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Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies
Nutrition, Metabolism & Cardiovascular Diseases (2015) xx, 1e12
Available online at www.sciencedirect.com
Nutrition, Metabolism & Cardiovascular Diseases journal homepage: www.elsevier.com/locate/nmcd
META-ANALYSIS
Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies Z. Asemi a,1, P. Saneei b,c,d,1, S.-S. Sabihi b,c, A. Feizi e, A. Esmaillzadeh b,c,*,1 a
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Isfahan, Iran Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran c Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran d Students’ Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran e Department of Epidemiology and Biostatistics, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran b
Received 18 September 2014; received in revised form 14 March 2015; accepted 16 March 2015 Available online - - -
KEYWORDS Calcium; Mortality; Meta-analysis; Diet
Abstract Aims: This systematic review and meta-analysis of observational studies was conducted to summarize the evidence on the association between calcium intake and mortality. Methods and results: PubMed, Institute for Scientific Information (ISI) (Web of Science), SCOPUS, SciRUS, Google Scholar, and Excerpta Medica dataBASE (EMBASE) were searched to identify related articles published through May 2014. We found 22 articles that assessed the association between total, dietary, and supplementary intake with mortality from all-causes, cardiovascular disease (CVD), and cancer. Findings from this meta-analysis revealed no significant association between total and dietary calcium intake and mortality from all-causes, CVD, and cancer. Subgroup analysis by the duration of follow-up revealed a significant positive association between total calcium intake and CVD mortality for cohort studies with a mean follow-up duration of >10 years (relative risk (RR): 1.35; 95% confidence interval (CI): 1.09e1.68). A significant inverse association was seen between dietary calcium intake and all-cause (RR: 0.84; 95% CI: 0.70e1.00) and CVD mortality (RR: 0.88; 95% CI: 0.78e0.99) for studies with a mean follow-up duration of 10 years. Although supplemental calcium intake was not associated with CVD (RR: 0.95; 95% CI: 0.82e1.10) and cancer mortality (RR: 1.22; 95% CI: 0.81e1.84), it was inversely associated with the risk of all-cause mortality (RR: 0.91; 95% CI: 0.88e0.94). Conclusions: We found a significant relationship between the total calcium intake and an increased risk of CVD mortality for studies with a long follow-up time and a significant protective association between dietary calcium intake and all-cause and CVD mortality for studies with a mean follow-up of 10 years. Supplemental calcium intake was associated with a decreased risk of all-cause mortality. ª 2015 Elsevier B.V. All rights reserved.
* Corresponding author. Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, PO Box 81745-151, Iran. Tel.: þ98 311 7922720; fax: þ98 311 6682509. E-mail address: [email protected] (A. Esmaillzadeh). 1 Co-first author.
Introduction Findings from epidemiological studies have indicated an inverse association between dietary calcium intake and
http://dx.doi.org/10.1016/j.numecd.2015.03.008 0939-4753/ª 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
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risk of hypertension, obesity, and type 2 diabetes [1,2]. In addition, calcium supplements are widely used in elderly population [3]. More than 50% of older men and almost 70% of older women in the United States used calcium supplements [4]. Although the role of calcium in the prevention and treatment of osteoporosis, normal growth, and development of the skeleton and teeth is well established, its effect on nonskeletal outcomes including cardiovascular events or cancers remains largely unknown [5e10]. High calcium intake has been suggested to increase fat excretion [11], which in turn might result in a decreased risk of cardiovascular disease (CVD). By contrast, calcium is present in atherosclerotic lesions, raising the possibility that an increased dietary and supplemental calcium intake may increase the risk of CVD [12,13]. Prior studies have examined the association between calcium intake from diet and supplements and allcause mortality; however, findings were inconsistent [14e17]. Some prospective studies have reported an inverse association between dietary calcium intake and risk of mortality from CVD [18e20]. Others have shown that not only dietary but also supplemental calcium intake was inversely associated with deaths from CVD [17e21] and prostate cancer [22,23]. In a prospective cohort study, Van der Pols et al. [24] demonstrated that childhood calcium intake was inversely associated with stroke mortality. In another cohort study, calcium supplements, up to 1000 mg/d, and an increased dietary intake of calcium were associated with a reduced risk of mortality in women [17]. With increasing number of older men and women taking calcium supplements to avoid osteoporosis [25], examining the association between calcium intake and mortality is of great interest. Although several studies have assessed the relationship between dietary and supplemental calcium intake and mortality, we are aware of no meta-analysis that summarized findings from previous publications. Given the inconsistent findings about the association between calcium intake and risk of all-cause mortality, this study aimed to systematically review the current evidence on the association between calcium intake and risk of all-cause, CVD, and cancer mortality, and to summarize the available findings in a meta-analysis, if possible. Methods Search strategy A systematic search of the literature published earlier than May 2014 was conducted in PubMed, Institute for Scientific Information (ISI) (Web of Science), SCOPUS, SciRUS, Google Scholar, and Excerpta Medica dataBASE (EMBASE) by three independent investigators (Z.A., P.S., and SeS.S.) to identify related articles. The following keywords were used in our search strategy: “calcium” OR “milk” OR “dairy” in combination with “mortality” OR
Z. Asemi et al.
“fatal” OR “death” OR “survive.” All keywords were selected from the Medical Subject Headings (MeSH) database. In addition, a manual search of references of the published papers was performed to find other relevant articles. No language and time restrictions were applied. No attempt was made to include unpublished studies. Duplicate citations were then removed. The full text of related articles was obtained, in some cases, by contacting the corresponding author. Eligibility criteria The following inclusion criteria were adopted: (1) observational cohort or nested caseecontrol studies that considered any source of calcium intake (total, dietary, or supplemental) and all-cause or specific cause of mortality; (2) publications that had provided estimates of relative risks (RRs) (odds ratios (ORs), hazard ratios (HRs), or rate ratios) with corresponding 95% confidence intervals (CIs). Studies that met these criteria were included in our analysis. Excluded studies Totally, 1522 articles were found in our initial search. We excluded 1428 articles through reading the title and abstract. The other 72 papers were excluded because of the following reasons: animal study (n Z 1), studies that examined the effects of calcium plus vitamin D cosupplementation on mortality (n Z 3), or assessed the relationship between serum calcium levels and mortality (n Z 45) or reported the effects of dairy intake, not calcium separately, on mortality (n Z 23). Finally, 22 prospective cohort studies [2,3,5,6,10,14e17,21,24,26e36] were included in this meta-analysis (Fig. 1). Out of these 22 studies, four studies had reported the association between total, dietary, and supplemental calcium intake with mortality [14,21,27,36], seven papers had assessed the association between total and dietary calcium intake and mortality [14,15,21,27,28,31,36], five studies had examined the association between total and supplemental calcium intake and mortality [14,21,27,32,36], and seven papers had reported the association between dietary and supplemental calcium intake, but not total calcium intake, with mortality [2,3,5,14,21,27,36]. When two studies had reported data for all-cause mortality from the same population [33,35], we only included the study with the larger sample size in the analysis [33], to avoid double-counting data [37,38]. We extracted the RRs for the highest versus the lowest calcium intake; however, in two articles the reference for comparisons was the subjects who had the highest intake of calcium [33,35]. Therefore, we converted the reported RRs and CIs in these two studies to obtain the RRs and CIs for subjects with the highest intake versus the subjects who had the lowest intake as reference. One study had nested the caseecontrol design [10]. Due to the similarity of exposure assessment in such study designs to cohort studies, we included this publication in our analysis.
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
Calcium intake and mortality
3
Figure 1
The flow diagram of search strategy and study selection process.
