Effect of calcium from dairy and dietary supplements on faecal fat excretion: a meta-analysis of randomized controlled trials.

Abstract

Observational studies have found that dietary calcium intake is inversely related to body weight and body fat mass. One explanatory mechanism is that dietary calcium increases faecal fat excretion. To examine the effect of calcium from dietary supplements or dairy products on quantitative faecal fat excretion, we performed a systematic review with meta-analysis. We included randomized, controlled trials of calcium (supplements or dairy) in healthy subjects, where faecal fat excretion was measured. Meta-analyses used random-effects models with changes in faecal fat excreted expressed as standardized mean differences, as the studies assessed the same outcome but measured in different ways. An increased calcium intake resulted in increased excretion of faecal fat by a standardized mean difference of 0.99 (95% confidence intervals: 0.63-1.34; P < 0.0001; expected to correspond to approximately 2g day(-1)) with moderate heterogeneity (I(2) = 49.5%) indicating some inconsistency in trial outcomes. However, the dairy trials showed homogeneous outcomes (I(2)=0%) indicating consistency among these trials. We estimated that increasing the dairy calcium intake by 1241 mg day(-1) resulted in an increase in faecal fat of 5.2 (1.6-8.8) g day(-1). In conclusion, dietary calcium has the potential to increase faecal fat excretion to an extent that could be relevant for prevention of weight (re-)gain. Long-term studies are required to establish its potential contribution.

Full text

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Other Review
Effect of calcium from dairy and dietary supplements
on faecal fat excretion: a meta-analysis of randomized
controlled trials
R. Christensen1, J. K. Lorenzen2, C. R. Svith1,2, E. M. Bartels1,3, E. L. Melanson4, W. H. Saris5,
A. Tremblay6and A. Astrup2
1The Parker Institute, Musculoskeletal
Statistics Unit, Frederiksberg Hospital,
Frederiksberg, Denmark;2Department of
Human Nutrition, Centre for Advanced Food
Studies, Faculty of Life Sciences, University of
Copenhagen, Frederiksberg, Denmark;
3Copenhagen University Library,
Copenhagen, Denmark;4Division of
Endocrinology, Metabolism, and Diabetes,
University of Colorado Denver, Aurora, CO,
USA;5Nutrition and Toxicology Research
Institute Maastricht, Department of Human
Biology, Maastricht University, Maastricht, The
Netherlands;6Division of Kinesiology (PEPS),
Department of Social and Preventive
Medicine, Laval University, Québec, Canada
Received 28 October 2008; revised 16 March
2009; accepted 17 March 2009
Address for correspondence: Professor A
Astrup, Department of Human Nutrition, LMC,
Faculty of Life Sciences, University of
Copenhagen, DK-1958 Frederiksberg,
Denmark. E-mail: ast@life.ku.dk
Summary
Observational studies have found that dietary calcium intake is inversely related
to body weight and body fat mass. One explanatory mechanism is that dietary
calcium increases faecal fat excretion. To examine the effect of calcium from
dietary supplements or dairy products on quantitative faecal fat excretion, we
performed a systematic review with meta-analysis. We included randomized,
controlled trials of calcium (supplements or dairy) in healthy subjects, where
faecal fat excretion was measured. Meta-analyses used random-effects models
with changes in faecal fat excreted expressed as standardized mean differences, as
the studies assessed the same outcome but measured in different ways.
An increased calcium intake resulted in increased excretion of faecal fat by a
standardized mean difference of 0.99 (95% confidence intervals: 0.63–1.34;
P < 0.0001; expected to correspond to ~2g day-1) with moderate heterogeneity
(I2= 49.5%) indicating some inconsistency in trial outcomes. However, the dairy
trials showed homogeneous outcomes (I2=0%) indicating consistency among
these trials. We estimated that increasing the dairy calcium intake by 1241 mg
day-1resulted in an increase in faecal fat of 5.2 (1.6–8.8) g day-1. In conclusion,
dietary calcium has the potential to increase faecal fat excretion to an extent that
could be relevant for prevention of weight (re-)gain. Long-term studies are
required to establish its potential contribution.
Keywords: Dairy products, dietary calcium, faecal fat excretion, meta-analysis.
obesity reviews (2009)
Introduction
An inverse association between dietary calcium intake and
body weight was first reported in the mid-1980s based on
data from the first National Health and Nutritional Exami-
nation Survey in the US. (1). Since then, similar associations
between calcium intake, or intake of dairy products, and
body weight and body fat mass have been found in several
observationalstudies(2–6),butnotinall(7,8).Anumberof
randomized intervention studies examining the effect of
calcium supplements or dairy calcium have not produced a
clearanswerastowhethercalciummayhavearoleinenergy
balance.Inseveralstudies,Zemelandcolleagueshavefound
that subjects randomized to a high-calcium intake achieve a
significantly greater reduction in body weight and body fat
during energy restriction than those with a low-calcium
intake (9–11). However, a recent meta-analysis of interven-
tion studies that examined the effect of calcium on weight
loss showed that the results of the available trials are het-
erogeneous – with contradictory results (12).
The mechanism responsible for the potential effect of
increased calcium intake on energy balance is not clear, but
obesity reviews
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a number of different mechanisms have been suggested.
