Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomised controlled trials
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.38950.561400.55 (Published 12 October 2006) Cite this as: BMJ 2006;333:775
All rapid responses
As far as I can see, this research does not address the issue of
calcium loss through the kidneys, which must accompany the excretion of
the metabolites of excessive protein. In Third World countries, average
dietary protein intake is significantly lower than in the First World: my
understanding is that this is a major factor in their relatively low
incidence of osteoporosis.
Dairy products have high levels of both calcium and protein, perfect
for calves, but not necessarily so good for humans. Those of us who are
vegans get most of our calcium from foods with lower levels of protein,
such as green leafy vegetables, broccoli, swede, almonds, and brazils, as
well as some from high-protein foods like tofu and fortified soya milk.
I am uncomfortable about the way the dairy industry promotes their
products as a good source of calcium, because, if the above is true, they
are not so good at providing calcium which is retained by the human body.
I would be very keen to see more research done in this field,
specifically some which monitors protein as well as calcium intake.
Competing interests:
None declared
Competing interests: No competing interests
A meta-analysis by Winzenberg and colleagues (1) used areal bone
mineral density (BMD) to evaluate the effects of calcium supplementation
on the growing skeleton. However, bone material and structural properties
strongly affect its strength (2). A recent first prospective cohort study
including 6,213 children in southwest England showed that an increased
risk of fracture was associated with lower areal BMD (OR per SD decrease =
1.12), lower volumetric BMD (1.89) and smaller bone size relative to body
size (1.51) (3). Therefore, areal BMD would not be a good marker of
fracture risk in children; analysis using this marker could underestimate
the effects of calcium supplementation. The small positive effect of
calcium supplementation on upper limb areal BMD may result in significant
reduction of fracture risk in upper limbs, the most common fracture site
in children (4).
In addition, the positive effect on upper limb, but not hip or lumbar
spine, areal BMD (1) appears to suggest that adequate calcium intake is
required for bone gain at non-weight-bearing sites. Among 19 studies in
their meta-analysis (1), the trials by Iuliano-Burns et al, Stear et al,
Specker et al and Courteix et al found that calcium supplementation
supported the exercise-induced site-specific increase in areal BMD,
although subgroup analysis by level of physical activity showed no effect
modification (1). Bone strain from mechanical loads is an important factor
to control the skeleton, and bone mineralization in children is much lower
than that in adults. Thus, the lower material stiffness during growth
would accelerate load-induced bone gain and calcium incorporation into
bones could partly depend on their mechanical circumstances (5). In
children, high physical activity with appropriate calcium intake is a
candidate strategy for preventing fractures and it will be required to
determine the optimum amount of daily calcium intake dependent on physical
activity.
Toshihiro Sugiyama, M.D., Ph.D.
Department of Orthopaedic Surgery, Yamaguchi University School of
Medicine, Yamaguchi 755-8505, Japan; and Department of Veterinary Basic
Sciences, The Royal Veterinary College, University of London, London NW1
0TU, UK
References
1. Winzenberg T, Shaw K, Fryer J, Jones G. Effects of calcium
supplementation on bone density in healthy children: meta-analysis of
randomized controlled trials. BMJ 2006;333:775-78.
2. Seeman E, Delmas PD. Bone quality: the material and structural
basis of bone strength and fragility. N Engl J Med 2006;354:2250-61.
3. Clark EM, Ness AR, Bishop NJ, Tobias JH. Association between bone
mass and fractures in children: a prospective cohort study. J Bone Miner
Res 2006;21:1489-95.
4. Cooper C, Dennison EM, Leufkens HGM, Bishop N, van Staa TP.
Epidemiology of childhood fractures in Britain: a study using the General
Practice Research Database. J Bone Miner Res 2004;19:1976-81.
5. Sugiyama T, Taguchi T, Kawai S. Adaptation of bone to mechanical
loads. Lancet 2002;359:1160.
Competing interests:
None declared
Competing interests: No competing interests
The meta-analysis on role of calcium supplementation in children by
Winzenberg et al is an important meta-analysis to answer the role of
calcium supplementation in improving bone mineral density (BMD) in
children whether such a supplementation can prevent fractures in later
life especially in postmenopausal women where osteoporosis is a
significant problem especially post various recent studies on role of
estrogen replacement therapy with negative results. There is a real need
to find out alternatives to estrogens for management of osteoporosis a
very big problem in menopausal women with high fracture rates especially
in spine and hip. Calcium is one such alternative. Unfortunately
Winzenberg's results are contrary. The calcium supplementation does not
improve BMD in children especially in vertebral column and hip which
really matter as these are the sites of fractures in later life. Moreover
with prolonged calcium supplementation there is danger of hypercalcaemia
with all its consequences. Hence calcium supplementation in children
should be used with caution. However, in areas of calcium deficiency
especially in developing countries like India, calcium should be given
more liberally for its immediate actions.
