Relevant Clinical Inquiry Assignment

23/01/11

Vitamin K and Osteoporosis

The Inquiry:
In 2001, my mother and I arrived home from work to find my grandmother lying on the
bathroom floor with a broken hip. She was hospitalized for two months but her hip was never
repaired and within six months she passed away. The doctors were unable to repair her hip
because she was 82 years old with bones too brittle due to advanced osteoporosis. Osteoporosis
is a disease characterized by a significant decrease in bone density and the continued
deterioration of bone tissue. This process leads to an increase in bone fragility and the risk of
fractures particularly of the hip, spine and wrist. In North America osteoporosis affects 30% of
women and 12% of men over the age of 50.1
Current Naturopathic treatment practices for osteoporosis include prevention methods such as
increase weight bearing exercise and supplementation with calcium and vitamin D. However, for
over ten years researchers have been studying the use of vitamin K in the prevention and
treatment of osteoporosis. Vitamin K is a fat soluble vitamin generally known for its biological
role in the blood coagulation process. Recent research shows that bone forming cells synthesises
a protein called osteocalcin which is vitamin K dependant and may aid in the prevention of bone
mineral loss.2 In light of this the aim of this paper is to analyze current research in an effort to
answer the question Does vitamin K supplementation prevent bone density loss in patients with
osteoporosis thus reducing fracture risk?
Research Stratergy:
My Pub Med searches were: (Without limits)
1. Osteoporosis

Results: 51555

2. Osteoporosis Treatment

Results: 32104

3. Osteoporosis Prevention

Results: 13870

4. Vitamin K AND Osteoporosis

Results: 396

(Limits: Humans, Meta-Analysis, Randomized Control Trials, Reviews)

5. Vitamin K AND Osteoporosis

Results: 227 (31 free full text)

6. Peak Bone Mass AND Osteoporosis

Results: 372 (42 free full text)

All of my references, except for MD Consult, were found within the search results listed above. I
was also able to obtain the full texted articles from among the 31 free full text articles returned
from the limited search. This paper will focus mainly on the efficacy of Vitamin K
supplementation as a preventative measure against fracture risk in osteoporosis however some
mention will also be made as to its effects as a treatment option to improve bone mineral density
in persons with osteoporosis.
Discussion:
What is Osteoporosis?
Osteoporosis is a skeletal disease that affects the entire system. It is characterized by low bone
mass and continued deterioration of bone tissue thus increasing bone fragility. The most
important clinical significance of osteoporosis is fracture risk which may lead to disability and
increased mortality. The common sites for fractures are the vertebral discs, distal radius and
proximal femur.3 Osteoporosis is generally asymptomatic and is often time only diagnosed when
a fracture occurs. Risk factors for primary osteoporosis include advancing age and estrogen
deficiency seen after menopause. However, secondary osteoporosis can be caused by endocrine
disorders, inflammatory diseases, the use of certain medications like corticosteroids or
glucocorticoids, and also nutritional deficiencies.4
As previously mentioned osteoporosis is generally asymptomatic therefore screening guidelines
have been put in place to detect bone mineral loss at an earlier age. The population of greatest
risk of osteoporosis is postmenopausal women usually over the age of 65, however, younger
women may also be screened if there is a history of low trauma fracture, history of osteoporotic
fracture in 1st degree relative, low body weight (<127 lbs).5 The Dual X-ray Absorptiometry
(DXA) scan is the gold standard technique for measuring bone mineral density using two scores
the T-score and the Z-score. The T-score is a measure of the individuals bone mass density
compared to that of a normal young adult. The Z-score is another measure used which compares
the score to individuals in the same peer population. An individual with a measured T-score of
-2.5 is diagnosed as osteoporotic.4
Conventional Treatment Methods:
The two main goals of conventional treatment for osteoporosis is to prevent fractures and
maintain or add bone mass. Drug therapy includes strontium ranelate used in the United
Kingdom and Europe, Bisphosphonates (Alendronate), Selective estrogen modulators
(Raloxifene) and Hormones (Teriparatide/Calcitonin). Non-drug therapy includes exercise,
nutrition and dietary supplementation e.g. Calcium and Vitamin D, smoking cessation and
alcohol consumption.4