Zemel and colleagues have advocated a hypothesis that
calcium intake plays a regulatory role in lipid metabolism
by influencing intracellular calcium levels via hormonal
regulation (13). According to this hypothesis, an increase in
dietary calcium would result in increased lipolysis and
decreased de novo lipogenesis, thereby stimulating loss of
body weight and fat (13). However, the hypothesis is
mainly supported by animal studies, while recent human
studies do not indicate that adipocyte and whole body fat
metabolism are affected by dietary calcium intakes (14–
17). Although it has been suggested that high-calcium
intake may increase fat oxidation under conditions of acute
energy deficit, a number of studies have failed to detect any
consistent effect of calcium on energy expenditure during
energy balance (14,15,18–20). However, a reduction in
body fat stores cannot occur without either affecting energy
intake, faecal energy loss, or increasing energy expenditure.
It has recently been suggested that supplementation with a
calcium plus vitamin D in subjects with a habitual low
intake of calcium results in a decrease in ad libitum intake
of energy and fat (21). More research is needed to establish
if and how calcium intake affects human appetite regula-
tion. Another mechanism, suggested by a number of studies
in both humans and animals, is that dietary calcium inter-
feres with fat absorption in the intestine by forming
insoluble calcium soaps with fatty acids (FAs) and/or
binding of bile acids, resulting in a decrease in the digestible
energy of the diet (15,18,22–25).
We carried out a quantitative systematic review on ran-
domized, controlled trials to determine the effectiveness of
calcium supplementation – from either dairy products or
dietary supplements – on changes in faecal fat excretion. A
secondary aim was to explore whether an increased faecal
fat loss could be explained by typical bias items, such as
blinding and randomization, affecting individual trials’
internal validity (26,27). Finally, we examined whether the
effect could be explained by the amount of calcium admin-
istered, and whether the level of protein in the diet could
modify any effect of dietary calcium on faecal fat excretion
(15,18).
Methods
Study selection, assessment of eligibility criteria, data
extraction and statistical analysis were performed based on
a predefined protocol according to the Cochrane Collabo-
ration guidelines (28). This article was prepared in accor-
dance with the Quality of Reporting of Meta-analyses
statement (29).
Literature search
The following databases were searched: Medline (Mid-
1950s to May 2008), EMBASE (1980 to May 2008), Web
of Science (1945–54 to May 2008), BiosisPreviews (1980
to May 2008), Scifinder (1907 to May 2008), Agricola
(1970 to May 2008), Food Science Technical Abstracts
[FSTA] (1969 to May 2008), CAB Abstracts (1973 to May
2008), Cochrane Central Register of Controlled Trials
(until May 2008). The search strategy contained the fol-
lowing: (calcium* OR milk* OR dairy*) AND (lipid* OR
fat*) AND (faeces* OR feces* OR faecal* OR fecal* OR
stool*) AND human*. There were no limits on language or
publication type. As a supplement to the systematic litera-
ture search, two reviewers (J. K. L. & A. A.) contacted (via
email) other known experts in the field (including all first
authors of the papers retrieved). Searching for potentially
unpublished data was supervised by three experts in
the field (E. L. M., W. H. S., A. T.). The reference lists of
relevant reviews or potentially eligible papers were also
checked for other possible eligible trials. Finally the Global
Dairy Platform (Chicago, US) was contacted in order to
reveal any extra data not already available in the public
domain.
Selection criteria
All randomized and quasi-randomized controlled trials
were considered eligible if they (i) Enrolled healthy partici-
pants, whether adults, adolescents or children more than 6
years of age; (ii) Examined the effect of intake of calcium
from dairy products or dietary supplements and (iii)
Reported changes in faecal fat – i.e. either as total fat or as
FAs. There was no upper limit to the duration of trials
considered eligible. In order to ensure adequate methodol-
ogy, studies were eligible for inclusion if the time from
starting the intervention to the measurement of the faecal
fat excretion was at least 3 days. Studies with a crossover
design were considered eligible for inclusion in the meta-
analysis as the risk of carry-over effect was considered
minimal (30). The preliminary literature search for poten-
tially eligible studies (conducted by J. K. L. & C. R. S.) was
supervised by an experienced research librarian (E. M. B.).
Two investigators (J. K. L. & C. R. S.) concluded the
literature search by eliminating/including studies according
to the agreed eligibility criteria, and obtained approval of
the result via a consensus call with the other content expert
reviewers (E. L. M., W. H. S., A. T., and A. A.).
Data extraction and quality assessment
The included studies were scrutinized and reviewed
(without blinding of reviewers). Data were extracted using
a customized form (Microsoft Excel®spreadsheet) pro-
vided by a fourth reviewer (R. C.), including (i) Character-
istics of included studies; (ii) The Cochrane Collaboration’s
tool for assessing risk of bias and (iii) Outcome mea-
sures applicable for the subsequent data analyses. Two
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investigators (R. C. & J. K. L.) were responsible for the
assessment and extraction of data. The extracted outcome
was the difference between the intervention and control
groups (i.e. the paired mean difference in crossover
studies), and the variance measure was obtained for each
trial according to a standardized procedure using a data
abstraction form. Data were collected on trial design (par-
allel vs. crossover), duration of the trial, type of calcium
(dairy product, dietary supplement), calcium dosage
applied compared with the control group (mg) and the
estimated average level of protein intake in the study. Fur-
thermore, data were extracted on sample size and charac-
teristics of the study population, including the subjects’
average age and sex (proportion of men).