Data extraction The following information was extracted by three independent reviewers (Z.A., P.S., and SeS.S.): the first author’s last name, date of publication, country, participants’ age range, gender, sample size, number of cases, duration of follow-up, method of measurement of exposure and outcome, comparisons, ORs or RRs for all-cause mortality, as well as for cause-specific. In case of disagreements, a principal investigator (A.E.) was consulted. Discrepancies were resolved by consensus. Assessment of methodological quality The quality of included studies was examined by using the NewcastleeOttawa Scale (NOS) [39]. For cohort and caseecontrol studies that included in the analysis, we used their own specific methods. The NOS assigns a maximum of nine points to each cohort study: four for selection, two for comparability, and three for assessment of outcomes (nine represented the highest quality). Any discrepancies were resolved by discussion.
assessing dietary intake. Between-subgroup heterogeneity was examined through the fixed-effects model. Sensitivity analysis was done to explore for the extent to which inferences might depend on a particular study. Publication bias was assessed by visual inspection on Begg’s funnel plots. Formal statistical assessment of funnel plot asymmetry was done using Egger’s regression asymmetry test. For the doseeresponse meta-analysis, the method proposed by Greenland and Longnecker [40] and Orsini et al. [41] was used to compute the trend from the correlated log RRs across categories of calcium intake. The number of deaths and the total number of participants for each category, the RRs with CIs for at least two exposure categories, and the mean or median calcium intake in each category were extracted. Linear associations between calcium intake and mortality were tested by using a twostage random-effects doseeresponse meta-analysis. All statistical analyses were conducted using STATA version 11.2 (STATA Corp., College Station, TX, USA). P-values <0.05 were considered statistically significant for all tests including Cochran’s Q-test. Results
Statistical analysis All reported RRs, HRs, and ORs (and their 95% CIs) were used to calculate the log RR and its standard error. As the prevalence of outcome was relatively low, ORs and HRs were directly considered as RRs. Using a random-effects model that takes between-study variation into account, the overall effect size was calculated. Between-study heterogeneity was assessed using Cochran’s Q-test and I2statistic. In case of significant between-study heterogeneity, we used subgroup analysis to find out the possible sources of heterogeneity. Subgroup analyses were performed according to the duration of the study, geographical area, gender of participants, and tools applied for
Of the 1522 retrieved papers, 21 prospective cohort studies [2,3,5,6,8,14e17,21,24,26e28,30e36] and one nested caseecontrol study [10] were included in this systematic review. These studies are summarized in Table 1. In total, 2,346,368 participants aged 8 to >65 years were included in 22 studies. All studies were published between 1992 and 2013. Overall, the studies include 81,298 deaths. The duration of follow-up for the studies was between 4.6 and 28 years. Five studies had reported their findings for males [10,14,16,27,32], five for females [8,21,26,28,31], five other studies for males and females combined [2,5,15,24,30], and seven studies [3,6,17,33e36] for males and females,
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
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Authors (y)
Country
Age range
Gender
N total
Cases
Follow-up (y)
Outcomes
Measurement
Comparison
OR or RR (95% CI)
Quality score
US
40e75
M
39,800
428
12
Fatal IHD mortality
FFQ
Q5 versus Q1
1.10 (0.79e1.51)
7
US
40e75
M
47,750
312
15
FPC mortality
FFQ
2000 versus 500e749
2.02 (1.14e3.58)
7
Sweden
53.7٭
F
61,433
US US US Japan Japan US Australia
40.65٭ 40.65٭ 55e69 40e79 40e79 50e71 25e78
M F F M F M F/M
8849 9865 34,486 23,117 35,609 29,3888 1529
Levitan et al., 2012 Dietary calcium intake Al-Delaimy et al., 2003 Giovannucci et al., 2006 Michaelsson et al., 2013 Van Hemelrijck et al., 2013 Bostick et al., 1999 Bonthuis et al., 2010
US
50e79
F
3340
11,944 3862 855 1015 387 685 644 178 177 61 1433
19 19 6 6 8 9.6 9.6 6 14.4 14.4 4.6
All-cause mortality CVD mortality CVD mortality CVD mortality IHD mortality CVD mortality CVD mortality FPC mortality All-cause mortality CVD mortality All-cause mortality
FFQ FFQ Recall Recall FFQ FFQ FFQ FFQ FFQ FFQ FFQ
1400 versus 600e999 1400 versus 600e999 >2000 versus 1000e1300 >2000 versus 1000e1300 Q4 versus Q1 Q5 versus Q1 Q5 versus Q1 1500e2000 versus 500e750 T3 versus T1 T3 versus T1 Q4 versus Q1
1.4 (1.25e1.57) 1.51 (1.23e1.84) 1.01 (0.44e2.29) 0.84 (0.44e1.62) 0.67 (0.47e0.94) 0.97 (0.64e1.48) 1.14 (0.74e1.74) 1.05 (0.54e2.05) 1.27(0.74e1.17) 1.31(0.52e3.29) 0.91(0.77e1.09)
8 8 7 7 6 6 6 7 8 8 6
US
40e75
M
39,800
337
12
Fatal IHD mortality
FFQ
Q5 versus Q1
1.21 (0.85e1.71)
7
US
40e75
M
47,750
288
15
FPC mortality
FFQ
933 versus <585
1.36 (0.97e1.92)
7
Sweden
53.7٭
F
61,433
US US US Australia
40.65٭ 40.65٭ 55e69 25e78
M F F F/M
8849 9865 34,486 1529
Levitan et al., 2012 Li et al., 2012 Van der Pols et al., 2009
US Germany UK and Scotland
50e79 35e64 8٭
F F/M F/M
3340 23,980 4374
11944 3862 855 1015 387 177 61 1433 267 1468
19 19 6 6 8 14.4 14.4 4.6 11 65
All-cause mortality CVD mortality CVD mortality CVD mortality IHD mortality All-cause mortality CVD mortality All-cause mortality CVD mortality All-cause mortality
FFQ FFQ Recall Recall FFQ FFQ FFQ FFQ FFQ Recall
1400 versus 1400 versus >1300 versus >1300 versus Q4 versus Q1 T3 versus T1 T3 versus T1 Q4 versus Q1 Q4 versus Q1 Q4 versus Q1
1.40 1.49 0.78 1.10 0.76 0.86 0.99 0.92 1.18 0.77
(1.17e1.67) (1.09e2.02) (0.50e1.22) (0.61e1.97) (0.53e1.11) (0.50e1.48) (0.38e2.56) (0.76e1.11) (0.82e1.72) (0.60e0.98)
8 8 7 7 6 8 8 6 7 8
65 65 12 12 9 9 9 11 28
CHD mortality Stroke mortality CVD mortality CVD mortality All-cause mortality CVD mortality Cancer mortality Cancer mortality All-cause mortality
Recall Recall Recall Recall FFQ FFQ FFQ FFQ Recall
Q4 versus Q1 Q4 versus Q1 Q5 versus Q1 Q5 versus Q1 1599 versus <1230 1599 versus <1230 1599 versus <1230 Q4 versus Q1 585 versus >1245
0.64 (0.38e1.07) 0.41 (0.16e1.05) 1.04 (0.97e1.12) 1.04 (0.94e1.15) 0.75 (0.63e0.88) 0.77 (0.58e1.01) 0.87 (0.65e1.17) 0.90 (0.68e1.20) 1.1 (0.70e1.60)
8 8 8 8 7 7 7 8 6
28 28 28
All-cause mortality Cancer mortality Cancer mortality
Recall Recall Recall
585 versus >1245 585 versus >1245 585 versus >1245
1.20 (0.80e1.90) 1.00 (0.60e1.60) 1.10 (0.60e2.10)
6 6 6
Total calcium intake Al-Delaimy et al., 2003 Giovannucci et al., 2006 Michaelsson et al., 2013 Van Hemelrijck et al., 2013 Bostick et al., 1999 Umesawa et al., 2006 Park et al., 2007 Bonthius et al., 2010