Indications for the use of Vitamin K in preventing osteoporosis:

Bone is one of the tissues in our bodies that changes frequently over our lifetime as minerals are
deposited and reabsorbed continually. Peak bone mass is established by age 30, especially in
women, and remains constant until the onset of menopause or advance age in men. If an
adequate peak bone mass is not established in the early years then individuals would be at risk
for developing osteoporosis later in life.8 Bone mineral density is an important measure for
determining the onset of osteoporosis in post menopausal women and the elderly. This test
measures the density of minerals like calcium in the bone and helps to determine bone strength.
In the event that bone density is lower than normal supplementation with calcium and vitamin D
is part of conventional treatment, however, there is now evidence to show that Vitamin K
supplementation could also be beneficial.2
Osteocalcin, a protein synthesised by bone forming cells called osteoblasts, has been found to
play a role in the formation of bone matrix and mineralization. Vitamin D has been shown to
regulate the synthesis of this protein however research shows that the proper functioning of this
protein depends on Vitamin K.2 Vitamin K is known mostly for its blood coagulation property,
however, it also plays an important, yet underrated role against osteoporosis. Research is now
showing that Vitamin K has the ability to regulate calcium binding through the amino acid
gamma-carboxyglutamic acid (Gla), and the protein osteocalcin. Vitamin K regulates the
carboxylation of osteocalcin and the product of this process is believed to have mineral binding
properties. This process helps maintain calcium in bone and out of the plasma and soft tissue.
Undercaboxylated osteocalcin is now being considered a sensitive measure of vitamin K status in
bone as low plasma levels of Vitamin K are associated with low bone mineral density.6, 7
Analysis of study findings:
Type

Reference
and Date

Number of
studies/
Participants
5 (n=5691)

Type of
Vitamin K
studied

Summary of results

Phylloquinone
(K1) and
Menatetrenone
(K2)

No benefit to BMD or
fracture risk was seen with K1
and K2 was not associated
with a reduction in fracture
risk.
Supplementation with both
K2 and K1 reduces bone loss.
There was also a reduction of
fracture risk in Japanese
women.
Supplementation helped to

Metaanalysis

Stevenson
et al 20093

Metaanalysis

Cockayne et 13 (n=1266)
al 20069

Phytonadione
(K1) and
Menaquinone
(K2)

Meta-

Iwamoto et

Menatetrenone

analysis

al 200610

(n=unspecified)

Systematic
Review

10
(n=unspecified)

Randomized
Control Trial

RyanHarshman
et al 200411
Binkley et
al 200912

Randomized
Control Trial

Booth et al
20086

452 (men and

women)

Randomized
Control Trial

Knapen et
al 200713

325
Menatetrenone
(postmenopausal
women)

Clinical
Booth et al
Study
20047
(Framingham
Offspring
Study)

Phylloquinone

381
Phylloquinone
(postmenopausal and
women)
Menatetrenone

Phylloquinone

1604 (741 men

Phylloquinone
and 863 women)

reduce fracture risk in

postmenopausal women and
was more effective in
increasing BMD when used
in conjunction with
bisphosphates.
Dietary intake of < 100g K1
is not optimal for bone
health.
No effect was seen in bone
turn over or BMD of the
lumbar, hip and femur
regions. Reduced serum
uncarboxylated osteocalcin
was reported.
Supplementation at a dose
attainable through diet does
not have any additional
benefit on bone health at the
hip or spine. Done in
conjunction with Calcium
and Vitamin D.
Supplementation increased
bone mass content (BMC)
and femoral neck width but
had no effect on DXA-BMD.
Low plasma K1 was
associated with low BMD at
the hip in men and spine in
postmenopausal women not
on estrogen therapy.

