data point toward
a regulatory function of osteocalcin in bone mineral maturation. In
an osteocalcin knock-out mouse model, bone formation was increased, whereas bone mineralization was altered.27,28 To a large
extent, newly synthesized osteocalcin is incorporated into the
extracellular matrix of bone, but a small fraction of it is also
released into the bloodstream, which then can be assayed. Osteocalcin is widely accepted as a marker of bone turnover.29
In fact, the extent to which osteocalcin is being carboxylated is
believed to be a more sensitive measure of vitamin K status25,30 –32
than the conventional tests involving blood coagulation: high
serum levels of undercarboxylated osteocalcin (ucOC) are indicative of low vitamin K status, and vice versa.
As reported recently, vitamin K seems to be involved in several
other mechanisms considered essential for bone metabolism. There
is evidence that vitamin K positively influences calcium balance, a
key mineral in bone metabolism. In ovariectomized rats33 supplemented with vitamin K and humans on a diet rich in vitamin K,34
an increase of calcium retention was found. ␥-Carboxyl glutamic
acid may contain proteins located in the kidney, which may be
involved in the calcium homeostasis of the kidney, that contribute
to this effect.35 Also, recent in vitro36 and in vivo37 data suggest
TABLE II.
EPIDEMIOLOGIC STUDIES: VITAMIN K SERUM LEVELS AND BONE HEALTH
Study
Population
Parameters*
Results
Schoon et al.49
32 patients with Crohn’s disease
Serum vitamin K, ucOC, bone mineral
density
Tamatani et al.46
27 elderly males
Kanai et al.43
71 postmenopausal women
Tamatani et al.45
27 elderly males
Serum vitamin K1, MK-7, bone
mineral density
Serum vitamins K1 and K2, bone
mineral density
Serum vitamin K1, MK-7, bone
mineral density
Hodges et al.44
89 elderly women
Serum vitamin K1, MK-7, MK-8, hip
fractures
Hodges et al.42
29 patients with fractures,
17 controls
Serum vitamin K1, MK-7, MK-8, hip
and vertebral fractures
Hart et al.41
Group 1: 16 patients with hip
fracture
Group 2: 14 patients with
vertebral fractures
Group 3: 15 controls
Serum vitamin K1, hip and vertebral
fractures
Vitamin K was significantly decreased in patients
with Crohn’s disease compared with controls;
ucOC was inversely associated with bone
mineral density
Serum vitamin K1 and MK-7 were significantly,
positively correlated with bone mineral density
Women with lower bone mineral density had
lower serum vitamin K1 and K2 values
Serum vitamin K1, MK-7, and 25hydroxyvitamin D were significantly,
positively correlated with bone mineral density
Vitamin K1, MK-7, and MK-8 values were
significantly lower in the hip fracture group
than in the controls
Median vitamin K1, MK-7, and MK-8 values
were significantly lower in the fracture groups
than in the control group
Mean vitamin K1 values (pg/mL)
Group 1: 71
Group 2: 79
Group 3: 335
* MK-7 and MK-8 are serum vitamin K2 with side chains of different lengths.
MK-7, menaquinon-7; MK-8, menaquinon-8; ucOC, undercarboxylated osteocalcin.
882
Weber
Nutrition Volume 17, Number 10, 2001
TABLE III.
EPIDEMIOLOGIC STUDIES: VITAMIN K INTAKE, UNDERCARBOXYLATED OSTEOCALCIN, AND BONE HEALTH
Study
Population
Parameters
Sugiyama et al.52
14 children
ucOC, ultrasound
Kaneki et al.55
74 Japanese postmenopausal
women
Framingham Heart Study, 553
women, 335 men; mean age:
75.2 y, 7-y follow-up
Natto intake, hip fracture rate
Nurses Health Study, 72 327
women; age: 38–69 y,
prospective study, 10-y
follow-up
183 elderly women, prospective
3-y study
Vitamin K intake by food-frequency
questionnaire, hip fracture rate
Jie et al.47
113 postmenopausal women
ucOC, bone mineral density
Szulc et al.50
98 elderly women
ucOC, bone mineral density
Szulc et al.48
195 elderly women, prospective
18-mo study
ucOC, hip fracture rate
Vermeer et al.22
148 subjects
Vitamin K intake, bone mineral density
Booth et al.54
Feskanich et al.53
Szulc et al.51
Vitamin K intake by food-frequency
questionnaire, hip fracture rate, bone
mineral density
ucOC, hip fracture rate
Results
Ratio of serum carboxylated osteocalcin to serumintact osteocalcin was positively related to the
velocity of ultrasound, which is considered an
emerging measure of bone quality
Natto consumption and hip fracture incidence was
inversely associated
Those in quartile 4 (median vitamin K intake: 254
␮g/d) had significantly reduced risk of fractures by
65% when compared with quartile 1 (median
vitamin intake: 56 ␮g/d); There was no significant
association between vitamin K intake and bone
mineral density
The risk of a hip fracture was significantly reduced
by 30% in women with vitamin K intake ⬎ 109
␮g/d
The risk of hip fracture was 3.1-fold higher in
women with raised ucOC levels at the start of the
study
ucOC and bone mineral density were inversely
correlated
ucOC and bone mineral density, measured at various
points, were inversely correlated
Those patients who at the start of the study had
higher ucOC values had a 5.9-fold increased
relative risk of having a hip fracture during the
observation period
Those with lower bone density had a mean vitamin K
intake of 161 ␮g/d; those with higher bone density,
217 ␮g/d
ucOC, undercarboxylated osteocalcin.