Xiao et al., 2013 Kaluza et al., 2010
Li et al., 2011 Slob et al., 1993
US US Sweden
50e71 50e71 45e79
M F M
21,9059 16,9170 23,366
Germany Dutch, Amsterdam
35e64 40e65
F/M M
24,323 1321
378 121 7904 3874 2358 819 738 513 290
F M F
1270 1321 1270
171 232 127
600e999 600e999 1000e1300 1000e1300
Z. Asemi et al.
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
Table 1 Calcium intake and all-cause, CVD, and cancer mortality: an overview of selected studies for meta-analysis.a
28 28 9.1 9.1 9 9 9 9 9 9 5
CVD mortality CVD mortality All-cause mortality CVD mortality All-cause mortality All-cause mortality CVD mortality CVD mortality Cancer mortality Cancer mortality CVD mortality
Recall Recall FFQ FFQ FFQ FFQ FFQ FFQ FFQ FFQ FFQ
585 versus >1245 445 versus >850 Q4 versus Q1 Q4 versus Q1 T3 versus T1 T3 versus T1 T3 versus T1 T3 versus T1 T3 versus T1 T3 versus T1 T3 versus T1
1.30 (0.80e1.90) 1.10 (0.60e2.00) 0.63 (0.49e0.81) 0.75 (0.44e1.30) 1.08 (0.94e1.25) 0.82 (0.68e0.99) 1.08 (0.83e1.40) 0.75 (0.54e1.05) 0.92 (0.74e1.15) 0.81 (0.61e1.07) 1.0 (0.80e1.40)
5 5 7 7 7 7 7 7 7 7 5
M
39,800
428
12
Fatal IHD mortality
e
Q5 versus nonusers
0.61 (0.34e1.10)
7
40e75
M
47,750
288
15
FPC mortality
e
400 versus 0
1.51 (1.09e2.10)
7
Langsetmo et al., 2013 Prentice et al., 2013 Mursu et al., 2011
US US US US Germany US US Canada Canada US US
40.65٭ 40.65٭ 55e69 50e71 35e64 50e71 50e71 60.38 60.38 50e79 61.6
M F F M F/M M F M F F F
8849 9865 34,486 29,3888 951 21,9059 21,9059 2746 6287 29,502 38,163
Chan et al., 2013
China
>65
F/M
3139
855 1015 387 178 9 7904 3874 423 737 1506 15,301 5601 4828 529 114
6 6 8 6 11 12 12 10 10 7.2 19.6 19.6 19.6 9.1 9.1
CVD mortality CVD mortality IHD mortality FPC mortality CVD mortality CVD mortality CVD mortality All-cause mortality All-cause mortality All-cause mortality All-cause mortality CVD mortality Cancer mortality All-cause mortality CVD mortality
e e e e e e e e e e e e e e e
2000 versus nonusers 2000 versus nonusers >500 versus nonusers 400e1000 versus nonusers Users versus nonusers 1000 versus nonusers 1000 versus nonusers 1000 versus nonusers 1000 versus nonusers Users versus nonusers Users versus nonusers Users versus nonusers Users versus nonusers Users versus nonusers Users versus nonusers
1.44 (0.37e5.66) 0.82 (0.54e1.25) 0.88 (0.64e1.23) 1.46 (0.83e1.72) 1.02 (0.51e2.00) 1.20 (1.05e1.36) 1.06 (0.96e1.18) 0.83 (0.40e1.72) 0.88 (0.65e1.18) 0.94 (0.81e1.09) 0.91(0.88e0.94) 0.87(0.82e0.92) 0.89(0.83e0.94) 0.83 (0.62e1.11) 0.59 (0.30e1.18)
7 7 6 7 7 8 8 7 7 6 7 7 7 7 7
Dutch
40e65
M F F/M
1340 1265 3139
China
>65
Dai et al., 2013
China
40e70
45e64
F M F M F M M
Ross et al., 1997 Supplemental calcium Al-Delaimy et al., 2003 Giovannucci et al., 2006 Van Hemelrijck et al., 2013 Bostick et al., 1999 Park et al., 2007 Li et al., 2012 Xiao et al., 2013
China intake US
40e75
US
Calcium intake and mortality
*Age mean. a F, Female; M, Male; IHD, Ischemic heart disease; FPC, Fatal prostate cancer; CVD, Cardiovascular disease; OR, Odds ratio; RR, Relative risk; CI, Confidence interval; NR, Not reported; FFQ, Food frequency questionnaire; Q5, Quintile 5; Q4, Quintile 4; Q1, Quintile 1; T3, Tertiles 3; T1, Tertiles 1. Quality scores are according to NOS criteria.
5
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
73,232 61,414 73,232 61,414 73,232 61,414 18,244
NR NR 529 114 3806 2418 1147 800 1616 1051 245
Van der Vijver et al., 1992 Chan et al., 2013
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separately. Nine studies were conducted in the United States [3,8,14,21,26e28,32,36], two in Sweden [16,31], one in Japan [34], one in Australia [15], one in Canada [17], two in Germany [2,30], one in United Kingdom [24], two in the Netherlands [33,35], and three in China [5,6,10]. The lower and upper values of ORs or RRs for total calcium intake were between 0.44 and 3.58, for dietary calcium intake, these were between 0.16 and 2.56, and for supplemental calcium intake, these were between 0.30 and 5.66, respectively. Dietary calcium intake was assessed by Food Frequency Questionnaire (FFQ) in 12 investigations and through dietary recall in five studies. Mortality was examined based on death registries by linkage to the National Death Index, and on annual contact with family, friends, or health-care providers. Meta-analysis on total calcium intake and mortality Of the 22 studies included in the systematic review, nine papers that reported the association between total calcium intake and mortality were included in this meta-analysis [14,15,21,27,28,31,32,34]. In total, 559,666 subjects aged 25e79 years were studied in these nine studies. Findings from the meta-analysis on these nine papers revealed no significant association between total calcium intake and all-cause, CVD, or cancer mortality (Fig. 2). A significant between-study heterogeneity was observed for all-cause mortality (I2 Z 87.1%; P < 0.001). This heterogeneity was completely disappeared after excluding the study of Levitan et al. [28] (I2 Z 0%; P Z 0.73). For the relationship between total calcium intake and CVD mortality, a significant between-study heterogeneity was found as well (I2 Z 68.6%; P < 0.001). Neither gender nor dietary assessment tools could explain this heterogeneity (Table 2). When the analyses were performed based on the duration of follow-up, we observed that the total calcium intake was significantly associated with an increased risk of CVD mortality in cohort studies with a mean duration follow-up of >10 years (RR: 1.35; 95% CI: 1.09e1.68); however, such a relationship was not seen for investigations with a mean duration follow-up of 10 years (RR: 0.88; 95% CI: 0.71e1.08). Subgroup analysis based on study location revealed a positive association with CVD mortality in non-US countries (RR: 1.28; 95% CI: 1.01e1.61), but no significant association in the United States (RR: 0.88; 95% CI: 0.66e1.15). No evidence for publication bias was found (Begg’s test: 0.60, 0.99, and 0.32 and Egger’s test: 0.79, 0.22, and 0.20 for all-cause, CVD, and cancer mortality, respectively).