Based on the studies listed above there seems to be some contradiction in the results as to the
efficacy of Vitamin K as a preventative option against bone loss and fracture risk. This does not
mean however that consideration should not be made of this line of treatment. Meta-analysiss
are considered gold standard in determining the overall effectiveness of an intervention and of
the three mentioned above two reported positive results for the use of Vitamin K
supplementation.

Limitations:

One of the main limitations of the studies was heterogeneity both in the design of the study and
in the type of Vitamin K used. The studies lacked consistency in the population being studied
with some concentrating on just postmenopausal women and others studying both men and
women. One review found benefit in the use of Vitamin K1 however the population studied was
postmenopausal Japanese women who generally have a lower bone mass density compared to
Caucasian women therefore the study cannot be considered comparable to a North American
population.3 As it pertains to type of Vitamin K studied, two of the meta-analysiss reviewed
studies that assessed both vitamin K1 and K2 while the other only assessed studies showing the
efficacy of Vitamin K2.
In terms of population studied, of the studies that assessed postmenopausal women only one
study made mention of separating the population into women on estrogen therapy and those that
are not. This distinction is very important as it can help to determine the true efficacy of the
intervention of Vitamin K as estrogen therapy has also been proven to improve bone loss and
decrease fracture risk.7 Stevenson et al (2009) also reported a population limitation from one of
the studies reviewed stating that the OF study appears to have recruited participants at
substantially lower risk of vertebral fracture than did the smaller studies. This discrepancy in
population studied could potentially skew the outcome.
The actual outcome measures can also be considered limitations. Knapen et al (2007) suggested
that the outcome measures most important in determining bone strength and fracture risk are
bone mineral content and femoral neck width. The other studies assessed bone mineral content
by using the DXA scan however, this method does not take into account the size and thickness
(geometry) of bone, two properties that are considered to have independent contribution to bone
strength and fracture risk.13 Fracture risk as an outcome measure was challenged by one metaanalysis as the researchers of one study reported number of fractures as opposed to the number in
the population that received those fractures. This made it difficult to calculate relative risk.2
Although there were significant limitations the quality of the reviews and clinical trials cited was
good. Many of the studies suggested that supplementation with Vitamin K whether in the
Phylloquinone or Menatetrenone form would have some benefit in reducing fracture risk in
individuals with osteoporosis, however, more homogenous studies would need to be done to
solidify this finding.
Dose and Response duration:
The doses of Vitamin K used in the studies differed by type rather than by study. Most of the
studies used low dose for the assessment of Phylloquinone of 1 5 mg while some studies used
45 mg in the assessment of Menatetrenone.3, 9, 10, 12, 13 Two studies assessed the association of
dietary Vitamin K with low bone mass and found that a dietary intake of <100g to be
suboptimal however another supplemented with 500g and found no benefit.6, 11 in relation to
5