In order to apply the Cochrane Collaboration’s tool for
assessing risk of bias, two reviewers (R. C., J. K. L.) inde-
pendently assessed whether each of the following domains
would be considered adequate – i.e. presumably with a low
risk of bias (i) ‘Adequate sequence generation’; (ii) ‘Alloca-
tion concealment’; (iii) ‘Blinding’; (iv) ‘Incomplete outcome
data addressed’; (v) ‘Free of selective reporting’ and (vi)
‘Free of other biases’ (published as a peer-reviewed paper).
Each of these key components of methodological quality
was assessed on a Yes/Unclear/No basis, handled as A, B
and C, respectively (http://www.cochrane-handbook.org/).
Any differences between reviewers were resolved at a
subsequent consensus meeting (with A. A.).
Data synthesis and analysis
For crossover trials lacking data on standard errors (SEs)
for paired differences (SED), the pooled SE was estimated
assuming a correlation at a conservative level of 0 between
intervention and control periods (r = 0.0) in crossover
trials (30). We anticipated that the type of outcome
measurement would vary across individual studies, so the
standardized mean difference (SMD including Hedges’s
adjustment for small sample bias (31)) was used as the
summary statistic in the meta-analysis – assessing the same
outcome measured in a variety of ways (32). The SMD
expresses the size of the treatment effect relative to the
variability observed in that trial ([mCalcium- mControl]/s), using
slightly different calculi for parallel or crossover trial
designs (31,33). To combine the individual study results,
we performed meta-analyses using SAS software (PROC
MIXED version 9.1.3; SAS Institute Inc., Cary, NC, USA),
applyingarestricted maximum
method to estimate the between-study variance (i.e. t2) and
the combined efficacy (34). We examined heterogeneity
between trials with a standard Q-test statistic (35), and we
present the I2value (36), which can be interpreted as the
amount of inconsistency in the reported results between the
individual studies (37). We performed a number of pre-
defined sensitivity analyses, subgroup analyses stratifying
the available trials according to calcium from dairy
products vs. dietary supplements, and analyses of varying
degrees of risk of bias according to the Cochrane Collabo-
ration’s tool for assessing risk of bias. REML-based (i.e.
random-effects) meta-regression analysis (38) was applied
in order to answer the specific question raised by the sec-
ondary hypothesis – whether the amount of extra calcium
could predict the quantitative changes in faecal fat loss.
likelihood(REML)
Results
Results of the search
We identified more than 300 studies in the database
searches, of which 62 studies were potentially relevant and
therefore read in full text (Fig. 1). Of these, a total of 45
Figure 1 Quality of Reporting of
Meta-analyses (QUOROM) flowchart.
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studies were immediately excluded: 10 studies did not
report original research (reviews, etc.); one was an in vitro
study; 16 studies did not include a separate calcium or
dairy intervention and the isolated contrast associated with
supplementation could therefore not be evaluated; 12 had
no measurement of faecal fat excretion but only measured
fat in a single stool; one study only measured the fat
content in faecal water; one study was judged methodologi-
cally insufficient because of problems with separation of
stools from the two intervention periods; and five studies
focused on patients or subjects with previous or current
gastrointestinal diseases. This left 17 potentially eligible
studies. However, four of these studies were not random-
ized in any way and were therefore excluded. The remain-
ing 13 studies were deemed eligible for inclusion in the
systematic review (15,18,39–49). Two of these studies
could be handled as having a factorial design (15,40),
resulting in a final total of 15 substudies included in the
meta-analysis.
Description of studies
The average characteristics of the included studies are
shown in Table 1. The trials were published between 1964
and 2008, and varied in participant size. The majority of
trials were crossover trials. A total of 168 participants were
assessed (focusing solely on the individuals included in the
analyses) – receiving extra calcium, an appropriate control,
or both. The length of the trials varied from 3 days to 1
month. The studies had more or less the same primary end
point – either total fat excreted via faeces or a specific focus
on free FAs (Table 1). In two of the included studies, the
time from starting the intervention to the measurement of
the faecal fat excretion was less than 3 days (45,49). In the
study by Bendsen et al., the intervention started 2 days
before the faecal collection was started (49): in this study
the mean transit time was estimated by non-absorbable
faecal markers to be ~40 h and it was therefore included. In
the study by Murata et al., the subjects were given two
different oral trace markers, one at the beginning and one
at the end of the diet period (45). Excretion of these trace
markers was used to determine when to begin and when to
end faecal collection.