Competing interests:
None declared
Competing interests: No competing interests
Editor
We welcome the chance to respond to the letter from Drs Heaney and
Weaver. We disagree with their viewpoint in several areas.
1. The key question with calcium supplementation in children is
whether this prevents fractures. There are no trials that have been large
enough to answer this question in either younger or later life. The
relationship between peak bone mass and fracture risk in later life
appears substantial (1) but estimating an effect of calcium
supplementation in children on fracture in later life would be at best a
guess. The next question is which bone variable is the best surrogate
marker of fracture in children. While the response from Drs Heaney and
Weaver has some theoretical merit, this is not actually supported by hard
data in children. In direct contrast to their assertion, we have recently
reported that volumetric density (an estimate of true bone density) is the
best correlate of fracture risk in children and is closely followed by
areal BMD (2). The small change in bone size is of uncertain significance
as there is little data relating it to fracture in children and BMC and
bone area (which are the DXA variables that correlate most closely with
bone size) were unable to discriminate children with fracture from
controls (2). Furthermore, increasing bone size may actually be harmful as
increased tibial cross-sectional area increases the risk of subsequent
cartilage damage (3) which leads to cartilage loss (4) based on recent
prospective MRI based studies from our institution. In the meta-analysis,
we wanted to use volumetric density as the primary outcome but this was
not reported in any studies. Areal BMD was, therefore, the next most valid
measure. We also had data relating BMD to fracture as well as fracture
incidence in children in our location (5) which allowed us to estimate the
effect of calcium supplementation on fracture which was small. Other bone
measures which are associated with fractures in children such as
metacarpal index (6), skeletal age deviation (7) and heel ultrasound (G
Jones, unpublished) may also be suitable for use as surrogate markers but
again there is little data relating them to calcium intake.
2. The criticism about a lack of an appropriate control group is
untenable. From a meta-analysis of calcium balance studies, Dr Heaney
suggests around 1400 mg/day is needed (8), much more than the average 700
mg/day in the control groups, thus, according to this standard, all the
studies in our review could be regarded as low intake. However, even
restricting the analysis to the lowest quartile of supplementation
(<_582 mg="mg" day="day" showed="showed" no="no" beneficial="beneficial" effect="effect" even="even" though="though" three="three" out="out" of="of" four="four" studies="studies" in="in" this="this" subgroup="subgroup" had="had" mean="mean" baseline="baseline" intakes="intakes" _400="_400" day.="day." our="our" analysis="analysis" that="that" increasing="increasing" to="to" levels="levels" suggested="suggested" as="as" necessary="necessary" maintain="maintain" increase="increase" calcium="calcium" balance="balance" did="did" very="very" little="little" casting="casting" doubt="doubt" on="on" the="the" validity="validity" and="and" perhaps="perhaps" indicating="indicating" bodys="bodys" ability="ability" adjust="adjust" much="much" lower="lower" intakes.="intakes." p="p"/> 3. We were disappointed and a little surprised that such well
respected bone investigators seemed unaware of our group’s longstanding
bone research program with its emphasis on children. The assumption that
we lack content expertise is erroneous. Our review protocol was designed
with content and methodological input. We would suggest that Dr’s Heaney
and Weaver reassess their own viewpoints in the light of our results,
rather than shooting the messenger when the data don’t support their
position.
References
1. Jones G. Relevance of peak bone mass to osteoporosis and fracture risk
in later life. In Lane N, Sambrook P (eds). Osteoporosis and the
osteoporosis of rheumatic diseases. Mosby, New York, 2006, p22-26.
2. Jones G, Ma D, Cameron F. Bone density interpretation and relevance in
Caucasian children aged 9-17 years of age: insights from a population
based fracture study. Journal of Clinical Densitometry 2006 9:202-9
3. Ding C, Cicuttini F, Scott F, Cooley H, Boon C, Jones G. Natural
history of knee cartilage defects and factors influencing change. Archives
of Internal Medicine 2006 166:651-8.
4. Ding C, Cicuttini F, Scott F, Boon C, Jones G. Prevalent and incident
knee cartilage defects are associated with knee cartilage loss: a
longitudinal study. Arthritis and Rheumatism 2005 12:3918-27.
