Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care
BMJ 2005; 330 doi: https://doi.org/10.1136/bmj.330.7498.1003 (Published 28 April 2005) Cite this as: BMJ 2005;330:1003All rapid responses
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Dear Editor:
We read with interest the design of the study by Porthouse and
colleagues concluding that they found no evidence that calcium and vitamin
D reduced clinical fractures in elderly women.(1) The treatment
intervention was nurse-delivered lifestyle advice in conjunction with
daily oral supplementation of calcium and vitamin D. However, the authors
conclude that it was calcium and vitamin D supplementation that was
ineffective at reducing the fracture rate.(1)
We are concerned with discrepancy between the description and setting
of the intervention and the reporting of the results. The published title
compared with the ISRCTN registry title of the article (A randomized trial
of nurse led clinics to promote increased use of calcium with vitamin D
supplements for fracture prevention in women over 70 years) further
questions whether the original intervention was meant to be pharmaceutical
in nature or one of counseling, or both. This highlights the value of
clinical trial registries and, given this description, the study results
would be more fairly represented as nurse led clinics can promote
increased use of calcium and vitamin D supplements by counseling and
providing medication, but this did not lead to a reduced risk of
fractures.
Respectfully,
Daniela Gallo, BScPhm, RPh
Toronto, Canada
Andrew Wyllie, BScPhm, PharmD, RPh
Mount Sinai Hospital
Toronto, Canada
Reference
1. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T et al.
Randomised controlled trial of calcium and supplementation with
cholecalciferol (vitamin D3) for prevention of fractures in primary care.
BMJ 2005;330:1003.
Competing interests:
None declared
Competing interests: No competing interests
Dear editor,
J. Porthouse and coworkers conducted a trial in elderly women (> 70
years) with risk factors for hip fractures and found no effect of calcium
and supplementation with vitamin D3 on the rate of clinical fractures
compared to a control group. In addition, there was no effect on frequency
of falls and quality of life. However, these results should not be
interpreted in such a way, that there would be no rationale for the
supplementation of calcium and vitamin D in elderly people in order to
prevent fractures. Vitamin D deficiency and the resulting secondary
hyperparathyroidism are important pathophysiological causes for fractures
in elderly people. Therefore, the correction of vitamin D deficiency and
improving the calcium supply appear as a logical consequence. In
population with a high prevalence of vitamin D deficiency, several studies
have demonstrated the ability of calcium and vitamin D to reduce the
incidence of peripheral fractures (Chapuy et al. 1992, Dawson-Hughes et
al.1997, Larsen et al 2004).
Several reasons may be responsible for the
missing effect of calcium and vitamin D in the present study of Porthouse
and coworkers: The participating women were identified by risk factors
like low body weight (> 1/3 of participants), poor or fair health
(> 1/3 of participants), and genetic predisposition (maternal history
of hip fracture). These criteria may have selected women, who are at risk
for hip fracture resulting from other causes than vitamin D or calcium
deficiency. The average nutritional calcium intake of the participating
women was rather high (1075 mg daily in the intervention group and 1084 mg
daily in the control group) compared to other population (for example, the
average calcium intake in Germany is about 850 mg calcium daily). Data on
the vitamin D status are not reported. Only 7 % of the originally
identified women were recruited into the study. Therefore the sample may
not be representative for the population at risk. After 6 months only 61.3
% of the women in the intervention group were adherent to the treatment.
In the control group up to 6 % of the women reported to take calcium and
vitamin D. This percentage may have been greater since all women had been
instructed about the importance of adequate calcium and vitamin D intake.
Otherwise than stated by the authors, a dilution effect could have had a
greater impact on the results.
The ability of calcium and vitamin D to reduce the risk for falls and
fractures is underscored by a recent prospective double blind study in
Germany and Austria, which was conducted in elderly women with vitamin D
insufficiency (serum 25-OH-vitamin D <78 nmol/l) (Pfeifer et al.
2005). Therefore the recommendation to provide a sufficient supply of
calcium and vitamin D for elderly people should not be dismissed. This is
especially true for countries with a high prevalence of vitamin D
deficiency such as Germany (Scharla et al. 1996).
Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. N Engl J Med 337
(1997) 670-676
Chapuy MC, Arlot ME, Duboeuf F, et al. N Engl J Med 327 (1992) 1637-
1642
Larsen ER, Mosekilde L, Foldspang A. Journal of Bone and Mineral
Research 2004;19:370-378
Pfeifer M, Dobnig H, Minne HW, Suppan K. Osteoporos Int
2005;16(Supplement 3):S45
Scharla SH, Scheidt-Nave C, Leidig G, Woitge H, W¸ster C, Seibel MJ,
Ziegler R. Exp Clin Endocrinol Diabetes 1996; 104:289-292
Stephan Scharla, MD
Specialist in Internal Medicine/Endocrinology
Faculty member of the LMU University Munich
Salinenstrasse 8,
83435 Bad Reichenhall,
Germany
Competing interests:
None declared
Competing interests: No competing interests
Randomised controlled trial of supplementation with calcium and
vitamin D for prevention of fractures in primary care
It is not surprising that the York Trials Unit found no evidence that
supplementation with calcium and vitamin D reduced the risk of fractures
in women over 70.1 In 1984 Aitken found that those who suffered fractures
of the femoral neck had the same bone density as controls,2 thereby
showing that the essential cause of these age related fractures is loss of
balance and falling.
A week after the publication of the York trial a similar study from
Aberdeen was published which also showed no benefit from calcium and
vitamin D supplementation.3 We need therefore to turn from chemical
treatments for osteoporosis and direct our attention to physical
treatments which will not only prevent falls but also maintain bone
strength..
In 1970 Chalmers and Ho presented demographic evidence that fractures
of the femoral neck were inversely related to the level of physical
activity.4 Maintaining physical activity into old age not only prevents
osteoporosis, more importantly it preserves muscle coordination and
balance which are crucially important in preventing falls and fractures.
Alan W Fowler
1. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T,
Baverstock M, Birks Y, Dumville J, Francis RM, Iglesias C, Puffer S,
Sutcliff A, Watt I, Torgerson DJ. Randomised controlled trial of
supplementation with calcium and cholecalciferol (vitamin D¬Ù) for
prevention of fractures in primary care, BMJ 2005;330:1003-6.
2. Aitken JM. Relevance of osteoporosis in women with fractures of
the femoral neck. BMJ 1984;288:597-601.
3. The RECORD trial group. Oral vitamin D3 and calcium for secondary
prevention of low-trauma fractures in elderly people: a randomised placebo
controlled trial. Lancet 2005;365:1621-28.
4. Chalmers J, Ho KC. Geographical variations in senile
osteoporosis. J.Bone Jt. Surg. 1970;52B:667-675.
Competing interests:
None declared
Competing interests: No competing interests
In contrast to the general view, Porthouse et al. reported that the
daily supplementation with calcium and vitamin D did not result in any
significant reduction of bone fracture rates in community dwelling,
elderly women in the UK. As already raised in previous ‘rapid responses’
to this publication, the study suffers from a number of flaws mainly by
lacking: (1) any measurement of the calcium and vitamin D status to
control the effect of supplementation [1]; (2) proper control, since the
control group also got advice on how to improve dietary calcium and
vitamin D uptake, which even worsens point (1); (3) no information on
vitamin D status of the cohort at baseline.
The authors report that based on the results of a food questionnaire
the mean dietary calcium intake of subjects at study entry exceeded 1000
mg/day. Previous publications, which demonstrated a reduction of hip
fractures among institutionalised elderly women by supplementation with
calcium and vitamin D, consistently reported initial dietary calcium
intakes of about 500-600 mg/day [2,3]. This is in agreement with dietary
calcium intakes reported in several other recent studies in the US [4,5],
Scandinavia [6] or the SU.VI.MAX study in France.
Indeed, dietary calcium uptake in the UK might be higher than in
other countries, since foods such as bread and baked products, breakfast
bars and cereals or juices and other beverages are commonly fortified in
the UK. For example, 100 g of flour is required by law to be supplemented
with 200-400 mg of calcium [The UK Expert Group on Vitamins and Minerals;
www.food.gov.uk/multimedia/pdfs/evm0112p.pdf]. Thus, the high calcium
intakes reported in this study may reflect a British particularity,
although reports of lower calcium intakes in the UK also exist [7,8].