Effect of intervention
Calcium supplementation resulted in an increased excre-
tion of faecal fat and FAs compared with control groups,
with a SMD of 0.99 (95% confidence intervals [CI]: 0.63–
1.34; z = 5.44, P < 0.0001; Fig. 2). There was no evidence
to indicate a difference between the calcium supplements
and calcium from dairy products (1.04 vs. 0.90, respec-
tively; z = 0.30, P = 0.76). Assuming an average (?SD) fat
excretion in the population of 5.4 (?2.0) g day-1(43), we
estimate that applying extra calcium (with a range from
800 to 6000 mg day-1) would result in an increase of 2.0
(95% CI: 1.3–2.7) g faecal fat excreted (37% increase)
each day. The meta-analysis was based on studies showing
a moderate degree of heterogeneity (I2= 49.5%), support-
ing the use of a random-effects meta-analysis. As a sensi-
tivity analysis, the same meta-analysis based on a fixed-
effects model resulted in a combined SMD of 0.80 (95%
CI: 0.55–1.04, P < 0.0001). When the studies were divided
into studies using calcium supplementation and studies
using dairy calcium, a relatively high degree of heterogene-
ity (I2= 58.5%) was found among the studies using
calcium supplements. In contrast, the dairy calcium studies
showed homogeneity (I2= 0%). We therefore conducted a
meta-analysis with the faecal fat excretion expressed as
gram per day as all the dairy trials used the same outcome
measure. An increased dairy calcium intake of 1241 mg
day-1increased faecal fat excretion by 5.2 g day-1com-
pared with low-calcium (<700 mg day-1) dairy diet (95%
CI: 1.6–8.8; see Fig. 3). One of the inclusion criteria was
that the time from starting the intervention to measurement
of faecal fat excretion was at least 3 days. However,
as mentioned previously, two studies departed somewhat
from this condition (44,49). In a sensitivity analysis, we
therefore grouped these two studies as potentially inad-
equate compared with the other studies (see Table 1). There
was no significant difference between the two subgroups
(z = 1.07, P = 0.28), although the studies indexed as being
adequate showed a less pronounced efficacy (SMD = 0.91
[SE = 0.19]) when compared with those categorized as
potentially inadequate (SMD = 1.56 [SE = 0.57]).
Risk of bias in included studies
Table 2 presents results from stratified analyses. Estimates
of effect sizes varied to some degree depending on the
quality of the trials. When meta-analysing the trials, with
explicit focus on the adequacy of random and concealed
allocation, the studies indexed as adequate had the least
pronounced effect size compared with those indexed as
inadequate. The same pattern applied for handling of
incomplete outcome data, free of selective outcome report-
ing, and whether or not the study had been presented in a
peer-reviewed journal. In contrast, the adequately double-
blinded trials seemed to have a more pronounced effect
than those with an unclear risk of bias (not significant,
P = 0.78).
Association between intake and size of faecal
fat excretion
We found no relationship between amounts of extra
calcium applied in the individual trials (see Fig. 4A) and the
increase in faecal fat excretion expressed as SMD, as the
slope was not significantly different from null (z = 0.37,
P = 0.71). Accordingly the overall efficacy associated with
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Table 1 Study characteristics of all participants in the eligible trials (i.e. substudies)
Study
Year
Country
Population
Intervention
Design
Calcium
intake in
Ca(-)
(mg day-1)
Outcome
Faecal fat
excretion
(g day-1)
Duration
Energy
intake
(kJ day-1)
Protein
intake
(Energy%)
Individuals
included in
analysis
Men
(no, %)
Age
(years)
Supplements
Ca(+)
Ca(-)
Intervention Fecal
collection
Lutwak et al.
1964
United
States
Healthy girls
Controlled diet
with: Ca(+):
bread enriched
with calcium
(phosphate)
Ca(-): regular
bread
Parallel: twogroups
1295*
Total fat
(g day-1)
4.93 ? 2.05†
2.44 ? 0.61 24 days‡
24 days
~10 600
14
Parallel
groups:
NCa(+)= 10
NCa(-)= 8
0 (0%)
9 (range
8–11)
Bhattacharyya
et al. (PUFA)
1969
United
States
Healthy young
men
Controlled dietwith high PUFA
and:
Ca(+): bread
enriched withcalcium
(carbonate and
gluconate)
Ca(-): regular
bread
Crossover:
2 ¥ 2
factorial
design
254*
Fatty acids
(g day-1)
1.49 ? 0.34
1.20 ? 0.39 2 weeks
7 days
~12 600§
15§
Crossover:N = 11
11 (100%)
Range:
21–26
Bhattacharyya
et al. (SFA)
1969
United
States
Healthy young
men
Controlled dietwith high SFA
and:
Ca(+): bread
enriched with calcium
(carbonate and
gluconate)
Ca(-): regular
bread
Crossover:
2 ¥ 2
factorial
design
254*
Fatty acids
(g day-1)
4.11 ? 1.29†
1.19 ? 0.21 2 weeks
7 days
~12 600§
15§
Crossover:N = 10
10 (100%)
Range:
21–26
Saunders
et al.
1988
United
States
Students/personnel
in the Health
Science Building
Controlled diet
plus: Ca(+):
calcium tablets
(carbonate)
Ca(-):
Crossover:
two-group
comparison
NA
Fatty acids
(meq day-1)
16.8 ? 5.4†
7.9 ? 1.4
3 weeks
7 days
NA
15
Crossover:
N = 8
5 (62.5%) NA
Denke et al.