Z. Asemi et al.
and all-cause (RR: 0.89; 95% CI: 0.75e1.04), CVD (RR: 0.97; 95% CI: 0.88e1.06), or cancer (RR: 0.94; 95% CI: 0.83e1.06) mortality (Fig. 3). However, a significant between-study heterogeneity was seen in the case of allcause (I2 Z 79.6%; P < 0.001) and CVD mortality (I2 Z 42.4%; P Z 0.03). Findings from subgroup analysis by the duration of follow-up, gender, dietary assessment tools, and study location are shown in Table 2. A significant inverse association was seen between dietary calcium intake and all-cause mortality for studies that had a mean follow-up duration of 10 years (RR: 0.84; 95% CI: 0.70e1.00). This was not the case for studies with a mean follow-up duration of >10 years (RR: 0.95; 95% CI: 0.70e1.29). In addition, the dietary calcium intake was inversely associated with all-cause mortality in studies conducted on men (RR: 0.79; 95% CI: 0.70e0.90) or on both gender (RR: 0.71; 95% CI: 0.60e0.84); however, a trend toward the positive association was seen in studies conducted on women (RR: 1.07; 95% CI: 0.87e1.32). The association between dietary calcium intake and CVD mortality was significant in studies with a mean duration follow-up of 10 years (RR: 0.88; 95% CI: 0.78e0.99), but not in those with a mean duration followup of >10 years (RR: 1.04; 95% CI: 0.93e1.17). No evidence of heterogeneity was found in these subgroups (Table 2). We did not find any evidence of publication bias (Begg’s test: 0.59, 0.43, and 0.45 and Egger’s test: 0.34, 0.14, and 0.62 for all-cause, CVD, and cancer mortality, respectively). Meta-analysis on supplemental calcium intake and mortality We included 11 studies to explore the association between supplemental calcium intake and mortality in this metaanalysis [2,3,5,8,14,17,21,26,27,32,36]. In total, 954,153 subjects aged 35 to >65 years were examined in these 11 studies. Although supplemental calcium intake was not associated with CVD (RR: 0.95; 95% CI: 0.82e1.10) and cancer mortality (RR: 1.22; 95% CI: 0.88e1.84), it was significantly associated with a decreased risk of all-cause mortality (RR: 0.91; 95% CI: 0.88e0.94) (Fig. 4). To find the source of between-study heterogeneity, we performed subgroup analysis based on confounding variables, for studies that reported the relation between supplemental calcium intake and CVD mortality (Table 2). None of the confounders could completely explain the between-study heterogeneity. No evidence of publication bias was found (Begg’s test: 0.33, 0.99, and 0.60 and Egger’s test: 0.44, 0.91, and 0.06 for all-cause, CVD, and cancer mortality, respectively). Doseeresponse meta-analysis
Meta-analysis on dietary calcium intake and mortality Overall, 17 studies had reported data for dietary calcium intake in relation to mortality [2,3,5,6,10,14e 16,21,24,27,28,30,31,33,35,36]. Totally, 832,549 subjects aged 8 to >65 years were studied in these 17 studies. The summarized RRs from these publications revealed no significant association between dietary calcium intake
Six studies were not included in the doseeresponse metaanalysis because the dose of calcium intake [10], or the number of deaths or participants in each category were not reported [15,27,32,35,36]. In a doseeresponse metaanalysis, after adjustment for gender and duration of follow-up in the studies, dietary calcium intake was not associated with all-cause (RR: 1.00; 95% CI: 0.71e1.40;
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
Calcium intake and mortality
Figure 2
7
Forest plot of the association between total calcium intake and all-cause, CVD- and cancer-mortality risk. RR stands for relative risk.
n Z seven studies), CVD (RR: 1.00; 95% CI: 0.81e1.23; n Z nine studies), or cancer mortality (RR: 1.00; 95% CI: 0.99e1.00; n Z four studies) in a linear fashion. The total calcium intake was also not related to all-cause (RR: 0.99; 95% CI: 0.82e1.21; n Z two studies) or CVD mortality (RR: 1.00; 95% CI: 0.54e1.86; n Z four studies) in a linear fashion after adjustment for confounders (Supplementary Table 1). For supplemental calcium intake, a doseeresponse meta-analysis was not possible, due to the use of supplemental calcium intake as a dichotomous variable (user vs. nonuser) in the studies [2,5,8,26], or to the lack of information about the number of deaths and participants in each category [3,14,17,21,27,32,36]. Discussion This meta-analysis of prospective cohort studies indicated a significant relationship between the total calcium intake and an increased risk of CVD mortality when the mean follow-up duration was >10 years. In addition, dietary calcium intake was protectively associated with all-cause and CVD mortality for studies with a mean follow-up duration of 10 years. Supplemental calcium intake was associated with a decreased risk of all-cause mortality. The inclusion of population-based prospective studies with large sample sizes is the strength of the current metaanalysis. In addition, we assessed the relationship between total, dietary, and supplemental calcium intake with allcause, CVD, and cancer mortality in the current metaanalysis. Subgroup analysis based on follow-up duration and study location might also provide further information. In the present meta-analysis of observational studies, no significant relationship between total, dietary, or
supplemental calcium intake and the risk of CVD mortality was found. However, findings from a meta-analysis of 11 randomized clinical trials (RCTs) (n Z 11,921, mean duration Z 4.0 years) showed that calcium supplements (without co-administered vitamin D) were associated with a modest increase in the risk of CVD (RR for myocardial infarction: 1.27; 95% CI: 1.01e1.59) [42]. The same conclusion was also reached in the Women’s Health Initiative (WHI) calciumevitamin D (CaeD) study [43]. On the other hand, in a meta-analysis of RCTs, calcium supplementation led to a significant decrease in systolic blood pressure [44]. In addition, a significant decrease in serum low density lipoprotein (LDL)echolesterol levels was observed with calcium and vitamin D supplementations during a weight-loss intervention in healthy, overweight, or obese women [45]. Differences in the amount of calcium intake, the duration of intervention and follow-up, as well as the existence of several confounders in observational studies may explain the inconsistencies in findings from the meta-analysis of observational studies and RCTs. Although previous investigations proposed the hypothesis that the safety of calcium for CVD outcomes in the elderly was questionable [46], in a recent RCT, a 3-year calcium supplementation did not increase either carotid artery intimal medial thickness or carotid atherosclerosis [47]. Also, in the WHI trial, the calcium carbonateevitamin D3 supplementation versus placebo did not alter coronaryartery-calcified plaque burden among postmenopausal women [48]. Findings from this meta-analysis also revealed no significant association between total calcium intake and all-cause and CVD mortality; however, when the analyses were performed based on the duration of follow-up, we observed a significant positive association
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Table 2 Subgroup analysis for total, dietary, and supplemental calcium intake and all-cause and CVD mortality in prospective cohort studies. Total calcium intake and CVD mortality (Ref)
Effect sizes
Overall [14,15,21,31,34,36] 8 Duration 10 years [14,15,31] 3 <10 years [21,34,36] 5 Gender Female [21,31,34,36] 4 Male [14,34,36] 3 Both [15] 1 Dietary assessment tools FFQ [14,15,21,31,34] 6 Food recall [36] 2 Location United States [14,21,36] 4 Non-US [15,31,34] 4 Dietary calcium intake and all-cause mortality (Ref) Overall [5,6,15,16,24,28,31,33] 10 Duration 10 years [15,24,31,33] 5 <10 years [5,6,16,28] 5 Gender Female [6,28,31,33] 4 Male [6,16,33] 3 Both [5,15,24] 3 Dietary assessment tools FFQ [5,6,15,16,28,31] 7 Food recall [24,33] 3 Dietary calcium intake and CVD mortality (Ref) Overall [2,3,5,6,10,14,16,21,24,31,35,36] 17 Duration 10 years [2,3,14,15,24,31,35] 9 <10 years [5,6,10,16,21,36] 8 Gender Female [6,28,31,33] 6 Male [6,16,33] 7 Both [5,15,24] 4 Dietary assessment tools FFQ [2,5,6,10,14e16,21,31] 10 Food recall [3,24,35,36] 7 Location United States [3,14,21,36] 6 Non-US [2,5,6,10,15,16,24,31,35] 11 Supplemental calcium intake and CVD mortality (Ref) Overall [2,3,5,8,14,21,36] 9 Duration 10 years [2,3,8,14] 5 <10 years [5,21,36] 4 Gender Female [3,8,21,36] 4 Male [3,14,36] 3 Both [2,5] 2 Dietary assessment tools FFQ [25,14] 2 Food recall [2,3,8,21,36] 7 Location United States [3,8,14,21,36] 7 Non-US [2,5] 2