Taking this into account, it is most unfortunate that Porthouse and
colleagues did not screen for hypercalcemia and hypercalciuria either,
which can be suspected to have occurred in the supplemented subjects.
Thus, putting aside the experimental flaws, Porthouse et al. may
simply have confirmed what is common sense: that calcium and vitamin D
supplementation is of no additional use in the prevention of fractures for
subjects who already benefit from an optimal dietary calcium intake.
References:
1. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D
concentrations, and safety. Am J Clin Nutr 1999;69(5):842-56.
2. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al.
Vitamin D3 and calcium to prevent hip fractures in the elderly women. N
Engl J Med 1992;327(23):1637-42.
3. Chapuy MC, Pamphile R, Paris E, Kempf C, Schlichting M, Arnaud S, et
al. Combined calcium and vitamin D3 supplementation in elderly women:
confirmation of reversal of secondary hyperparathyroidism and hip fracture
risk: the Decalyos II study. Osteoporos Int 2002;13(3):257-64.
4. Ensrud KE, Duong T, Cauley JA, Heaney RP, Wolf RL, Harris E, et al. Low
fractional calcium absorption increases the risk for hip fracture in women
with low calcium intake. Study of Osteoporotic Fractures Research Group.
Ann Intern Med 2000;132(5):345-53.
5. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of calcium and
vitamin D supplementation on bone density in men and women 65 years of age
or older. N Engl J Med 1997;337(10):670-6.
6. Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI.
Can vitamin D supplementation reduce the risk of fracture in the elderly?
A randomized controlled trial. J Bone Miner Res 2002;17(4):709-15.
7. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3
(cholecalciferol) supplementation on fractures and mortality in men and
women living in the community: randomised double blind controlled trial.
Bmj 2003;326(7387):469.
8. Gregory J, Foster K, Tyler H, Wiseman M. The Dietary and Nutritional
Survey of British Adults. London: HMSO, 1990.
Competing interests:
None declared
Competing interests: No competing interests
Compliance with offered treatment is always difficult.
The reported adherence rate in the intervention group was 69% of
women completing follow up at 24 months and suggested to be 55% with the
inclusion of those known to be alive.
In figure 1 of the article I found some data on this where at 18
months follow up the adherence rate is published to be 58.6% (514/877).
This was apparently calculated by subtracting those who had died and ought
to include the ones that failed to return the questionnaires. All goes
well at 6 and 12 months when there appears to be a sudden unexplained
death rate (from 1185 to 877). By my calculations the adherence rate at 18
months can at best be 514/1185 44.3%, assuming no deaths between 12 and 18
months follow up.
I can try to conjure up the amount of patients that became adherent
between 18 months and 24 months but will leave that for now...
Competing interests:
None declared
Competing interests: No competing interests
Further to the study by Porthouse and colleagues (1), a timely meta-
analysis of double-blind randomised, controlled trials of oral vitamin D
supplementation (cholecalciferol) with or without calcium supplementation
vs calcium supplementation or placebo in older persons ( 60 years) has
just been published in the Journal of the American Medical Association
(2). The authors concluded that oral vitamin D supplementation between 700
to 800 IU/day appears to reduce the risk of hip and any nonvertebral
fractures (by 26% and 23% respectively), but that an oral vitamin D dose
of 400 IU/d is not sufficient for fracture prevention.
References
1. Porthouse J, Cockayne S, King C, et al. Randomised controlled
trial of calcium and supplementation with cholecalciferol (vitamin D3) for
prevention of fractures in primary care. BMJ 2005;330:1003-1008.
2. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture
Prevention With Vitamin D Supplementation: A Meta-analysis of Randomized
Controlled Trials . JAMA 2005;293:2257-2264.
Competing interests:
None declared
Competing interests: No competing interests
The study by Porthouse and colleagues (1) was seriously flawed, and
indeed, by the authors’ own admission, was so underpowered that they
‘could not reliably exclude a reduction in all fractures of less than
30%’; one wonders whether it should have been published at all. Certainly
it would be entirely inappropriate to conclude from this study that
calcium and vitamin D don't prevent fractures.
No reference was made to vitamin D status of the study participants
(which was presumably not assessed) but it would be expected that a
significant number would have been vitamin D deficient at the start of the
study.