1993
United
States
Men: moderate
hypercholesterol aemia
Controlled diet
plus: Ca(+):
juice/muffin
enriched withcalcium and calcium tablets
(mixed salts)
Ca(-): regular
juice/muffin and
placebo tablets
Crossover:
two-group
comparison
410 ? 33
Fatty acids
(g day-1)¶
5.40*,†
2.63*
10 days
3 days
~11 000§
11§
Crossover:N = 13
13 (100%)
43 ? 4
(Range:
38–49)
Welberg et al.
1994
Netherlands Healthy
volunteers
Habitual diet plusCa(+): calcium
tablets
(carbonate)
Ca(-): placebo
tablets
Parallelgroup: twogroups
Diet:
1450 ? 481
Total fat
(g day-1)
7.0 ? 2.6
5.4 ? 2.0
1 week
3 days
~9 200
~16
Parallel
group:
NCa(+)= 7
NCa(-)= 8
NA
NA
Govers et al.
1996
Netherlands Healthy men
Habitual diet plus
Ca(+): regular
milk products
Ca(-): calcium
depleted milkproducts
Double-blind,
crossover:
two-group
comparison
765 ? 145
Total fat
(g day-1)
9.3 ? 2.5†
6.7 ? 2.2
1 week
3 days
~13 000
~14
Crossover:
N = 13
13 (100%)
38 ? 7
Murata et al.
1998
Japan
Healthy men
Controlled diet
with: Ca(+):
chocolate enriched withcalcium (derived
from eggshells)
Ca(-): regular
chocolate
Crossover:
two-group
comparison
504 ? 35
Total fat
(g day-1)
7.5*,†
2.8*
3 days
~3 days**
~7 700
11
Crossover:
N = 9
9 (100%)
NA
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Table 1 Continued
Study
Year
Country
Population
Intervention
Design
Calcium
intake in
Ca(-)
(mg day-1)
Outcome
Faecal fat
excretion
(g day-1)
Duration
Energy
intake
(kJ day-1)
Protein
intake
(Energy%)
Individuals
included in
analysis
Men
(no, %)
Age
(years)
Shahkhalili
et al.
2001A Switzerland
Healthy men
Controlled diet
with:Ca(+): chocolate
enriched withcalcium
(carbonate)
Ca(-): regular
chocolate
Parallel: twogroups
Diet: NA
Total fat
(g day-1)
10.4*,†
5.9*
2 weeks
7 days
NA
NA
Parallel
group:
NCa(+)= 6
NCa(-)= 6
NA
NA
Shahkhalili
et al.
2001
Switzerland
Healthy men
Controlled diet
with:Ca(+): chocolate
enriched withcalcium
(carbonate)
Ca(-): regular
chocolate
Crossover:
two-group
comparison
950 ? 59
Total fat
(g day-1)
8.40 ? 1.01†
4.36 ? 0.43 2 weeks
7 days
~13 000 14§
Crossover:N = 9
9 (100%)
NA
Ditscheid
et al.
2005
Germany
Healthy men and
women
Controlled diet with: Ca(+):
bread enriched
calcium
(phosphate)
Ca(-): regular
bread
Crossover:
two-group
comparison
1193 ? 295
Total fat
(g day-1)
4.3 ? 1.1
3.9 ? 1.4
4 weeks
5 days
~9 000 16
Crossover:
N = 31
15 (48%)
25
(range:
21–29)
Boon et al.
(supplement)
2007
Netherlands Healthy men and
women
Controlled diet
plus: Ca(+)
calcium
supplement
(carbonate)
Ca(-) low
calcium
Crossover:
2 ¥ 1 pseudo
factorial
design
348 ? 28††
Total fat
(g day-1)
6.7 ? 3.8
4.8 ? 2.5
1 week
3 days
~10 000††
20
Crossover:
N = 10
5 (50%)
28 ? 6
Dairy products
Jacobsen
et al.
2005
Denmark
Healthy men and
women
Controlled dietwith: Ca(+) high
calcium from
dairy products
Ca(-) low
calcium
Crossover:
two-group
comparison
474*,††
Total fat
(g day-1)
14.2 ? 6†
6.0 ? 2
1 week
3 days
~10 000††
15
Crossover:
N = 8
NA
NA
Boon et al.
(Dairy)
2007
Netherlands Healthy men and
women
Controlled diet with: Ca(+) high
calcium from
dairy products
Ca(-) low
calcium
Crossover:
2 ¥ 1 pseudo
factorial
design
348 ? 28††
Total fat
(g day-1)
7.2 ? 3.5
4.8 ? 2.5
1 week
3 days
~10 000††
20
Crossover:
N = 10
5 (50%)
28 ? 6
Bendsen
et al.
2008
Denmark
Healthy men and
women
Controlled dietwith: Ca(+) high
calcium from
dairy products
Ca(-) low
calcium
Crossover:
two-group
comparison
698 ? 153††
Total fat
(g day-1)
11.5 ? 4.6†
5.4 ? 1.7
1 week
5 days
~12 500††
15
Crossover:
N = 11
5 (45%)
33
(range
25–47)
Values are Means ? SD unless otherwise stated.
*SD not stated in the paper.