between total calcium intake and CVD mortality for cohort studies with a mean follow-up duration of >10 years, while a protective association was seen between dietary calcium intake and all-cause and CVD mortality for cohort studies with a mean follow-up duration of 10 years. In addition, in a previous meta-analysis, no significant association was found between serum concentrations of calcium and all-cause mortality in individuals with chronic
I2
Q-test
RR (95% CI)
60.8
0.01
1.05 (0.83e1.34)
21.8 0.5
0.28 0.40
1.35 (1.09e1.68) 0.88 (0.71e1.08)
82 0 e
0.001 0.89
1.02 (0.66e1.58) 1.04 (0.81e1.34) 1.31 (0.52e3.29)
70.2 0
0.005 0.73
1.08 (0.81e1.42) 0.90 (0.54e1.50)
27.6 26.9
0.25 0.24
0.88 (0.66e1.215) 1.28 (1.01e1.61)
79.6
<0.001
0.89 (0.75e1.04)
77.7 78.5
0.001 0.001
0.95 (0.70e1.29) 0.84 (0.70e1.00)
75.1 0 0
0.007 0.65 0.42
1.07 (0.87e1.32) 0.79 (0.70e0.90) 0.71 (0.60e0.84)
85.5 0
<0.001 0.81
0.91 (0.74e1.11) 0.81 (0.67e0.96)
42.4
0.03
0.97 (0.88e1.06)
45.7 0
0.06 0.46
1.04 (0.93e1.17) 0.88 (0.78e0.99)
37.5 45.6 50.4
0.16 0.09 0.11
1.06 (0.91e1.24) 0.92 (0.80e1.06) 0.84 (0.58e1.22)
49.7 37.8
0.04 0.14
0.98 (0.84e1.15) 0.97 (0.87e1.09)
0 51.8
0.42 0.02
1.03 (0.97e1.09) 0.92 (0.78e1.09)
73.9
<0.001
0.95 (0.82e1.10)
85.7 0
<0.001 0.66
0.99 (0.83e1.18) 0.83 (0.66e1.06)
72.8 59.7 18.7
0.101 0.08 0.27
0.93 (0.80e1.08) 0.98 (0.59e1.64) 0.78 (0.45e1.33)
0 77.6
0.94 <0.001
0.60 (0.39e0.94) 0.99 (0.85e1.15)
79.2 18.7
<0.001 0.27
0.96 (0.83e1.12) 0.78 (0.45e1.33)
P between 0.001
0.64
e
0.33
0.002
0.006
<0.001
0.14
0.006
0.26
0.62
0.15
0.31
0.001
0.05
0.44
kidney disease [20]. However, another meta-analysis showed a significant relationship between higher-thanreferent levels of serum calcium and mortality in patients with end-stage renal disease [19]. Total, dietary, and supplemental calcium intake in the current meta-analysis were not related to the risk of cancer mortality. This finding needs to be interpreted with caution as events (n Z 5294) from three studies
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Calcium intake and mortality
Figure 3
9
Forest plot of the association between dietary calcium intake and all-cause, CVD- and cancer-mortality risk. RR stands for relative risk.
[8,27,32] reported that the relationships might result in such finding. In the Iowa Women’s Health Study [8], with 4828 incident of cancer mortality, the use of calcium supplements was inversely related to cancer mortality (RR: 0.89; 95% CI: 0.83e0.94), while a metaanalysis of 10 RCTs (n Z 10,496) revealed that calcium supplementation, for a mean duration of 3.9 years, did not alter the risk of total cancer (RR: 0.95; 95% CI: 0.76e1.18), or cancer-related mortality (RR: 0.96; 95% CI: 0.74e1.24) [49]. It seems that concentrations of serumionized calcium might influence gene polymorphisms [50]. Another proposed mechanism by which supplemental calcium intake has been suggested to affect cancer is by downregulating the synthesis of 1,25dihydroxyvitamin D, the bioactive vitamin D metabolite involved in regulating cellular differentiation and proliferation of epithelia [51]. We found no significant association between dietary calcium intake and all-cause and CVD mortality for studies that had a mean follow-up duration of >10 years, while a significant inverse association was seen between dietary calcium intake and all-cause as well as CVD mortality for studies with a mean follow-up duration of 10 years. In line with ours, a recent meta-analysis showed no significant association between dietary calcium intake and coronary artery disease or stroke [52]. Some studies have also shown no association between dietary calcium intake and breast cancer risk in postmenopausal women [53,54], while others found an inverse association between high calcium intake [55] and high serum calcium levels [56], and the risk of breast cancer. In contrast with our meta-
analysis, dietary calcium intake was inversely associated with stroke in populations with low to moderate calcium intake as well as in Asian populations [57]. Several lines of evidence have pointed to a beneficial effect of dietary calcium on a decreased risk of all-cause mortality. The influence of dietary calcium on blood pressure, serum cholesterol levels, and plasma glucose might explain the beneficial effects of dietary calcium intake on reduced mortality [16]. We did not find a doseeresponse association between total or dietary calcium and all-cause, CVD, or cancer mortality. However, Michaëlsson et al. [31] suggested a nonlinear relationship between both total and dietary calcium intake and mortality outcomes, with higher rates concentrated around the highest total intake (1400 mg/ day) as well as the higher death rate with a low dietary calcium intake (<600 mg/day), compared with the intake between 600 and 1000 mg/day [31]. Regarding the use of random- and fixed-effects models in the analysis, some investigators believe that the heterogeneity is better to be examined using the randomeffects modeling [58]; others have suggested that the fixed-effects model, which assumes that a single common (or “fixed”) effect underlies every study, should be used to summarize the associations across studies in the metaanalysis, as the random-effects models give larger weights to small extreme studies [59]. We used the random-effects model in the assessment of heterogeneity; however, when we repeated the analysis by using the fixed-effects model, CIs became relatively narrow, but the results did not change significantly.
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
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Figure 4 Forest plot of the association between supplemental calcium intake and all-cause, CVD- and cancer-mortality risk. RR stands for relative risk.
In conclusion, we found a significant relationship between the total calcium intake and an increased risk of CVD mortality for studies with a long follow-up time, while a significant protective association was seen between dietary calcium intake and all-cause and CVD mortality for studies with a mean follow-up of 10 years. In addition, supplemental calcium intake was associated with a decreased risk of all-cause mortality. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.numecd.2015.03.008.
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META-ANALYSIS
Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies Z. Asemi a,1, P. Saneei b,c,d,1, S.-S. Sabihi b,c, A. Feizi e, A. Esmaillzadeh b,c,*,1 a
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Isfahan, Iran Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran c Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran d Students’ Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran e Department of Epidemiology and Biostatistics, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran b
Received 18 September 2014; received in revised form 14 March 2015; accepted 16 March 2015 Available online - - -
KEYWORDS Calcium; Mortality; Meta-analysis; Diet
Abstract Aims: This systematic review and meta-analysis of observational studies was conducted to summarize the evidence on the association between calcium intake and mortality. Methods and results: PubMed, Institute for Scientific Information (ISI) (Web of Science), SCOPUS, SciRUS, Google Scholar, and Excerpta Medica dataBASE (EMBASE) were searched to identify related articles published through May 2014. We found 22 articles that assessed the association between total, dietary, and supplementary intake with mortality from all-causes, cardiovascular disease (CVD), and cancer. Findings from this meta-analysis revealed no significant association between total and dietary calcium intake and mortality from all-causes, CVD, and cancer. Subgroup analysis by the duration of follow-up revealed a significant positive association between total calcium intake and CVD mortality for cohort studies with a mean follow-up duration of >10 years (relative risk (RR): 1.35; 95% confidence interval (CI): 1.09e1.68). A significant inverse association was seen between dietary calcium intake and all-cause (RR: 0.84; 95% CI: 0.70e1.00) and CVD mortality (RR: 0.88; 95% CI: 0.78e0.99) for studies with a mean follow-up duration of 10 years. Although supplemental calcium intake was not associated with CVD (RR: 0.95; 95% CI: 0.82e1.10) and cancer mortality (RR: 1.22; 95% CI: 0.81e1.84), it was inversely associated with the risk of all-cause mortality (RR: 0.91; 95% CI: 0.88e0.94). Conclusions: We found a significant relationship between the total calcium intake and an increased risk of CVD mortality for studies with a long follow-up time and a significant protective association between dietary calcium intake and all-cause and CVD mortality for studies with a mean follow-up of 10 years. Supplemental calcium intake was associated with a decreased risk of all-cause mortality. ª 2015 Elsevier B.V. All rights reserved.