response duration, the meta-analysiss reviewed studies that had a duration of response ranging
from 6 36 months while the RCTs cited had a response range from 12 36 months.
Adverse effects:
Only two of the RCTs cited made mention of adverse effects of Vitamin K supplementation,
Knapen (2007) reported minor side effects from K2 supplementation specifically but did not
mention any exact conditions. Binkley (2009) reported that serious adverse events occurred in 29
of their participants but again the actual conditions were not mentioned. They also reported that
non serious events were more common however none of the effects were related to
Phylloquinone or Menatetrenone supplementation. Stevenson (2009) reported that there were no
adverse effects associated with Vitamin K supplementation for the studies they reviewed and
while Cockyne (2006) reported no adverse effects some of the authors of the studies they
reviewed reported minor gastrointestinal problems.
Clinical Implications:
The role of Vitamin K as an important factor in the functioning of the osteocalcin protein found
in bone cannot be ignored however the evidence of efficacy is so varied that it makes it difficult
to determine clinical relevance. Vitamin K deficiency has been associated with low bone mass
density therefore, based on the evidence reviewed I am confident to suggest that an increase in
dietary intake of Vitamin K, found in leafy dark green vegetables, especially for postmenopausal
women would have positive effects in stabilizing bone loss but not necessarily reversing it. This
is very significant as fracture risk can be reduced if bone loss is reduced. Therapeutically I would
suggest the use of Menatetrenone (K2), at a dose of 45 mg, as the form of Vitamin K that would
be most effective in reversing bone loss and reducing fracture risk. Also consideration would be
made to use this therapy in conjunction with bisphosphates as one meta-analysis reported that
treatment with both was more effective in preventing fractures than the use of the bisphosphates
alone.10
Conclusion:
Does vitamin K supplementation prevent bone density loss in patients with osteoporosis thus
reducing fracture risk? The contradictory results of the studies reviewed leaves this question
somewhat unanswered yet I believe there is still room for much consideration. The fact that
osteocalcin is an important protein in the process of mineral binding in bone and that Vitamin K
is needed for this protein to function adequately is sufficient indication for the need of optimum
levels of Vitamin K in the body. The evidence is also there to prove that therapeutic doses of
Vitamin K2 can also help to improve bone loss and reduce fracture risk however the limitations
of the studies place the results into question. I believe that once the limitations are addressed

more standardized trials should be undertaken in order to solidify the claims of the studies
already done.

References
1. Nova Scotia Department of Health. Managing osteoporosis. Report of the provincial
osteoporosis committee. June 2002.
2. Shearer, M. J. The roles of vitamins D and K in bone health and osteoporosis prevention.
Proceedings of the Nutrition Society. 1997:56(3):915-937.
3. Stevenson, M, et al. Vitamin K to prevent fractures in older women: systematic review
and economic evaluation. Health Technology Assessment. 2009:13(45)
4. Osteoporosis. MD Consult. [cited Feb 2009]. Available from
http://www.firstconsult.com .ezproxy.ccnm.edu/das/pdxmd/body/2354017753/1117299697?type=med&eid=9-u1.0-_1_mt_1014748
5. Hochberg, MC. Recommendations for Bone Mineral Density and identifying persons to
be treated for osteoporosis. Rheumatic Diseases Clinics of North America. 32(2006) 681
-689.
6. Booth, S.L. et al. Effect of vitamin K supplementation on bone loss in elderly men and
women. The Journal of Clinical Endocrinology Metabolism. April 2008, 93(4):1217
1223
7. Booth, S.L. et al. Associations between vitamin K biochemical measures and bone
mineral density in men and women. The Journal of Clinical Endocrinology Metabolism.
October 2004, 89(10):49044909
8. Bonjour, JP. et al. The importance and relevance of peak bone mass in the prevalence of
osteoporosis. Salud Publica of Mexico. 2009;51(1):S5-S17
9. Cockayne, S. Et al. Vitamin K and the prevention of fractures. Archives of Internal
Medicine. 2006;166:1256-1261
10. Iwamoto, J. Et al. Menatetrenone (Vitamin K2) and bone quality in the treatment of
postmenopausal osteoporosis. Nutrition Review. 2006;64(12):509-517
11. Ryan-Harshman, M. Et al. Bone health: New role of vitamin K? Canadian Family
Physician. 2004;50:993-997.

12. Binkley, N. Et al. Vitamin K treatment reduces undercarboxylated osteocalcin but does
not alter bone turnover, density, or geometry in healthy postmenopausal north american
women. The Journal of Bone and Mineral Research. 2009;24(6):983-991
13. Knapen, M. Et al. Vitamin K2 supplementation improves hip bone geometry and bone
strength indices in postmenopausal women. Osteoporosis International. 2007;18:963-972