†Significant different from Ca(-) (P < 0.05).
‡The subjects had consumed a diet similar to the experimental diet for at least one year prior to the study.
§Standard serving of controlled diet. Intake adjusted according to individual energy requirement by removing or adding carbohydrate food.
¶Only major fatty acids (14 : 0, 16 : 0, 18 : 0 and 18 : 1) were included.
**Subjects were given two different oral trace markers, one in the beginning and one in end of the diet period. Excretion of these trace markers were used to determent when to begin and when to end faecal collection.
††Mean intake. Intake adjusted according to individual energy requirement.
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-3.5-2.5-1.5-0.50.5 1.52.5 3.5
Favours calciumFavours placebo/control
Subtotal: supplements
Test for homogeneity: χ2= 26.49, P = 0.005, I2= 58.5%
Jacobsen (2005)
Boon (2007)
Bendsen (2008)
Subtotal: dairy products
Pooled standardized mean difference
Test for homogeneity: χ2= 27.71, P = 0.02, I2= 49.5%
Test for overall effect: z = 5.44, P < 0.0001
Welberg (1994)
Govers (1996)
Murata (1998)
Shahkhalili (2001A)
Shahkhalili (2001)
Ditscheid (2005)
Boon (2007)
Lutwak (1964)
Bhattacharyya (1969): PUFA
Bhattacharyya (1969): SFA
Saunders (1988)
Denke (1993)
Supplements
Dairy products
1.15 (-0.03 to 2.33)
0.51 (-0.35 to 1.37)
1.14 (0.12 to 2.17)
0.64 (-0.34 to 1.62)
0.96 (0.07 to 1.85)
2.55 (0.69 to 4.41)
2.44 (1.01 to 3.88)
3.29 (0.98 to 5.59)
0.26 (-0.23 to 0.74)
0.38 (-0.45 to 1.22)
1.64 (0.60 to 2.67)
0.50 (-0.32 to 1.33)
2.33 (0.68 to 3.99)
1.42 (0.10 to 2.73)
0.50 (-0.27 to 1.27)
1.04 (0.62 to 1.47)
0.90 (0.07 to 1.73)
0.99 (0.63 to 1.34)
Test for homogeneity: χ2= 1.16, P = 0.56, I2= 0.0%
Standardized
mean difference
(95% CI)
Figure 2 Effects of calcium supplementation on faecal fat excretion; presented as supplements or dairy products. Every square represents the
individual study’s SMD with 95% CI indicated by horizontal lines; square sizes are directly proportional to the precision of the estimate.
-2.00.02.0 4.06.08.0 10.012.0 14.0
Extra faecal fat excreted (g day–1)
Dairy products
Jacobsen (2005)
Boon (2007)
Bendsen (2008)
Pooled mean difference
8.2 (3.8 to 12.6)
1.9 (-0.9 to 4.7)
6.1 (3.2 to 9.0)
5.2 (1.6 to 8.8)
Mean difference
(95% CI)
Figure 3 Amount of faecal fat excreted among
the homogeneous studies following extra
calcium from dairy products. Every square
represents the individual study’s mean
difference with 95% CI indicated by horizontal
lines; square sizes are directly proportional to
the precision of the estimate.
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Table 2 Results of the stratified meta-analyses: standardized mean difference in faecal fat excreted following extra calcium opposed to control intervention
Study
Design
Dose
(Ca: mg day-1)
Random all1
Concealed all2
Double blinding3
Incomplete OD4
FoSOR5
FoB6
Supplements
Lutwak et al. (1964)
PG
991
C
C
B
B
A
A
Bhattacharyya et al. (1969)
CO
2000
A
B
B
B
A
A
Bhattacharyya et al. (1969)
CO
2000
A
B
B
B
A
A
Saunders et al. (1988)
CO
6000
A
B
A
B
B
A
Denke et al. (1993)
CO
1800
B
B
A
B
B
A
Welberg et al. (1994)
PG
2000
B
B
A
B
A
A
Govers et al. (1996)
CO
1080
B
B
A
B
B
A
Murata et al. (1998)
CO
1150
B
B
A
B
B
A
Shahkhalili et al. (2001A)
PG
1000
B
B
A
B
B
C
Shahkhalili et al. (2001)
CO
900
B
B
A
B
A
A
Ditscheid et al. (2005)
CO
1060
B
B
A
B
A
A
Boon et al. (2007)
CO
800
A
A
B
A
A
A
Dairy products
Jacobsen et al. (2005)
CO
1300
A
A
B
A
A
A
Boon et al. (2007)
CO
800
A
A
B
A
A
A
Bendsen et al. (2008)
CO
1600
A
A
B
A
A
C
CO: 0.85 (0.49–1.22)
(See Figure 4)
A: 0.91 (0.36–1.45)
A: 0.75 (0.06–1.44)
A: 1.07 (0.53–1.60)
A: 0.75 (0.05–1.45)
A: 0.86 (0.44–1.29)
A: 0.87 (0.52–1.22)
PG: 1.43 (0.65–2.21)
B: 1.01 (0.46–1.57)
B: 1.06 (0.59–1.53)
B: 0.96 (0.41–1.50)
B: 1.12 (0.67–1.57)
B: 1.28 (0.63–1.93)
B) NA
C: 1.64 (0.21–3.06)
C: 1.64 (0.21–3.07)
C: NA
C: NA
C: NA
C: 1.64 (0.64–2.64
Values are Hedges’s standardized mean differences (95% confidence intervals) stratified according potential risk of bias, and regressed vs. extra calcium dosage applied.