* Corresponding author. Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, PO Box 81745-151, Iran. Tel.: þ98 311 7922720; fax: þ98 311 6682509. E-mail address: [email protected] (A. Esmaillzadeh). 1 Co-first author.
Introduction Findings from epidemiological studies have indicated an inverse association between dietary calcium intake and
http://dx.doi.org/10.1016/j.numecd.2015.03.008 0939-4753/ª 2015 Elsevier B.V. All rights reserved.
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
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risk of hypertension, obesity, and type 2 diabetes [1,2]. In addition, calcium supplements are widely used in elderly population [3]. More than 50% of older men and almost 70% of older women in the United States used calcium supplements [4]. Although the role of calcium in the prevention and treatment of osteoporosis, normal growth, and development of the skeleton and teeth is well established, its effect on nonskeletal outcomes including cardiovascular events or cancers remains largely unknown [5e10]. High calcium intake has been suggested to increase fat excretion [11], which in turn might result in a decreased risk of cardiovascular disease (CVD). By contrast, calcium is present in atherosclerotic lesions, raising the possibility that an increased dietary and supplemental calcium intake may increase the risk of CVD [12,13]. Prior studies have examined the association between calcium intake from diet and supplements and allcause mortality; however, findings were inconsistent [14e17]. Some prospective studies have reported an inverse association between dietary calcium intake and risk of mortality from CVD [18e20]. Others have shown that not only dietary but also supplemental calcium intake was inversely associated with deaths from CVD [17e21] and prostate cancer [22,23]. In a prospective cohort study, Van der Pols et al. [24] demonstrated that childhood calcium intake was inversely associated with stroke mortality. In another cohort study, calcium supplements, up to 1000 mg/d, and an increased dietary intake of calcium were associated with a reduced risk of mortality in women [17]. With increasing number of older men and women taking calcium supplements to avoid osteoporosis [25], examining the association between calcium intake and mortality is of great interest. Although several studies have assessed the relationship between dietary and supplemental calcium intake and mortality, we are aware of no meta-analysis that summarized findings from previous publications. Given the inconsistent findings about the association between calcium intake and risk of all-cause mortality, this study aimed to systematically review the current evidence on the association between calcium intake and risk of all-cause, CVD, and cancer mortality, and to summarize the available findings in a meta-analysis, if possible. Methods Search strategy A systematic search of the literature published earlier than May 2014 was conducted in PubMed, Institute for Scientific Information (ISI) (Web of Science), SCOPUS, SciRUS, Google Scholar, and Excerpta Medica dataBASE (EMBASE) by three independent investigators (Z.A., P.S., and SeS.S.) to identify related articles. The following keywords were used in our search strategy: “calcium” OR “milk” OR “dairy” in combination with “mortality” OR
Z. Asemi et al.
“fatal” OR “death” OR “survive.” All keywords were selected from the Medical Subject Headings (MeSH) database. In addition, a manual search of references of the published papers was performed to find other relevant articles. No language and time restrictions were applied. No attempt was made to include unpublished studies. Duplicate citations were then removed. The full text of related articles was obtained, in some cases, by contacting the corresponding author. Eligibility criteria The following inclusion criteria were adopted: (1) observational cohort or nested caseecontrol studies that considered any source of calcium intake (total, dietary, or supplemental) and all-cause or specific cause of mortality; (2) publications that had provided estimates of relative risks (RRs) (odds ratios (ORs), hazard ratios (HRs), or rate ratios) with corresponding 95% confidence intervals (CIs). Studies that met these criteria were included in our analysis. Excluded studies Totally, 1522 articles were found in our initial search. We excluded 1428 articles through reading the title and abstract. The other 72 papers were excluded because of the following reasons: animal study (n Z 1), studies that examined the effects of calcium plus vitamin D cosupplementation on mortality (n Z 3), or assessed the relationship between serum calcium levels and mortality (n Z 45) or reported the effects of dairy intake, not calcium separately, on mortality (n Z 23). Finally, 22 prospective cohort studies [2,3,5,6,10,14e17,21,24,26e36] were included in this meta-analysis (Fig. 1). Out of these 22 studies, four studies had reported the association between total, dietary, and supplemental calcium intake with mortality [14,21,27,36], seven papers had assessed the association between total and dietary calcium intake and mortality [14,15,21,27,28,31,36], five studies had examined the association between total and supplemental calcium intake and mortality [14,21,27,32,36], and seven papers had reported the association between dietary and supplemental calcium intake, but not total calcium intake, with mortality [2,3,5,14,21,27,36]. When two studies had reported data for all-cause mortality from the same population [33,35], we only included the study with the larger sample size in the analysis [33], to avoid double-counting data [37,38]. We extracted the RRs for the highest versus the lowest calcium intake; however, in two articles the reference for comparisons was the subjects who had the highest intake of calcium [33,35]. Therefore, we converted the reported RRs and CIs in these two studies to obtain the RRs and CIs for subjects with the highest intake versus the subjects who had the lowest intake as reference. One study had nested the caseecontrol design [10]. Due to the similarity of exposure assessment in such study designs to cohort studies, we included this publication in our analysis.
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
Calcium intake and mortality
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Figure 1
The flow diagram of search strategy and study selection process.
Data extraction The following information was extracted by three independent reviewers (Z.A., P.S., and SeS.S.): the first author’s last name, date of publication, country, participants’ age range, gender, sample size, number of cases, duration of follow-up, method of measurement of exposure and outcome, comparisons, ORs or RRs for all-cause mortality, as well as for cause-specific. In case of disagreements, a principal investigator (A.E.) was consulted. Discrepancies were resolved by consensus. Assessment of methodological quality The quality of included studies was examined by using the NewcastleeOttawa Scale (NOS) [39]. For cohort and caseecontrol studies that included in the analysis, we used their own specific methods. The NOS assigns a maximum of nine points to each cohort study: four for selection, two for comparability, and three for assessment of outcomes (nine represented the highest quality). Any discrepancies were resolved by discussion.