that vitamins K and D work synergistically on bone metabolism. In
a rat model, ovariectomy-induced bone loss was reduced in the
group receiving vitamins K and D, but not in the groups receiving
vitamin K only or vitamin D only.38
As to whether vitamin K inhibits prostaglandin E239 and
interleukin-6 production,40 which are potent bone-resorbing
agents, requires further investigation.
EPIDEMIOLOGIC STUDIES
Vitamin K Status and Bone Health
There is a wealth of epidemiologic studies investigating the association of vitamin K status and various markers of bone health
including clinical endpoints such as BMD and fracture rate (Tables
II and III). Consistently, these epidemiologic studies have suggested a beneficial effect of vitamin K on bone health, as discussed
below in more detail.
The first report linking vitamin K serum levels to the risk of
osteoporotic fractures (Table II) appeared in 1985, when Hart et
al.41 demonstrated that patients with osteoporosis who had sustained an acute fracture (hip fracture) or suffered from a chronic
fracture (spinal crush fracture) had lower circulating vitamin K1
serum levels than control subjects. Those results were later confirmed by Hodges et al.42 who reported reduced levels of vitamin
K1 and its derivatives menaquinone-7 and menaquinone-8 in comparable groups of patients. Other studies in elderly women and
age-matched control women demonstrated reduced levels of vitamin K1, menaquinone-7, and menaquinone-8 in women who had
reduced BMD43 or hip fracture.44 Recently, similar findings have
been reported for men.45,46
The carboxylation of osteocalcin (ucOC) is a sensitive measure
to assess vitamin K status, as recently shown in healthy North
American adults of different ages.30 A number of studies investigated the association of ucOC with bone density or hip fracture
rate (Table III). For example, Jie et al.47 and Szulc et al.48 inversely
associated ucOC with bone density in postmenopausal women.
This finding was also seen in patients with Crohn’s disease.49 A
prospective study by Szulc et al.50,51 in elderly women reported
that those who later experienced hip fracture had higher baseline
levels of ucOC. In fact, the calculated relative risk for hip fractures
was 3.151 to 5.950 times higher in the subjects with elevated ucOC
serum levels. The ucOC associated positively with bone quality,52
as assessed by ultrasound. However, it should be mentioned that
for the time being ultrasound is still considered as an emerging tool
in bone diagnostics.
The association of dietary vitamin K intake and bone status as
assessed by BMD or fracture rate has been investigated. A pilot
study by Vermeer et al.22 found that vitamin K intakes of individuals in the lowest decile of bone density were significantly lower
than those of individuals in the highest decile (161 versus 217 ␮g
of vitamin K/d). These preliminary findings have been corroborated recently by two large, prospective cohort studies. In the
Nurses’ Health Study53 dietary intake of vitamin K was assessed
Nutrition Volume 17, Number 10, 2001
Vitamin K and Bone
883
TABLE IV.
INTERVENTION STUDIES: EFFECT OF VITAMIN K ON UNDERCARBOXYLATED OSTEOCALCIN
Study
Population
Daily dose/endpoint
Takahashi et al.70
113 women with fractures,
91 pre- and
postmenopausal controls
45 mg vitamin K2, 1 ␮g 1 ␣hydroxyvitamin D3, ucOC
Schaafsma et al.68
23 postmenopausal women
80 ␮g vitamin K1, ucOC
Binkley et al.30
219 healthy subjects age:
18–30 yr, ⱖ65 y
1 mg vitamin K, ucOC
Caillot-Augusseau et al.66
Craciun et al.67
2 cosmonauts
8 female marathon
runners, age: 20–44 y
1 mg vitamin K, ucOC
10 mg vitamin K, ucOC, markers
for bone turnover, urinary
calcium
Sokoll et al.64
9 persons, age: 20–33 y
Douglas et al.69
20 postmenopausal women
Plantalech et al.65
Knapen et al.71
30 older women
50 postmenopausal, 50
premenopausal women
Ca 420 ␮g vitamin K in the diet
ucOC
1 mg vitamin K1 or 1 mg vitamin
K1 plus 400 IU vitamin D
ucOC
1 mg vitamin K1, ucOC
1 mg vitamin K1, urinary
excretion of calcium and
hydroxyproline
Results
ucOC decreased significantly in the groups
receiving vitamin K (vitamin K only and
vitamins K ⫹ D); in the vitamin D–only group,
ucOC did not change significantly
80 ␮g/d vitamin K1 reduced the elevated
postmenopausal levels of ucOC to the values
seen in premenopausal women
Among all supplemented groups, mean ucOC
decreased from 7.6% to 3.4% without
significant differences by age or sex; 102 of 112
subjects had a decrease of ucOC ⬎ 1%
Vitamin K restored carboxylation of osteocalcin
15–20% increase in the markers of bone formation
was seen with a 20–25% reduction in the
markers of bone resorbtion; urinary calcium
excretion was reduced by 21%
Significant reduction in ucOC
Vitamin K1 improved the carboxylation of
osteocalcin, vitamins K1 plus D showed a
similar result
Significant reduction in ucOC
Urinary Ca and hydroxyproline excretion was
reduced in the postmenopausal women (“fast
losers”); similar reduction was seen in the
premenopausal women
ucOC, undercarboxylated osteocalcin.