1: random allocation, 2: concealed allocation, 3: double blinding, 4: incomplete outcome data, 5: free of selective outcome reporting, 6: free of other bias’ (i.e. published in a peer-reviewed journal)
A: adequate (i.e. low risk of bias).B: unclear (i.e. unclear risk of bias).
C: inadequate (i.e. high risk of bias in the analysis).
Int: intercept with the y-axis (i.e. calcium dose = 0 mg); Slp: Slope (i.e. increment in effect size with 1 mg of Ca added).
CO: crossover trial; PG: parallel group design; NA, not available.
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use of extra calcium was best explained by applying the
intercept, being a consequence of allocation to ‘extra
calcium’ per se – opposed to control of 0.90 (95% CI:
0.27–1.53; z = 2.82, P = 0.0048). On a post hoc level,
examining the impact of the concomitant level of protein
intake(Table 1)showedno
(z = 1.46, P = 0.14), although data might support a poten-
tial inverse association between faecal fat excreted and
energy intake from protein in the concomitant diet (see
Fig. 4B).
significantslopeeffect
Discussion
The major result of this meta-analysis is that dietary
calcium impairs the absorption of dietary fat and increases
faecal fat excretion. Although the effect was statistically
highly significant, its importance for the daily energy
balance and body-weight regulation may be minor. The
additional daily excretion of 2.0 g fat (~18 kcal) is equiva-
lent to ~0.7 kg body fat or ~1 kg body weight on an annual
basis, providing that no adaptation or counter regulatory
mechanism offsets the effect. However, the heterogeneity of
the trials (I2= 49.5%) suggests that the outcome of the
meta-analysis could be confounded by study characteris-
tics, such as differences in study design, methods used for
fat analyses, study population, calcium sources, matrix in
which calcium is provided, habitual diet and interaction
with other nutrients in the food matrix. In particular, high-
protein intake could interfere with the calcium soap forma-
tion and consequently with fat excretion (15,18). As the
dairy trials showed homogeneity (I2= 0%) the estimate
from the meta-analysis including only these studies may be
more certain than the pooled estimate from the meta-
analysis including all trials. The meta-analysis of these
trials showed that a weighted-average increase in dairy
calcium by 1241 mg day-1produced an increase in faecal
fat excretion of 5.2 g day-1, although based on a relatively
small sample (n = 29 participants). This is equivalent to
47 kcal day-1or 1.9 kg body fat or 2.2 kg body weight over
1 year. Without further studies to produce more robust
data, we estimate that increasing dietary calcium intake has
the potential to increase faecal fat excretion by 2–5.2 g
day-1, which corresponds to a change in body weight of -1
to -2.2 kg over 1 year. In comparison, orlistat, a gas-
trointestinal lipase inhibitor reducing dietary fat absorption
(50), has been shown to increase the amount of excreted fat
by 16.13 (SD: 7.27) g day-1(51). This amount of extra
faecal fat corresponds to a SMD of 2.2. Orlistat therefore
seems at least twice as efficacious as extra calcium (Fig. 2).
Some studies have found the effect of a high-calcium diet
on body-weight loss to be more pronounced than can be
explained by an increase in fat excretion, indicating that
there may be an additional relation between calcium and
body weight (9–11). Major et al. found recently that
supplementation with a calcium plus vitamin D supplement
decreases energy and fat intake in women with a low
habitual calcium intake (21). However, more research is
needed to establish whether calcium affects human appetite
regulation.
We failed to establish a clear dose–response relationship
between intake of calcium and faecal fat excretion, which
makes it difficult to make quantitative estimates of its
importance for energy balance, and to translate the findings
into importance for dietary guidelines. The failure to find a
dose–response relationship between calcium intake and
(a)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0 100020003000 4000 5000 60007000
Extra calcium applied (mg day–1)
Standardized mean difference
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
05 1015 2025
Average protein content in the diet (E%)
Standardized mean difference
(b)
Intercept (α) = 0.90 ± 0.32
Slope (β) = 0.00006 ± 0.0002
Intercept (α) = 2.33 ± 1.01
Slope (β) = -0.09 ± 0.06
Figure 4 Meta-regression analysis: The size of the circles is
proportional to the precision of the estimate used in the
meta-regression. The line indicates the predicted effects (regression
line). Values are given as the estimate ? SE. Effect sizes on the vertical
axis are plotted against (a) the estimated group mean difference in
calcium dose, and (b) the average protein content (energy%) in the
diet.