Vitamin D status is most commonly assessed by measuring serum levels
of 25-hydroxyvitamin D [25(OH)D], the major circulating form. Although
published lower reference values for circulating 25(OH)D levels are
generally in the range 30-50 nmol/L, assessing ‘normal’ levels based on a
Gaussian distribution is now considered to be a grossly inaccurate method
of determining the normal range.
Using functional indicators of vitamin D status (such as intact
parathyroid hormone, calcium absorption, and bone mineral density),
several studies have more accurately defined vitamin D deficiency as
circulating 25(OH)D levels </= 80 nmol/L (2); Veith argues for a lower
limit of 100 nmol/L (3).
Calcium absorption increases with increasing 25(OH)D concentrations
up to ~80-90 nmol/L, and plateaus above that level. Heaney and colleagues
found calcium absorption to be 65% higher at 25(OH)D levels averaging 86.5
nmol/L than at levels averaging 50 nmol/L (4).
The (UK) National Diet & Nutrition Survey (5) found that the mean
25-hydroxyvitamin D 25(OH)D level for men was 48.3 nmol/L and for women
49.6 nmol/L; 57% of men and 54% of women had a 25(OH)D level of less than
50 nmol/L; 91% of men and 88% of women had 25(OH)D levels less than 80
nmol/L; 98% of men and 97% of women had 25(OH)D levels less than 100
nmol/L. Thus it appears that the majority of British adults have
suboptimal 25OHD levels.
Vitamin D deficiency is an even greater problem amongst the elderly
as a result of reduced sunlight exposure, and also the age-related
reduction in capacity to produce previtamin D3 even when exposed to
sunlight.
A vitamin D3 dose of 800 IU/day is inadequate to attain optimal serum
25(OH)D concentrations in the absence of substantial cutaneous production
of vitamin D.
In the RECORD trial, a secondary prevention study in hospital based
fracture clinics in the UK, mean baseline concentrations of 25(OH)D for a
sample of 60 participants were 15.2 ng/ml (38 nmol/L), rising to 24.9
ng/ml (62 nmol/L) after 1 year of supplementation with vitamin D3 800
IU/day (6). Thus, subjects in this trial were vitamin D deficient at the
start of the trial, and the vitamin D dose of 800 IU/day failed to raise
25(OH)D levels sufficiently to maximise calcium absorption.
To ensure that 25(OH)D levels exceed 100 nmol/L, a total vitamin D
supply of 4,000 IU of vitamin D3 is required (3). However, in cases of
established vitamin D deficiency, oral vitamin D3 doses of 8-12,000 IU
daily for 3 months or more are not infrequently required to attain optimal
vitamin D status. (Although vitamin D is potentially toxic, published
cases of vitamin D toxicity with hypercalcaemia all involve intake of
>/= 40,000 IU/day.)
In addition to using an inappropriately low dose of vitamin D3, a
poor choice of calcium supplement was made. Calcium carbonate may be
poorly absorbed in the absence of adequate gastric acid; the elderly are
especially prone to hypochlorhydria. A more appropriate choice would be
calcium citrate, as absorption of this does not seem to be affected by low
gastric acid.
Future trails should utilise an appropriate dose of vitamin D3, in
combination with calcium citrate, and, ideally, other important bone
nutrients (including vitamin K, boron, manganese, zinc, silicon, and
perhaps strontium).
In the meantime, the continued failure to recognise and adequately
treat vitamin D deficiency in patients at risk of fractures (as well as a
range of other conditions related to vitamin D deficiency, such as
diabetes, heart disease and many cancers) is likely to result in a great
deal of unnecessary suffering, as well as substantial direct and indirect
costs.
References
1. Porthouse J, Cockayne S, King C, et al. Randomised controlled
trial of calcium and supplementation with cholecalciferol (vitamin D3) for
prevention of fractures in primary care. BMJ 2005;330:1003-1008.
2. Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of
vitamin D sufficiency: implications for establishing a new effective
dietary intake recommendation for vitamin D. J Nutr 2005;135:317-322.
3. Veith R. Vitamin D supplementation, 25-hydroxyvitamin D
concentrations, and safety. Am J Clin Nutr 1999;69:482-56.
4. Heaney RP, Dowell S, Hale CA, Bendich A. Calcium absorption varies
within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr
2003;22:142-146.