5. Jones G, Cooley H. Symptomatic fracture incidence in those under 50
years of age in Southern Tasmania. Journal of Paediatrics and Child Health
2002 33:278-83.
6. Ma D, Jones G. The association between bone mineral density, metacarpal
morphometry and upper limb fractures in children: a population based case-
control study. Journal of Clinical Endocrinology and Metabolism 2003
88:1486-1491.
7. Jones G, Ma D. Skeletal age deviation assessed by the Tanner Whitehouse
2 method is associated with bone mass and fracture risk in children. Bone
2005 36:352-7.
8. Heaney RP, Abrams S, Dawson-Hughes B, et al. Peak bone mass. Osteoporos
Int 2000;11:985-1009.
Competing interests:
None declared
Competing interests: No competing interests
Over the last decade, the number of subjects diagnosed with
hypercalcaemia has increased exponentially (5-fold) mainly because of
laboratory automation and the introduction of plasma calcium determination
in routine biochemical screening.1,2 Recent advances in our
understanding of the pathophyisological changes in metabolic bone diseases
(MBD) have resulted in increasing numbers of patients being treated with
calcium and/or vitamin D supplements.3,4 Hypercalcaemia is a serious and
not infrequent complication of malignant disease. Correct interpretation
and recognition of the underlying cause has a major impact on the
management and morbidity of these patients.5 We undertake this hospital-
based survey to determine the causes and the biochemical profile in
hypercalcaemic patients.
118286 calcium requests were received from 39360 patients between April 2003
and April 2004. Out of 118286 requests, the proportion with
hypercalcaemia (Adjusted Calcium >2.60 mmol/L) was 10% (11702). The
largest proportions were from subjects with chronic kidney disease (CKD),
renal transplant (RTX) and osteoporosis(OP), 53%, 21% and 6.7%,
respectively. The next commonest causes of hypercalcaemia from this survey
were malignancy followed by primary hyperparathyroidism (1o HPT), 11% and
3.5%, respectively. A characteristic pattern of hyperchloraemia and
normal anion-gap was revealed in patients with 1o HPT. The likelihood of
having 1o HPT was 3-5 fold higher in patients with Cl/PO4 ratio >129
compared to malignancy.
This survey has revealed that hypercalcaemia is a common metabolic
problem; iatrogenic factor is the commonest cause and need to be ruled out
before embarking on expensive investigations. Combining Cl/PO4 ratio to
the bone profile may help in the differentiation between 1oHPT and
malignancy.
References:
1. Fisken RA, Heath DA, Bold AM. Hypercalcaemia--a hospital survey. Q J
Med. 1980;49:405-18
2. Bilezikian JP, Silverberg SJ. Clinical practice. Asymptomatic primary
hyperparathyroidism. N Engl J Med. 2004; 22:1746-51.
3. Muhammedi MA, Piraino B, Rault R, Johnston JR, Puschett JB. Iatrogenic
hypercalcemia in hemodialysis patients.Clin Nephrol. 1991;36:258-61.
4. Kato Y, Sato K, Sata A, Omori K, Nakajima K, Tokinaga K, Obara T,
Takano K.
Hypercalcemia induced by excessive intake of calcium supplement
5. Burkhardt E, Kistler HJ. [Hypercalcemia in hospitalized patients.
Diagnostic and prognostic aspects] Schweiz Med Wochenschr.
Competing interests:
None declared
Competing interests: No competing interests
A meta-analysis of calcium supplementation in children in a recent
issue of the Journal reported a positive effect, but deemed it too small
to be useful (1). Service, in a Perspective on meta-analysis, noted that
many meta-analytic teams lack members with content expertise in the area
being summarized (2). As a consequence, while the meta-analyses may be
rigorous with respect to methodologic issues, they can overlook important
biological flaws in the studies concerned or pool studies that are
incommensurable. The publication by Winzenberg et al. (1) constitutes a
good case in point.
Among several biologic errors in this meta-analysis, two in particular
stand out: the use of bone mineral density (BMD) as the outcome variable
and the failure to ensure that all studies included a low calcium control
group. Both issues have been explored extensively elsewhere and are
treated in depth in at least one standard reference book (3–6).
Briefly, during growth, bone expands in three dimensions. BMD, as measured
(and by design), eliminates the increase in mass associated with two of
those dimensions. Thus BMD change misses most of the actual change in bone
mass during growth. (And when true density can be measured, it misses mass
change entirely.) In this instance, the meta-analysis found a significant
aggregate positive effect, but the authors concluded that it was too small
to be useful. They were apparently unaware 1) that changes in bone mass
during growth are typically several times larger than changes in BMD; and
2) that bone strength is directly related to mass and size, and only
indirectly to BMD.