with a food-frequency questionnaire in 72 327 women aged 38 to
62 y. During a 10-y follow-up 270 atraumatic hip fractures were
reported. Age-adjusted relative risk was significantly reduced by
30% in women with a vitamin K intake above 109 ␮g/d. In 335
male and female participants of the Framingham Heart Study54 the
association of dietary vitamin K intake with hip fracture and BMD
was investigated. Vitamin K intake was assessed with a foodfrequency questionnaire, and the follow-up period lasted 7 y.
Subjects in the highest quartile of vitamin K intake (median: 254
␮g/d) had a significantly lower adjusted relative risk of hip fracture
than those in the lowest quartile of intake (median: 56 ␮g/d). There
was no significant association between vitamin K intake and BMD.
It should be emphasized that food items rich in vitamin K
obviously can significantly contribute to bone health. In the
Nurses’ Health Study53 consumption of lettuce as a source of
vitamin K1 was inversely associated with the risk of hip fracture.
A pilot study in an Asian population who ate frequently natto, rich
in vitamin K2, also reported an inverse association between incidence of hip fractures and natto consumption.55
Vitamin K Antagonists and Bone Health
Because the commonly prescribed oral anticoagulants are vitamin
K antagonists, studies of patients taking those drugs have investigated the effect of vitamin K on bone status. Several such studies
have been conducted, with mixed results. Some studies56 –59 found
no relation between the use of a vitamin K antagonists and bone
status, whereas other studies did.60 – 63 These studies are criticized
for potential bias. For example, the fact that the participants were
severely ill with chronic vascular diseases might have influenced
physical activity, a very important factor in bone health. The impact of vitamin K antagonists on bone health remains controversial.
INTERVENTION STUDIES
Several research groups have conducted intervention studies investigating the effect of vitamin K intake in nutritional and pharmacological dosages in relation to changes in serum levels of
osteocalcin and/or bone density or fracture rates (Tables IV and
V).
Sokoll et al.64 provided nine young adult subjects diets containing approximately 420 ␮g/d of vitamin K and found that this
dietary intervention significantly reduced the concentration of circulating ucOC. This effect of vitamin K on ucOC has been
confirmed in a number of studies (Table IV): 1 mg of vitamin K1/d
in elderly women,65 1 mg of vitamin K1/d in young and elderly
men and women,30 1 mg of vitamin K1/d in cosmonauts,66 and 10
mg of vitamin K1/d in female athletes.67 These studies used different doses in different populations with the same finding: significant declines of ucOC. Actually, as little as 80 ␮g of vitamin K1/d
in addition to their diets sufficed to bring ucOC levels in postmenopausal women back to the values seen before menopause.68
Further, in a short-term study69 postmenopausal women with previous wrist fractures were given a supplement of 1 mg of vitamin
K1/d alone or vitamin K1 (1 mg/d) plus vitamin D (400 IU of
vitamin D2/d) for 2 wk. As expected, vitamin K normalized ucOC.
The addition of vitamin D had no additional effect on osteocalcin
levels. A similar finding was reported recently for vitamin K2. A
daily dose of 45 mg significantly decreased ucOC in Japanese
women who experienced fractures at various sites; vitamin D did
not have the same effect.70
It has been reported that vitamin K not only affects ucOC but
also reduces significantly urinary calcium excretion. In postmenopausal women receiving 1 mg/d of vitamin K171 or 45 mg/d of
vitamin K272 urinary calcium excretion was significantly reduced.
884
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Nutrition Volume 17, Number 10, 2001
TABLE V.
INTERVENTION STUDIES: EFFECT OF VITAMIN K ON BONE DENSITY AND FRACTURE RATE
Study
Population
Bolton-Smith et al.80
244 postmenopausal women,
age: 60–85 y
Shiraki et al.79
241 women with osteoporosis
(120 active/121 placebo).