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faecal fat excretion might be due to the small number of
trials, few participants in each trial and the observed het-
erogeneity of the trials. Furthermore, scatter plots of treat-
ment effect against the amount of extra calcium applied
should be compatible with there being no effect of no extra
calcium, and so a simple regression line should intercept the
vertical axis at zero treatment effect (27). In this case, with
the scatter plot indicating an effect independent of the
calcium dose, bias could be a possible explanation. Finally,
if subjects’ adherence to a treatment varied across trials, a
corresponding variation in treatment effects will occur. It is
therefore probable that some of the studies included in this
meta-analysis underestimated the true ability of calcium to
impair fat absorption, as the lack of adherence to the
prescribed calcium intake will tend to reduce the effect size.
However, many of the studies used faecal and urinary
calcium excretion as a compliance marker, and demon-
strated at least some adherence.
Normally the quantitative importance for body weight
would be assessed by large, controlled, randomized trials,
providing high- vs. low-calcium intakes over at least 1 year
in order to detect a change in body weight, but it is difficult
to maintain strict adherence to specific diets over such a
long period. In future trials, compliance should be moni-
tored by measuring faecal and urinary calcium excretion,
and the effect size should be adjusted to optimal compli-
ance. Good adherence to calcium intakes with low vs. high
intakes might be easier to achieve using calcium supple-
ments, but we would still question whether this can be
achieved and a meaningful efficacy assessment can be made
without the use of biological adherence markers. Further-
more, if calcium is to affect fat digestibility, it is a condition
that fat and calcium are present in the intestine at the same
time. Therefore the time of ingestion of calcium and
perhaps also the matrix in which calcium is provided (dairy
products, tablet, fortified food, etc.) is crucial. In the
Women’s Health Initiative trial on calcium supplementa-
tion (1000 mg elementary calcium plus 400 IU of cholecal-
ciferol [vitamin D] vs. placebo) 36 282 post-menopausal
were treated for 7 years (52). Women receiving calcium vs.
placebo had a consistently favourable difference in weight
change of -0.13 kg (-0.21 to -0.05; P = 0.001) (52). After
3 years of follow-up, women with daily calcium intakes less
than 1200 mg at baseline who were randomized to supple-
ments were 11% less likely to experience small weight
gains (1–3 kg) and 11% less likely to gain more moderate
amounts of weight (>3 kg). However, the true effect of
calcium is very likely to have been underestimated in this
study because of lack of compliance (only 55–63% of the
subjects consumed 80% or more of the supplements) (52).
As no biological markers of calcium intake were monitored
in this study, the true effect size remains an open question.
Boon et al. showed, in a 23-year follow-up cohort study,
that longitudinal calcium intake only had a positive effect
on body composition below an intake level of <800 mg
day-1(53). No relation was found in the group with a
calcium intake of 800–1200 mg day-1or in the group
>1200 mg day-1, suggesting a threshold of approximately
800 mg day-1below which the effect of dietary calcium on
body composition is most pronounced (53). It has been
suggested that the effect of increased calcium intake on
body weight and composition is most pronounced in sub-
jects with a low habitual intake (54). Furthermore, the
majority of the studies included in this meta-analysis,
which found a significant effect of increased calcium intake
on faecal fat excretion, compared a high intake of dietary
calcium with a relatively low intake of dietary calcium
(Table 2). Thus it is likely that subjects with a low habitual
calcium intake will benefit more from an increased calcium
intake than subjects with a high habitual calcium intake.
In conclusion, dietary calcium intake has the potential to
increase faecal fat excretion to an extent that could be
relevant for prevention of weight (re-) gain, and may poten-
tially accentuate weight loss if no compensation occurs.
The effect may be most pronounced in subjects with a low
habitual dietary calcium intake. There is a need for studies
of a longer duration to establish long-term effectiveness.
Conflict of Interest Statement
R. C. is a statistical editor in the Cochrane Collaboration
(CMSG and PHRG); this is not a Cochrane Review.
A. A. is a scientific member of the Global Dairy Plat-
form, and has received research funding from Arla and the
Danish Dairy Foundation.
Acknowledgements
We thank the personal and scientific support of Professor
Henning Bliddal (from The Parker Institute, Frederiksberg
Hospital, Denmark) and the linguistic support of Tina
Cuthbertson. We gratefully acknowledge financial support
from Global Dairy Platform (Chicago, USA), The Oak
Foundation, Frederiksberg Hospital and University of
Copenhagen.
The study was funded by an unrestricted grant from
Global Dairy Platform LLC, Chicago, USA, and the Oak
Foundation, who provide support to The Parker Institute.
The funding sources had no influence on the study, and did
not approve the manuscript before submission.
Contributions of authors
R. C. participated in the study conception and design, the
acquisition of data, the analysis/interpretation of data,
drafting and revision of the manuscript and the statistical
analyses. J. K. L. participated in the study conception and
design, the acquisition of data, the analysis/interpretation
10
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R. Christensen et al.
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Page 11

of data and drafting of the manuscript. C. R. S. participated
in the study conception and design. E. M. B. coordinated
the literature search, participated in the acquisition of data
and critical revision of the manuscript. E. L. M., W. H. S.
and A. T. participated in the study conception, interpreta-
tion of data, critical revision of the manuscript and super-
vision of the study. A. A. generated the idea and took
the initiative to conduct the study – participated in the
study conception and design, the acquisition of data,
the interpretation of data, and drafting and revision of the
manuscript. All authors have seen and approved the final
version of the manuscript.
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obesity reviews
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