assessing dietary intake. Between-subgroup heterogeneity was examined through the fixed-effects model. Sensitivity analysis was done to explore for the extent to which inferences might depend on a particular study. Publication bias was assessed by visual inspection on Begg’s funnel plots. Formal statistical assessment of funnel plot asymmetry was done using Egger’s regression asymmetry test. For the doseeresponse meta-analysis, the method proposed by Greenland and Longnecker [40] and Orsini et al. [41] was used to compute the trend from the correlated log RRs across categories of calcium intake. The number of deaths and the total number of participants for each category, the RRs with CIs for at least two exposure categories, and the mean or median calcium intake in each category were extracted. Linear associations between calcium intake and mortality were tested by using a twostage random-effects doseeresponse meta-analysis. All statistical analyses were conducted using STATA version 11.2 (STATA Corp., College Station, TX, USA). P-values <0.05 were considered statistically significant for all tests including Cochran’s Q-test. Results
Statistical analysis All reported RRs, HRs, and ORs (and their 95% CIs) were used to calculate the log RR and its standard error. As the prevalence of outcome was relatively low, ORs and HRs were directly considered as RRs. Using a random-effects model that takes between-study variation into account, the overall effect size was calculated. Between-study heterogeneity was assessed using Cochran’s Q-test and I2statistic. In case of significant between-study heterogeneity, we used subgroup analysis to find out the possible sources of heterogeneity. Subgroup analyses were performed according to the duration of the study, geographical area, gender of participants, and tools applied for
Of the 1522 retrieved papers, 21 prospective cohort studies [2,3,5,6,8,14e17,21,24,26e28,30e36] and one nested caseecontrol study [10] were included in this systematic review. These studies are summarized in Table 1. In total, 2,346,368 participants aged 8 to >65 years were included in 22 studies. All studies were published between 1992 and 2013. Overall, the studies include 81,298 deaths. The duration of follow-up for the studies was between 4.6 and 28 years. Five studies had reported their findings for males [10,14,16,27,32], five for females [8,21,26,28,31], five other studies for males and females combined [2,5,15,24,30], and seven studies [3,6,17,33e36] for males and females,
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
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Authors (y)
Country
Age range
Gender
N total
Cases
Follow-up (y)
Outcomes
Measurement
Comparison
OR or RR (95% CI)
Quality score
US
40e75
M
39,800
428
12
Fatal IHD mortality
FFQ
Q5 versus Q1
1.10 (0.79e1.51)
7
US
40e75
M
47,750
312
15
FPC mortality
FFQ
2000 versus 500e749
2.02 (1.14e3.58)
7
Sweden
53.7٭
F
61,433
US US US Japan Japan US Australia
40.65٭ 40.65٭ 55e69 40e79 40e79 50e71 25e78
M F F M F M F/M
8849 9865 34,486 23,117 35,609 29,3888 1529
Levitan et al., 2012 Dietary calcium intake Al-Delaimy et al., 2003 Giovannucci et al., 2006 Michaelsson et al., 2013 Van Hemelrijck et al., 2013 Bostick et al., 1999 Bonthuis et al., 2010
US
50e79
F
3340
11,944 3862 855 1015 387 685 644 178 177 61 1433
19 19 6 6 8 9.6 9.6 6 14.4 14.4 4.6
All-cause mortality CVD mortality CVD mortality CVD mortality IHD mortality CVD mortality CVD mortality FPC mortality All-cause mortality CVD mortality All-cause mortality
FFQ FFQ Recall Recall FFQ FFQ FFQ FFQ FFQ FFQ FFQ
1400 versus 600e999 1400 versus 600e999 >2000 versus 1000e1300 >2000 versus 1000e1300 Q4 versus Q1 Q5 versus Q1 Q5 versus Q1 1500e2000 versus 500e750 T3 versus T1 T3 versus T1 Q4 versus Q1
1.4 (1.25e1.57) 1.51 (1.23e1.84) 1.01 (0.44e2.29) 0.84 (0.44e1.62) 0.67 (0.47e0.94) 0.97 (0.64e1.48) 1.14 (0.74e1.74) 1.05 (0.54e2.05) 1.27(0.74e1.17) 1.31(0.52e3.29) 0.91(0.77e1.09)
8 8 7 7 6 6 6 7 8 8 6
US
40e75
M
39,800
337
12
Fatal IHD mortality
FFQ
Q5 versus Q1
1.21 (0.85e1.71)
7
US
40e75
M
47,750
288
15
FPC mortality
FFQ
933 versus <585
1.36 (0.97e1.92)
7
Sweden
53.7٭
F
61,433
US US US Australia
40.65٭ 40.65٭ 55e69 25e78
M F F F/M
8849 9865 34,486 1529
Levitan et al., 2012 Li et al., 2012 Van der Pols et al., 2009
US Germany UK and Scotland
50e79 35e64 8٭
F F/M F/M
3340 23,980 4374
11944 3862 855 1015 387 177 61 1433 267 1468
19 19 6 6 8 14.4 14.4 4.6 11 65
All-cause mortality CVD mortality CVD mortality CVD mortality IHD mortality All-cause mortality CVD mortality All-cause mortality CVD mortality All-cause mortality
FFQ FFQ Recall Recall FFQ FFQ FFQ FFQ FFQ Recall
1400 versus 1400 versus >1300 versus >1300 versus Q4 versus Q1 T3 versus T1 T3 versus T1 Q4 versus Q1 Q4 versus Q1 Q4 versus Q1
1.40 1.49 0.78 1.10 0.76 0.86 0.99 0.92 1.18 0.77
(1.17e1.67) (1.09e2.02) (0.50e1.22) (0.61e1.97) (0.53e1.11) (0.50e1.48) (0.38e2.56) (0.76e1.11) (0.82e1.72) (0.60e0.98)
8 8 7 7 6 8 8 6 7 8
65 65 12 12 9 9 9 11 28
CHD mortality Stroke mortality CVD mortality CVD mortality All-cause mortality CVD mortality Cancer mortality Cancer mortality All-cause mortality
Recall Recall Recall Recall FFQ FFQ FFQ FFQ Recall
Q4 versus Q1 Q4 versus Q1 Q5 versus Q1 Q5 versus Q1 1599 versus <1230 1599 versus <1230 1599 versus <1230 Q4 versus Q1 585 versus >1245
0.64 (0.38e1.07) 0.41 (0.16e1.05) 1.04 (0.97e1.12) 1.04 (0.94e1.15) 0.75 (0.63e0.88) 0.77 (0.58e1.01) 0.87 (0.65e1.17) 0.90 (0.68e1.20) 1.1 (0.70e1.60)
8 8 8 8 7 7 7 8 6
28 28 28
All-cause mortality Cancer mortality Cancer mortality
Recall Recall Recall
585 versus >1245 585 versus >1245 585 versus >1245
1.20 (0.80e1.90) 1.00 (0.60e1.60) 1.10 (0.60e2.10)
6 6 6
Total calcium intake Al-Delaimy et al., 2003 Giovannucci et al., 2006 Michaelsson et al., 2013 Van Hemelrijck et al., 2013 Bostick et al., 1999 Umesawa et al., 2006 Park et al., 2007 Bonthius et al., 2010