Yonemura et al.75
20 glomerulonephritis patients
receiving steroid treatment
Iwamoto et al.76
92 postmenopausal women,
age: 55–81 y
Ishida et al.78
120 postmenopausal women,
age: 46–96 y
Somekawa et al.77
110 women, mean age: 46.2 y,
GnRH agonist–induced
(Leuprolide) bone loss in
women with estrogendependent diseases (i.e.,
endometriosis)
Sato et al.74
108 patients with hemiplegia
after stroke
Orimo et al.81
80 patients with osteoporosis
Orimo et al.72
546 patients with osteoporosis
Akjba et al.73
17 dialysis patients
Daily dose/endpoint
Group 1: Vitamin K1 200 ␮g
Group 2: Vitamin D 10 ␮g ⫹
calcium 1 g
Group 3: combination of 2 and 3
Group 4: placebo
Duration: 2 y
Bone mineral density
45 mg vitamin K2, duration: 2 y
Fracture rate
45 mg vitamin K2, duration:
10 wk
Bone mineral density
Group 1: 0.75 ␮g 1-␣-25
hydroxyvitamin D3
Group 2: 45 mg vitamin K2
Group 3: vitamins D3 plus K2
Group 4: 2 g calcium lactate
Duration: 2 y
Bone mineral density
Group 1: 1 ␮g ␣-calcidiol
Group 2: 45 mg vitamin K2
Group 3: conjugated estrogens
Group 4: etidronate
Group 5: calcitonin
Duration: 1 y
Bone mineral density, fracture
rate
Group 1: Leuprolide
Group 2: Leuprolide plus
45 mg vitamin K
Group 3: Leuprolide plus 0.5 ␮g
1,25(OH)2D3
Group 4: Leuprolide plus 45 mg
vitamin K and 0.5 ␮g
1,25(OH)2 D3
Duration: 6 mo
Bone mineral density
45 mg vitamin K2, duration: 1 y
Bone mineral density
90 mg vitamin K2, duration: 2 y
Bone mineral density
Group 1: 45 mg vtamin K2,
Group 2: 1 ␮g 1-␣-vitamin D3
Duration: 48 wk
Bone mineral density
45 mg vitamin K2, duration: 1 y
Bone mineral density
GnRH, gonadotropin-releasing hormone; 1,25(OH)2D3, 1,25-dihydroxyvitamin D3.
Results
Combination of vitamins D ⫹ K1 significantly increased
bone mineral density at the ultradistal radius suggesting
a synergistic effect of vitamins D and K with regard to
bone mineral density
The vitamin K2 group had significantly fewer new fractures
than the placebo group (14 versus 35); most evidently
new occurring vertebral fractures were lower in the
vitamin K2 group (13 versus 30)
Vitamin K2 administration reduced steroid-induced bone
loss
Combined administration of vitamins K2 plus D3
significantly increased bone mineral density after 2 y of
treatment compared with the calcium-only group,
combined treatment of vitamins D and K was superior to
vitamin K–only and vitamin D–only therapies
Incidence of new fractures decreased significantly in all
groups, bone mineral density increased in all groups too,
yet this change was significant only in the estrogen
group
The GnRH agonist–induced bone loss was prevented by the
administration of vitamin K2 (to a greater extent than
after administration of vitamin D3); the best results were
seen with administration of vitamins K2 plus D3
A significant increase of 4.3% in bone mineral density was
seen on the paralyzed side in the vitamin K2 group
versus a reduction of 4.7% in the control group; for the
non-paralyzed body half, a reduction of 0.9% was seen
in the vitamin K2 group, with a reduction of 2.7% in the
control group
Bone density increased by 2.2% in the vitamin K group but
decreased 7.3% in the placebo group (P ⬍ 0.05); urine
calcium excretion was reduced in the vitamin K group
Arm bone mineral density increased by 2.1% in the vitamin
K group but decreased by 2.4% in the placebo group
(P ⬍ 0.001); no significant difference in vertebral bone
mineral density was seen
The loss of bone mass due to renal insufficiency was
reduced in the vitamin K group when measured at
different points of the skeleton
Nutrition Volume 17, Number 10, 2001
The same finding was reported for female marathon runners67
taking supplements containing 10 mg/d of vitamin K1.
The first human intervention study investigating the effect of
vitamin K on markers of bone strength such as BMD was published 10 y ago. In a small study73 comprising 17 patients on
hemodialysis with low-turnover bone disease, supplementation
with vitamin K2 (45 mg/d for 12 mo) prevented loss of bone
density. Orimo et al.72 confirmed those findings in a placebocontrolled clinical study comprising 546 patients with osteoporosis. The subjects receiving 45 mg/d of vitamin K2 had significantly
higher bone densities than did the controls after 1 y of treatment.