5. Rushton D, Hoare J, Henderson L, Gregory J. The National Diet
& Nutrition Survey: adults aged 19 to 64 years. Volume 4: Nutritional
status (anthropometry and blood analytes), blood pressure and physical
activity The Stationary Office, London, 2004.
6. The RECORD Trial Group. Oral vitamin D3 and calcium for secondary
prevention of low-trauma fractures in elderly people (Randomised
Evaluation of calcium Or vitamin D, RECORD): a randomised placebo-
controlled trial. The Lancet 2005;365:1621-1628.
Competing interests:
None declared
Competing interests: No competing interests
In their prospective randomised trial of calcium and vitamin D
supplementation, Porthouse et al. [1] found no evidence that this reduced
the risk of clinical fractures in women at risk. However, a number of
aspects of this study need closer examination before the therapeutic role
for these supplements can be defined.
Although these women all had risk factors for hip factors, they were
highly self-selected. Out of 48,987 originally invited, only 3314 (7%)
were eventually randomised. Median follow-up overall was only 25 months,
and the design of the recruitment process means that this must have
differed between the two groups. It is interesting that in the “unequally
allocated group”, followed for longer, there is greater evidence of a
benefit of the intervention.
It is unfortunate that no attempt was made to measure vitamin D
levels to see the prevalence of insufficiency, and whether this degree of
supplementation was able to produce a significant improvement in levels.
It would also have been informative to see if improved calcium absorption
was able to reduce PTH levels.
Perhaps the most important factor that must be considered is calcium
intake from the diet. The self-reported estimated intake in both groups
was over 1000mg/d, which is greater than in many other studies, and both
groups received literature on adequate calcium and vitamin D intake.
There is high-quality data from the US Study of Osteoporotic Fractures
Research Group regarding dietary calcium, intestinal calcium absorption
and hip fractures that the authors do not cite, and which put these
findings into context. Ensrud et al. [2] studied 5452 women with a mean
follow-up of 4.8 years. Approximately 33% had a dietary calcium intake
less than 400mg/d. In this group, when fractional calcium absorption was
below the mean, the risk of hip fractures was 2.5-fold greater than when
absorption was above average. It is logical to presume that this
combination of factors (low dietary calcium intake and low fractional
absorption) identifies women most likely to benefit from calcium and
vitamin D supplements.
Many factors contribute to hip fractures and many alternative
therapies are available. Hence it is important to identify those
individuals who have low calcium absorption, so they can be considered for
this simple, cheap, preventative intervention, and that appropriately
designed trials are performed. Attention must also be given to vertebral
fractures, which are usually undiagnosed, the differing effects that may
be found in men and women, and the other benefits, such as those found in
neoplasia, of vitamin D and calcium supplements.
1. Porthouse J, Cockayne S, King C, et al. Randomised controlled
trial of calcium and supplementation with cholecalciferol (vitamin D3) for
prevention of fractures in primary care. BMJ 2005;330:1003.
2. Ensrud KE, Duong T, Cauley JA, et al. Low fractional calcium
absorption increases the risk for hip fracture in women with low calcium
intake. Ann Intern Med 2000;132:345-53.
Competing interests:
None declared
Competing interests: No competing interests
Calcium supplements would not be expected to reduce the risk of
fracures because it is magnesium and not calcium which is needed to
prevent the loss of intra cellular calcium. The main causes of
reductions in serum bone specific alkaline phosphatase and increases in
urinary losses of minerals can to demonstrated to be deficiencies of zinc
and magnesium.1,2
1 McLaren-Howard J, Grant ECG, Davies S. Hormone Replacement Therapy
and Osteoporosis: Bone Enzymes and Nutrient Imbalances. J Nutr Environ Med
1998; 8: 129-138.
2 Grant ECG. Osteoporosis caused by zinc and magnesium deficiencies.
http://bmj.com/cgi/eletters/330/7496/859#104597, 22 Apr 2005
Competing interests:
None declared
Competing interests: No competing interests
Biochemists' perspective
Calcium and vitamin D in preventing fractures
Biochemists’ perspective
EDITOR -We read with interest the article by Porthouse et al1 in
which they report that there is no significant reduction in the risk of
clinical fractures in women supplemented with vitamin D3 and calcium.