Furthermore, use of BMD explicitly precludes finding an effect of the
intervention on bone size. The latter point is not simply a theoretical
objection, as several investigations have suggested that high calcium
intakes, in addition to improving bone mineral acquisition, can increase
bone size as well (7,8). Thus BMD is precisely the wrong outcome measure
for nutritional effects during growth.
Calcium, like iron, vitamin D, and many other nutrients, exhibits
threshold behavior, i.e., effects accrue up to only a certain threshold
intake value, above which further increases in intake produce no
additional effect (4,5). Studies without a low calcium intake contrast
group are not capable of testing whether calcium produces skeletal (or
other) benefits. Several of the studies included by Winzenberg et al.
exhibited precisely that problem.
The fact that the investigators in the studies assembled in this meta-
analysis had themselves made these same mistakes does not justify their
inclusion. One of the points of a meta-analysis is to weed out flawed
studies – flawed not just because of poor randomization or blinding, but
because of inapposite methods and poorly posed biological questions.
In both their title and their conclusions the authors are careful to use
the term “healthy children”, a designator which would logically include
the notion that their diets were adequate in all essential nutrients. In
that sense, therefore, one cannot disagree with the conclusion that more
calcium does not produce much benefit. But since that point has been shown
many times over and is implicit in the notion of a threshold nutrient, one
wonders why this analysis was done or published in the first place. It is
likely that the message for the average reader would be that calcium
intake in children is not important. That would be not only wrong, but
potentially dangerous, as well.
Robert P. Heaney, M.D.
Creighton University, Omaha, Nebraska, USA
Connie M. Weaver, Ph.D.
Purdue University, West Lafayette, Indiana, USA
References
1. Winzenberg T, Shaw K, Fryer J, Jones G. Effects of calcium
supplementation on bone density in healthy children: meta-analysis of
randomized controlled trials. BMJ 2006;
2. Service FJ. Idle thoughts from an addled mind. Endocr Prac 2002;8:135-
136.
3. Prentice A, Parsons TJ, Cole TJ. Uncritical use of bone mineral density
in absorptiometry may lead to size-related artifacts in the identification
of bone mineral determinants. Am J Clin Nutr 1994;60: 837-842.
4. Heaney RP. Design considerations for clinical investigations of
osteoporosis. In: Osteoporosis, 3rd Ed. Marcus R, Feldman D, Nelson D,
Rosen C, eds. Elsevier Inc., San Diego, CA (in press) 2007.
5. Heaney RP, Bachmann GA. Interpreting studies of nutritional prevention.
A perspective using calcium as a model. J Women’s Health 2005;14:990-897,
2005.
6. Heaney RP. BMD: The problem. Osteoporos Int 2005;16:1013-1015.
7. Prentice A, Ginty F, Stear SJ, Jones SC, Laskey MA, Cole TJ. Calcium
supplementation increases stature and bone mineral mass of 16-18 year old
boys. J Clin Endocrinol Metab 2005;90:3153-3161.
8. Bonjour J-P, Carrie AL, Ferrari S, Clavien H, Slosman D, Theintz G,
Rizzoli R. Calcium-enriched foods and bone mass growth in prepubertal
girls: a randomized, double-blind, placebo-controlled trial. J Clin Invest
1997;99:1287-1294.
Competing interests:
None declared
Competing interests: No competing interests
Effect size at the end of supplementation period in terms of g/cm2
To the Editor:
In the meta-analysis on role of
calcium supplementation in children, Winzenberg et al (1) used standardised mean differences (SMD) to summarize their results and to base their
conclusions. Although the use of SMD is recognized as a valid approach in summarizing mean
differences across trials in the Cochrane Review methodology (1), its primary
purpose is for comparing variables with different units and measurement scales
of different length (2). The SMD is calculated by dividing the group
differences by the standard deviation.
This converts a variable which has units to a unitless
score. In other words, a variable which
once had clinical meaning becomes clinically meaningless.
In Winzenberg et al.’s meta-analysis, all
measurements of bone mineral density (BMD) were reported as grams per square centimetre (mg/cm2).
Under these circumstances, we believe
that the use of SMDs is unnecessary. An alternate approach is to summarize the
treatment effects as absolute differences.