The effect of vitamin K2 on bone density was superior to that of
vitamin D (1 ␮g/d of ␣-hydroxyvitamin D3).72
In the ensuing years a number of human intervention studies
have investigated the possible role of vitamin K in bone health
(Table V). All but one of these studies used high dosages of
vitamin K2 and were carried out in Asian populations. In 108
patients with hemiplegia after stroke, a significant BMD increase
was seen on the paralyzed side after a daily treatment of 45 mg of
vitamin K2 for 1 y.74 In another study, a daily dose of 45 mg of
vitamin K2 given as part of a 10-wk prednisolone regimen prevented prednisolone-induced bone loss in 20 patients with glomerulonephritis, as measured by BMD.75 There is also evidence in
human clinical studies that vitamin D and vitamin K2 may work
synergistically as it relates to bone strength. In 92 postmenopausal
women, a combination of 45 mg of vitamin K2 plus 0.75 ␮g of
1-␣-25-hydroxyvitamin D3 per day for 2 y resulted in a significant
increase of BMD that was superior to that in the groups receiving
vitamin D3 only and vitamin K2 only.76 Another study evaluated
the effect of vitamin K2 and/or 1,25-dihydroxyvitamin D3 on
gonadotropin-releasing hormone agonist–induced bone loss in
women with estrogen-dependent diseases such as endometriosis.77
In the gonadotropin-releasing hormone agonist group BMD decreased 5.3% in 6 mo. The group receiving vitamin K2 plus
vitamin D3 had the lowest decrease of BMD. The effect of vitamin
K2 only on BMD was greater than that of vitamin D3 only.
Two studies78,79 reported that a daily dose of 45 mg of vitamin
K2 administered for 1 or 2 y not only increases BMD but also
significantly reduces fractures at different sites. During a 2-y
period 49 new fractures occurred in 190 osteoporotic patients, 35
of which were in the placebo group and 14 were in the vitamin K2
group.79 Most evidently, vertebral fractures were reduced (30
fractures in the placebo group versus 13 fractures in the vitamin K2
group).
Preliminary data from a placebo-controlled, randomized clinical trial investigating the effect of vitamin K1 on BMD in postmenopausal women have been published.80 To my knowledge, this
is the only published data from a well-controlled clinical trial on
the effect of vitamin K1 on BMD at an intake that can be obtained
from the diet. The study included 244 postmenopausal women who
daily received a placebo, 200 ␮g of vitamin K1, 10 ␮g of vitamin
D plus 1 g of calcium, or 200 ␮g of vitamin K1, 10 ␮g of vitamin
D, plus 1 g of calcium. After a 2-y intervention period, BMD of the
distal radius increased significantly in the group receiving vitamin
K1 plus vitamin D and calcium.
SAFETY
Vitamin K has a very wide safety range. No adverse effects or
hazards associated with the ingestion of natural sources of vitamin
K have been reported.19 In fact, the human clinical intervention
studies cited above impressively demonstrate the wide safety range
of this nutrient. It is noteworthy, that in a double-blind, placebocontrolled, human study, even a daily dose of 90 mg of vitamin K2
given for 2 y did not cause any relevant adverse effects.81 The
recommendations for the daily dietary intake of vitamin K82 as
issued recently by the Institute of Medicine also acknowledge the
wide safety margin of vitamin K: “A search of the literature
Vitamin K and Bone
885
revealed no evidence of toxicity associated with the intake of
either the phylloquinone (vitamin K1) or menaquinone (vitamin
K2) form of vitamin K.” It should be mentioned that in the United
States vitamin K has the status Generally Recognized as Safe.
CONCLUSIONS
Osteoporosis is a multifactorial chronic disease that may become
even more prevalent and more of a public health problem in the
decades to come.3,4 Recent research has indicated that a number of
macro- and micronutrients are involved in the development of
bone health.8 –14
In the past decade it has become evident that vitamin K has a
significant role to play in human health that is beyond its wellestablished function in blood clotting. There is a consistent line of
evidence in human epidemiologic and intervention studies that
clearly demonstrates that vitamin K can improve bone health. The
human intervention studies showed that vitamin K can increase
BMD72–75 in osteoporotic people and reduce fracture rates.78,79
Further, human intervention studies have shown that vitamins K
and D, a classic in bone metabolism, can work synergistically on
bone density.76,77 Most of these studies used vitamin K2 at rather
high doses in Asian populations, a fact that has been criticized as
a shortcoming of these studies. However, the preliminary results of
the first human intervention study80 using a daily dose of 200 ␮g
of vitamin K1 in a white population have shown that vitamin K
coadministered with vitamin D significantly increases BMD. Certainly, the complete evaluation of that trial will shed more light on
the role of vitamin K1 in bone health, as would a study on a daily
dose of 1 mg of vitamin K1 in postmenopausal women, which has
been launched recently by the National Institutes of Health.
Several mechanisms are suggested in the modulation by vitamin K on bone metabolism. Besides the ␥-carboxylation of osteocalcin, a protein believed to be involved in bone mineralization,24 –29
vitamin K also might affect other parameters of bone metabolism.
There is increasing evidence that vitamin K positively affects
calcium balance, a key mineral in bone metabolism. In epidemiologic studies, a diet rich in vitamin K was associated with calcium
retention34; and in several human intervention studies, decreased
calcium excretion was observed after vitamin K administration.67,71,81 The extent to which this effect is brought about by
␥-carboxyl glutamic acid– containing proteins in the kidney35 or
possibly other mechanisms requires further clarification.