There could be several reasons for the failure of an isolated
supplementation of vitamin D and calcium, in protecting against clinical
fractures.
Firstly, vitamin D by itself is inactive in promoting the absorption
of calcium in the intestines. It has to be converted to calcitriol by
successive hydroxylation reactions in the liver and the kidneys2. A
slowing down of one of these steps could negate the beneficial effects of
vitamin D administration. In fact oestrogens and progesterone are known to
stimulate the renal 1á- hydroxylase enzyme3 which means that, in post-
menopausal women, formation of active vitamin D is likely to be affected.
The use of calcitriol supplements instead of vitamin D3 would have
probably improved the clinical outcome.
Calcium absorption is favoured by an acidic environment in the
intestines. Most of the dietary calcium is absorbed in the proximal parts
of the intestines while the contents are still acidic. Elderly subjects in
whom there is a fall in gastric acid secretion would have an impaired
absorption. Calcium tends to form insoluble calcium soaps in alkaline
environments, in which form, it cannot be absorbed.
Vitamin K is said to have a role in the synthesis of bone proteins
such as osteocalcin. It is required for the ã-carboxylation of glutamate
residues of osteocalcin and bone matrix gla proteins4. Such post-
translationally modified ã-carboxy glutamate residues are capable of
chelating calcium ions. The idea of supplementation of populations prone
to fractures, with vitamin K, therefore has a scientific basis. As Dr
Radecki has pointed out, the study would have yielded valuable information
if vitamin K supplementation had been included5.
The functionally active form of vitamin K has the naphthoquinone
structure. During the K cycle this is regenerated from its epoxide form by
using NADPH. The generation of NADPH itself requires the operation of the
pentose phosphate pathway. NADPH is produced by the action of glucose-6-
phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. In the
osteoblasts, the enzyme glucose-6-phosphate dehydrogenase is regulated by
the polyamine putrescine 6. The formation of putrescine is by a pyridoxal
phosphate dependent ornithine decarboxylase reaction. Therefore there is
an indirect role for the vitamin pyridoxine in bone metabolism.
Collagen is a structural protein present in the bones. The proper
formation of collagen requires vitamin C as a co-factor for the
hydroxylation of proline and lysine residues7
Osteoporosis is characterized by not only loss of minerals but also the
organic matrix onto which the minerals are deposited.
Therefore it is important to realize that are several links in the
sequence of events associated with mineralization/ demineralization of
bone.
To cut a long story short, there are a multitude of factors which
work in concert to regulate mineral metabolism in the bones. The results
of the study conducted by Porthouse et al should be viewed from a
different perspective. It has served to prove the point that, for
supplementation to be effective, it should be in the form of a cocktail of
several other nutrients and that calcium and vitamin D alone would not
suffice.
C.V.Anand, Professor in Biochemistry
Usha Anand, Associate Professor in Biochemistry
M.S.Ramaiah Medical College, M.S.R.I.T. Post, Bangalore -560 054, India.
e-mail: anand_vasudevarao@yahoo.com
1.Porthouse J, Cockayne S, King C, Saxon I, Steele E, Aspray T, et
al. Randomised controlled trial of calcium and supplementation with
cholecalciferol (vitamin D3) for prevention of fractures in primary care.
BMJ 2005; 330:1003.
2.Garrett RH, Grisham CM. Principles of Biochemistry with a human focus.
1997, Books/Cole, Thomson Learning, USA, pp 465-7.
3.Murray RK, Granner DK, Mayes PA, Rodwell VW, eds, Harper’s Biochemistry,
Prentice Hall International Inc. 24 th ed, 1996, pp. 539-46.
4.Hauschika PV, Lian JB, Cole DBC, Gundberg CM. Osteocalcin and matrix gla
protein: vitamin K dependent proteins in bone. Physiol Rev 1989; 69: 990-
1047.
5.Radecki TE. Vitamin K supplementation has powerful effect. (Letter) BMJ
2005; 331:108.
6.Bachrach U. Physiological aspects of ornithine decarboxylase. Cell
Biochem Funct 1984; 2: 6-10.
7.Berg JM, Tymoczko JL, Stryer L.Biochemistry, W.H.Freeman and Co. New
York, 5 th ed, 2002, pp 216-225.
Competing interests:
None declared
Competing interests: No competing interests