We have re-constructed Table 2 from
the meta-analysis by calculating the effect size at the end of supplementation
period in terms of g/cm2, the usual units of measurement for BMD. We hope that our re-constructed Table will
help clinicians better-appraise the magnitude of effect size for this
meta-analysis.
In regards to interpreting the results from the Table,
all bone sites show consistent increase in BMD at the end of a median calcium
supplementation period of one year. We
disagree with Winzenberg
et al.’s claim
that the observed relative increase in upper limb body BMD is not clinically important.
Not only is this result statistically
significant, but a yearly 0.007 g/cm2 increase (or a 1.8% relative
increase) in BMD is a clinically meaningful change. If this increase continued throughout
childhood, it would likely translate to a substantial gain in bone strength.
We are concerned that the results of
Winzenberg et al.’s meta-analysis could be
construed to imply calcium is not important in childhood, even though the
meta-analysis focused on the role of calcium supplementation and did not
address calcium requirements. This interpretation of the results was promoted
by the accompanying Editorial (3).
It was written by a member of the Physicians Committee for Responsible
Medicine, a group that promotes vegan diets devoid of dairy products. This thinking is at odds with the American
Association of Clinical Endocrinologists (4), the National Institutes of Health
Consensus Development Panel on Osteoporosis Prevention, Diagnosis and Therapy (5), the Institute of Medicine (6), and the Scientific Advisory Council of
Osteoporosis Canada (7).
These groups recommend adequate intakes of calcium and vitamin D,
combined with weight bearing physical activity, throughout childhood to promote
the attainment of an optimal peak bone mass.
It is likely that calcium intake is a necessary but not sufficient
condition for the development of a strong skeleton, as physical activity and
calcium both play key roles in the attainment of a high peak bone mass (8).
Until we are absolutely certain
about what the minimum and optimum combinations of calcium, vitamin D, foods
from plant sources and physical activity are required to achieve a bone mass
that will sustain the bones of individuals through their older ages without
fragility fractures, it seems prudent to continue to follow the consensus-based
recommendations for intakes of calcium and vitamin D.
Sincerely,
Tanis R. Fenton, PhD Candidate, RDDepartment of Community Health SciencesUniversity of CalgaryMichael
Eliasziw, PhD
Department of Community Health SciencesUniversity of CalgaryCalgary AB, CanadaDavid A. Hanley, MD, FRCPCDepartments of Medicine, Oncology and Community Health SciencesUniversity of CalgaryEffects of calcium supplementation on BMD at
different sites (median treatment of one year)
Bone Site
Number of
studies
Number of
Participants
Mean BMD
Control
(g/cm2)
Mean BMD
Treatment
(g/cm2)
Mean BMD
Difference
(g/cm2)
Relative
Increase in
BMD (%)
P-value for
Control
versus
Treatment
Femoral neck
10
1073
0.798
0.810
0.012
1.5
0.055
Lumbar spine
11
1164
0.816
0.831
0.015
1.9
0.019
Upper limb
12
1579
0.390
0.397
0.007
1.8
0.003
References
1. Winzenberg
T, Shaw K, Fryer J, Jones G. Effects of calcium supplementation on bone density
in healthy children: meta-analysis of randomised controlled trials. BMJ 2006; 333:775.
2. Cohen
J. Statistical Power Analysis for the Behavioral
Sciences. New York: Academic Press; 1977.
3. LanouAJ. Bone
health in children.BMJ 2006; 333:763-4.
4. Hodgson
SF, Watts NB, Bilezikian JP, Clarke BL, Gray TK, Harris DW et al. American
Association of Clinical Endocrinologists medical guidelines for clinical
practice for the prevention and treatment of postmenopausal osteoporosis: 2001
edition, with selected updates for 2003. EndocrPract 2003; 9:544-64.
5. Osteoporosis prevention, diagnosis, and
therapy. JAMA 2001; 285:785-95.
6. Institute
of Medicine (IOM). Dietary Reference Intakes for calcium, phosphorus,
magnesium, vitamin D and fluoride. The National Academies
Press; 1997.
7. Brown
JP, JosseRG. 2002 clinical
practice guidelines for the diagnosis and management of osteoporosis in Canada.
CMAJ 2002; 167:S1-34.
8. Courteix D, Jaffre C, Lespessailles
E, Benhamou L. Cumulative effects of calcium
supplementation and physical activity on bone accretion in premenarchal
children: a double-blind randomised placebo-controlled trial. Int J Sports Med 2005; 26:332-8.
Competing interests:
Until 2006, DAH served on a research grant review panel for the Dairy Farmers of Canada, and received an honorarium for this activity.
Competing interests: No competing interests