In conclusion, the results of human studies published during the
previous decade on vitamin K and bone metabolism point to a
beneficial effect of that vitamin in bone health. In this context, it
appears noteworthy that the Institute of Medicine has recently
revised its recommendations for the daily dietary intake of vitamin
K.82 The dietary reference intakes for people 19 y and older are
now 90 ␮g/d for females and 120 ␮g/d for males, an increase of
approximately 50%. Experimental and placebo-controlled studies
in humans should clarify our understanding of the role vitamin K
plays in improving bone health.
REFERENCES
1. World Health Organization. Assessment of fracture risk and its application to
screening for postmenopausal osteoporosis. WHO Technical Report Series 843.
Geneva: World Health Organization, 1994
2. Miller PD, Bonnick SL. Clinical application of bone densitometry. In: Favus MJ,
ed. Primer on the metabolic bone diseases and disorders of mineral metabolism,
4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999:152
3. Melton LJ III. How many women have osteoporosis now? J Bone Miner
Res1995;10:175
4. NIH Consensus Statement. Optimal calcium intake. Nutrition 1995;11:409
5. Riggs BL, Melton LJ Jr. The worldwide problem of osteoporosis: insights
afforded by epidemiology. Bone 1995;17:505S
886
Weber
6. Cummings SR, Rubin SM, Black D. The future of hip fractures in the United
States. Clin Orthop 1990;252:163
7. Wasnich RD. Epidemiology of osteoporosis. In: Favus MJ, ed. Primer on the
metabolic bone diseases and disorders of mineral metabolism, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999:257
8. Ilich-Jasminka Z, Kerstetter JE. Nutrition in bone health revisited: A story
beyond calcium. J Am Coll Nutr 2000;19:715
9. Sellmeyer DE, Stone KL, Sebastian A, Cummings SR. A high ratio of dietary
animal to vegetable protein increases the rate of bone loss and risk of fracture in
postmenopausal women. Am J Clin NutrBone 2001;73:118
10. Heaney RP. Protein intake and bone health: the influence of believe systems.
Am J Clin NutrBone 2001;73:5
11. Heaney RP. Nutrition, and Osteoporosis. In. Favus MJ, ed. Primer on the
metabolic bone diseases and disorders of mineral metabolism, 4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999:270
12. New SA. Bone health: the role of micronutrients. Br Med Bull 1999;55:619
13. Weber P. The role of vitamins in the prevention of osteoporosis—a brief status
report. Int J Vitam Nutr Res 1999;69:194
14. Anderson JJB, Rondano P, Holmes A. Nutrition, life style and quality of life.
Scand J Rheumatol 1996;25:65
15. Shearer MJ, Bach A, Kohlmeyer M. Chemistry, nutritional sources, tissue distribution amd metabolism of vitamin K with special reference to bone health. J
Nutr 1996;126:1181S
16. Schurgers LJ, Geleijnse JM, Grobbee DE, et al. Nutritional intake of vitamin K1
(phylloquinone) and K2 (menaquinone) in the Netherlands. J Nutr Environ Med
1999;9:115
17. Lipsky JJ. Nutritional sources of vitamin K. Mayo Clin Proc 1994;69:462
18. Suttie JW. The importance of menaquinones in human nutrition. Annu Rev Nutr
1995;15:399
19. Suttie JW, Vitamin K. In: Rucker RB, Suttie JW, McCormick DB, Machlin LJ,
eds. Handbook of vitamins, 3rd ed, revised and expanded. New York: Marcel
Dekker, 2001:115
20. Berkner KL. The vitamin K– dependent carboxylase. J Nutr 2000;130:1877
21. Ferland G. The vitamin K-dependent proteins: an update. Nutr Rev 1998;56:223
22. Vermeer C, Knapen MHJ, Jie K-SG, Grobbee DE. Physiological importance of
extra-hepatic vitamin K-dependent carboxylation reactions. Ann NY Acad Sci
1992;669:21
23. Suttie JW. Vitamin K-dependent carboxylase. Annu Rev Biochem 1995;54:459
24. Binkley NC, Suttie JW. Vitamin K nutrition and osteoporosis. J Nutr 1995;125:
1812
25. Robey PG, Borkey AL. GLA-containing proteins. In: Marcus R, Feldman D,
Lelsey J, eds. Osteoporosis. Orlando: Academic Press, 1996:142
26. Price PA, GLA-containing proteins of bone. Connect Tissue Res 1989;21:51
27. Ducy P, Desbois C, Boyce B, et al. Increased bone formation in osteocalcindeficient mice. Nature 1996;382:448
28. Boskey AL, Gadaleta S, Gundberg C, et al. Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the
function of osteocalcin. Bone 1998;23:187
29. Khosla S, Kleerekoper M. Biochemical markers of bone turnover. In: Favus MJ,
ed. Primer on the metabolic bone diseases and disorders of mineral metabolism,
4th ed. Philadelphia: Lippincott Williams & Wilkins, 1999:128
30. Binkley NC, Krueger DC, Engelke JA, Foley AL, Suttie JW. Vitamin K supplementation reduces serum concentration of under-gamma-carboxylated osteocalcin in healthy young and elderly adults. Am J Clin Nutr 2000;72:1523
31. Shearer MJ. Vitamin K. Lancet 1995;345:229
32. Ferland G, Sadowski JA, O’Brien ME. Dietary induced subclinical vitamin K
deficiency in normal human subjects. J Clin Invest 1993;91:1761
33. Scholz-Ahrens KE, Bohme P, Schrezenmeir J. Vitamin K deficiency affects
calcium retention, bone mineralization and APb in growing and ovariectomized
rats. Osteoporos Int 1996;6:S141
34. Sakamoto N, Nishiike T, Iguchi H, Sakamoto K. The effect of diet on blood
vitamin K status and urinary mineral excretion assessed by a food questionnaire.
Nutr Health 1999;13:1
35. Angayarkanni-N, Selvam-R. Effect of gamma-glutamyl carboxylation of renal
microsomes on calcium oxalate monohydrate crystal binding in hyperoxaluria.
Nephron 1999;81:342
36. Koshihara Y, Hoshi K, Ishibashi H, Shiraki M. Vitamin K2 promotes
1-alpha,25(OH)-2 vitamin D-3–induced mineralization in human periosteal osteoblasts. Calcif Tissue Int 1996;59:466
37. Hara K, Akiyama Y, Tomiuga T, et al. Influence of vitamin D3 on inhibitory
effect of vitamin K2 on bone loss in ovariectomized rats. Folia Pharmacol Jpn
1994;104:101
38. Matsunaga S, Ito H, Sakou T. The effect of vitamin K and D supplementation on
ovariectomy-induced bone loss. Calcif Tissue Int 1999;65:285
39. Koshihara Y, Hoshi K, Shiraki M. Vitamin K2 (menatetrenon) inhibits prosta-
Nutrition Volume 17, Number 10, 2001
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
glandin synthesis in cultured human osteoblast-like periosteal cells by inhibiting
prostaglandin H synthase activity. Biochem Pharmacol 1993;46:1355
Reddi K, Henderson B, Meghji S, et al. Interleukin 6 production by
lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Cytokine 1995;7:287
Hart JP, Shearer MJ, Klenerman L, et al. Electrochemical detection of depressed
circulating levels of vitamin K1 in osteoporosis. J Clin Endocrinol Metab 1985;
60:1268
Hodges SJ, Pilkington MJ, Stamp TCB, et al. Depressed levels of circulating
menaquinones in patients with osteoporotic fractures of the spine and femoral
neck. Bone 1991;12:387
Kanai T, Takagi T, Masuhiro K, et al. Serum vitamin K level and bone mineral
density in post-menopausal women. Gynecol Obstet 1997;56:25
Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD. Circulating levels of
vitamins K1 and K2 decreased in elderly women with hip fracture. J Bone Miner
Res 1993;8:1241
Tamatani M, Morimoto S, Nakajima M, et al. Participation of decreased circulating levels of vitamin K in bone mineral loss of elderly men. J Bone Miner Res
1995;10:S248
Tamatani M, Morimoto S, Nakajiama M, et al. Decreased circulating levels of
vitamin K and 25-hydroxyvitamin D in osteoporotic elderly men. Metabolism
1998;47:195
Jie KSG, Bots ML, Vermeer C, Witteman JCM, Grobbee DE. Vitamin K status
and bone mass in women with and without aortic atherosclerosis: a populationbased study. Calcif Tissue Int 1996;59:352
Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest
1993;91:1769
Schoon EJ, Mueller MC, Vermeer C, et al. 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;48:473
Szulc P, Arlot M, Chapuy MC, et al. Serum undercarboxylated osteocalcin
correlates with hip bone mineral density in elderly women. J Bone Miner Res
1994;9:1591
Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture: a three year follow-up study. Bone
1996;18:487
Sugiyama T, Kawai S. Carboxylation of osteocalcin may be related to bone
quality:a possible mechanism of bone fracture prevention by vitamin K. J Bone
Miner Metab 2001;19:146
Feskanich D, Weber P, Willett WC, et al. Vitamin K intake and hip fractures in
women: a prospective study. Am J Clin Nutr 1999;69:74
Booth SL, Tucker KL, Chen H, et al. Dietary vitamin K intakes are associated
with hip fracture but not with bone mineral density in elderly men and women.
Am J Clin Nutr 2000;71:1201
Kaneki M, Hedges 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
Jamal SA, Browner WS, Bauer DC, Cummings SR. Warfarin use and risk for
osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group.
Ann Intern Med 1998;128:829
Houvenagel E, Leloire O, Vanderlinden T, et al. Taux d’osteocalcine et masse
osseuse chez les patients recevant des antivitamines K. Rev Rhumat Mal Osteoartic 1989;56:677
Rosen HN, Maitland LA, Suttie JW, et al. Vitamin K and maintenance of skeletal
integrity in adults. Am J Med 1993;94:62
Piro LD, Whyte MP, Murphy WA, Birge SJ. Normal cortical bone mass in
patients after long term coumadin therapy. J Clin Endocrinol Metab 1982;54:470
Caraballo PJ, Heit JA, Atkinson EJ, et al. Long-term use of oral anticoagulants
and the risk of fracture. Arch Intern Med 1999;159:1750
Resch H, Pietschmann P, Krexner E, Willvonseder R. Decreased peripheral bone
mineral content in patients under anticoagulant therapy with phenprocoumon. Eur
Heart J 1991;12:439
Monreal M, Olive A, Lafoz E, Del Rio L. Heparins, coumarin, and bone density.
Lancet 1991;338:706
Fiore CE, Tamburino C, Foti R, Grimaldi D. Reduced bone mineral content in
patients taking an oral anticoagulant. South Med J 1990;83:538
Sokoll LJ, Booth SL, O’Brien ME, et al. 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;65:779
Plantalech LC, Chapuy MC, Guillaumont M, et al. Impaired carboxylation of
serum osteocalcin in elderly women: effect of vitamin K1 treatment. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress Aps,
1990:345
Caillot-Augusseau A, Vico L, Heer M, et al. Space flight is associated with rapid
decrease of undercarboxylated osteocalcin and increases of markers of bone
Nutrition Volume 17, Number 10, 2001
67.
68.
69.
70.
71.
72.
73.
74.
resorption without changes in their circadian variation:observations in two cosmonauts. Clin Chem 2000;46:1136
Craciun AM, Wolf J, Knapen MHJ, Brouns F, Vermeer C. Improved bone
metabolism in female elite athletes after vitamin K supplementation. Int Sports
Med 1998;19:479
Schaafsma A, Muskiet FAJ, Storm H, et al. Vitamin D3 and vitamin K1 supplementation of Dutch postmenopausal women with normal and low bone mineral
densities:effects on serum 25-hydroxyvitamin D and carboxylated osteocalcin.
Eur J Clin Nutr 2000;54:626
Douglas AS, Robine SP, Hutchison JD, et al. Carboxylation of osteocalcin in
post-menopausal osteoporotic women following vitamin K and D supplementation. Bone 1995;17:15
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 2001;54:219
Knapen MHJ, Hamulyak K, Vermeer C. The effect of vitamin K supplementation
on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann
Intern Med 1989;111:1001
Orimo H, Shiraki M, Fujita T, et al. Clinical evaluation of Menatetrenone in the
treatment of involutional osteoporosis—a double-blind multicenter comparative
study with 1-a-hydroxyvitamin D3 (abstract). J Bone Miner Res 1992;7(suppl I):S122
Akjba T, Kurihara S, Tachibana K, et al. Vitamin K (K) increased bone mass
(BM) in hemo-dialysis patients (pts) with low-turnover bone disease. (LTOBD)
J Am Soc Nephrol 1991;608:42P
Sato Y, Honda Y, Kuno H, Oizumi K. Menatetrenone ameliorates osteopenia in
disuse-affected limbs of vitamin D- and K-deficient stroke patients. Bone 1998;
23:291
Vitamin K and Bone
887
75. Yonemura K, Kimura M, Miyaji T, Hishida A. Short-trem effect of vitamin K
administration on prednisolone-induced bone loss of bone mineral density in
patients with chronic glomerulonephritis. Calcif Tissue Int 2000;66:123
76. Iwamoto J, Takeda T, Ichimura S. Effect of combined administration of vitamin
D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J Orthop Sci 2000;5:546
77. Somekawa Y, Chiguchi M, Harada M, Ishibashi T. Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by
leuprolide. J Clin Endocrinol Metab 1999;84:2700
78. Ishida Y, Soh H, Ogawa S, Kawahara, Murata H. A one-year randomized
controlled trial of hormone replacement therapy, bisphosphonate, calcitonin,
vitamin D and vitamin K in women with postmenopausal osteoporosis. J Bone
Miner Res 2000;15(suppl 1):S310
79. 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
80. Bolton-Smith C, Mole PA, McMurdo MET, Paterson CR, Shearer MJ. Two-year
intervention with phylloquinone (vitamin K1), vitamin D and calcium effect on
bone mineral content of older women. Ann Nutr Metab 2001;45 (suppl 1)46
81. Orimo H, Shiraki M, Tomita A, et al. Effects of menatetrenone on the bone and
calcium in osteoporosis:a double-blind pacebo-controlled study. J Bone Miner
Metab 1998;16:106
82. Institute of Medicine. Vitamin K. In: Dietary reference intakes for vitamin A,
vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy
Press, 2001:127
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