Xiao et al., 2013 Kaluza et al., 2010
Li et al., 2011 Slob et al., 1993
US US Sweden
50e71 50e71 45e79
M F M
21,9059 16,9170 23,366
Germany Dutch, Amsterdam
35e64 40e65
F/M M
24,323 1321
378 121 7904 3874 2358 819 738 513 290
F M F
1270 1321 1270
171 232 127
600e999 600e999 1000e1300 1000e1300
Z. Asemi et al.
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
Table 1 Calcium intake and all-cause, CVD, and cancer mortality: an overview of selected studies for meta-analysis.a
28 28 9.1 9.1 9 9 9 9 9 9 5
CVD mortality CVD mortality All-cause mortality CVD mortality All-cause mortality All-cause mortality CVD mortality CVD mortality Cancer mortality Cancer mortality CVD mortality
Recall Recall FFQ FFQ FFQ FFQ FFQ FFQ FFQ FFQ FFQ
585 versus >1245 445 versus >850 Q4 versus Q1 Q4 versus Q1 T3 versus T1 T3 versus T1 T3 versus T1 T3 versus T1 T3 versus T1 T3 versus T1 T3 versus T1
1.30 (0.80e1.90) 1.10 (0.60e2.00) 0.63 (0.49e0.81) 0.75 (0.44e1.30) 1.08 (0.94e1.25) 0.82 (0.68e0.99) 1.08 (0.83e1.40) 0.75 (0.54e1.05) 0.92 (0.74e1.15) 0.81 (0.61e1.07) 1.0 (0.80e1.40)
5 5 7 7 7 7 7 7 7 7 5
M
39,800
428
12
Fatal IHD mortality
e
Q5 versus nonusers
0.61 (0.34e1.10)
7
40e75
M
47,750
288
15
FPC mortality
e
400 versus 0
1.51 (1.09e2.10)
7
Langsetmo et al., 2013 Prentice et al., 2013 Mursu et al., 2011
US US US US Germany US US Canada Canada US US
40.65٭ 40.65٭ 55e69 50e71 35e64 50e71 50e71 60.38 60.38 50e79 61.6
M F F M F/M M F M F F F
8849 9865 34,486 29,3888 951 21,9059 21,9059 2746 6287 29,502 38,163
Chan et al., 2013
China
>65
F/M
3139
855 1015 387 178 9 7904 3874 423 737 1506 15,301 5601 4828 529 114
6 6 8 6 11 12 12 10 10 7.2 19.6 19.6 19.6 9.1 9.1
CVD mortality CVD mortality IHD mortality FPC mortality CVD mortality CVD mortality CVD mortality All-cause mortality All-cause mortality All-cause mortality All-cause mortality CVD mortality Cancer mortality All-cause mortality CVD mortality
e e e e e e e e e e e e e e e
2000 versus nonusers 2000 versus nonusers >500 versus nonusers 400e1000 versus nonusers Users versus nonusers 1000 versus nonusers 1000 versus nonusers 1000 versus nonusers 1000 versus nonusers Users versus nonusers Users versus nonusers Users versus nonusers Users versus nonusers Users versus nonusers Users versus nonusers
1.44 (0.37e5.66) 0.82 (0.54e1.25) 0.88 (0.64e1.23) 1.46 (0.83e1.72) 1.02 (0.51e2.00) 1.20 (1.05e1.36) 1.06 (0.96e1.18) 0.83 (0.40e1.72) 0.88 (0.65e1.18) 0.94 (0.81e1.09) 0.91(0.88e0.94) 0.87(0.82e0.92) 0.89(0.83e0.94) 0.83 (0.62e1.11) 0.59 (0.30e1.18)
7 7 6 7 7 8 8 7 7 6 7 7 7 7 7
Dutch
40e65
M F F/M
1340 1265 3139
China
>65
Dai et al., 2013
China
40e70
45e64
F M F M F M M
Ross et al., 1997 Supplemental calcium Al-Delaimy et al., 2003 Giovannucci et al., 2006 Van Hemelrijck et al., 2013 Bostick et al., 1999 Park et al., 2007 Li et al., 2012 Xiao et al., 2013
China intake US
40e75
US
Calcium intake and mortality
*Age mean. a F, Female; M, Male; IHD, Ischemic heart disease; FPC, Fatal prostate cancer; CVD, Cardiovascular disease; OR, Odds ratio; RR, Relative risk; CI, Confidence interval; NR, Not reported; FFQ, Food frequency questionnaire; Q5, Quintile 5; Q4, Quintile 4; Q1, Quintile 1; T3, Tertiles 3; T1, Tertiles 1. Quality scores are according to NOS criteria.
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Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
73,232 61,414 73,232 61,414 73,232 61,414 18,244
NR NR 529 114 3806 2418 1147 800 1616 1051 245
Van der Vijver et al., 1992 Chan et al., 2013
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separately. Nine studies were conducted in the United States [3,8,14,21,26e28,32,36], two in Sweden [16,31], one in Japan [34], one in Australia [15], one in Canada [17], two in Germany [2,30], one in United Kingdom [24], two in the Netherlands [33,35], and three in China [5,6,10]. The lower and upper values of ORs or RRs for total calcium intake were between 0.44 and 3.58, for dietary calcium intake, these were between 0.16 and 2.56, and for supplemental calcium intake, these were between 0.30 and 5.66, respectively. Dietary calcium intake was assessed by Food Frequency Questionnaire (FFQ) in 12 investigations and through dietary recall in five studies. Mortality was examined based on death registries by linkage to the National Death Index, and on annual contact with family, friends, or health-care providers. Meta-analysis on total calcium intake and mortality Of the 22 studies included in the systematic review, nine papers that reported the association between total calcium intake and mortality were included in this meta-analysis [14,15,21,27,28,31,32,34]. In total, 559,666 subjects aged 25e79 years were studied in these nine studies. Findings from the meta-analysis on these nine papers revealed no significant association between total calcium intake and all-cause, CVD, or cancer mortality (Fig. 2). A significant between-study heterogeneity was observed for all-cause mortality (I2 Z 87.1%; P < 0.001). This heterogeneity was completely disappeared after excluding the study of Levitan et al. [28] (I2 Z 0%; P Z 0.73). For the relationship between total calcium intake and CVD mortality, a significant between-study heterogeneity was found as well (I2 Z 68.6%; P < 0.001). Neither gender nor dietary assessment tools could explain this heterogeneity (Table 2). When the analyses were performed based on the duration of follow-up, we observed that the total calcium intake was significantly associated with an increased risk of CVD mortality in cohort studies with a mean duration follow-up of >10 years (RR: 1.35; 95% CI: 1.09e1.68); however, such a relationship was not seen for investigations with a mean duration follow-up of 10 years (RR: 0.88; 95% CI: 0.71e1.08). Subgroup analysis based on study location revealed a positive association with CVD mortality in non-US countries (RR: 1.28; 95% CI: 1.01e1.61), but no significant association in the United States (RR: 0.88; 95% CI: 0.66e1.15). No evidence for publication bias was found (Begg’s test: 0.60, 0.99, and 0.32 and Egger’s test: 0.79, 0.22, and 0.20 for all-cause, CVD, and cancer mortality, respectively).
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and all-cause (RR: 0.89; 95% CI: 0.75e1.04), CVD (RR: 0.97; 95% CI: 0.88e1.06), or cancer (RR: 0.94; 95% CI: 0.83e1.06) mortality (Fig. 3). However, a significant between-study heterogeneity was seen in the case of allcause (I2 Z 79.6%; P < 0.001) and CVD mortality (I2 Z 42.4%; P Z 0.03). Findings from subgroup analysis by the duration of follow-up, gender, dietary assessment tools, and study location are shown in Table 2. A significant inverse association was seen between dietary calcium intake and all-cause mortality for studies that had a mean follow-up duration of 10 years (RR: 0.84; 95% CI: 0.70e1.00). This was not the case for studies with a mean follow-up duration of >10 years (RR: 0.95; 95% CI: 0.70e1.29). In addition, the dietary calcium intake was inversely associated with all-cause mortality in studies conducted on men (RR: 0.79; 95% CI: 0.70e0.90) or on both gender (RR: 0.71; 95% CI: 0.60e0.84); however, a trend toward the positive association was seen in studies conducted on women (RR: 1.07; 95% CI: 0.87e1.32). The association between dietary calcium intake and CVD mortality was significant in studies with a mean duration follow-up of 10 years (RR: 0.88; 95% CI: 0.78e0.99), but not in those with a mean duration followup of >10 years (RR: 1.04; 95% CI: 0.93e1.17). No evidence of heterogeneity was found in these subgroups (Table 2). We did not find any evidence of publication bias (Begg’s test: 0.59, 0.43, and 0.45 and Egger’s test: 0.34, 0.14, and 0.62 for all-cause, CVD, and cancer mortality, respectively). Meta-analysis on supplemental calcium intake and mortality We included 11 studies to explore the association between supplemental calcium intake and mortality in this metaanalysis [2,3,5,8,14,17,21,26,27,32,36]. In total, 954,153 subjects aged 35 to >65 years were examined in these 11 studies. Although supplemental calcium intake was not associated with CVD (RR: 0.95; 95% CI: 0.82e1.10) and cancer mortality (RR: 1.22; 95% CI: 0.88e1.84), it was significantly associated with a decreased risk of all-cause mortality (RR: 0.91; 95% CI: 0.88e0.94) (Fig. 4). To find the source of between-study heterogeneity, we performed subgroup analysis based on confounding variables, for studies that reported the relation between supplemental calcium intake and CVD mortality (Table 2). None of the confounders could completely explain the between-study heterogeneity. No evidence of publication bias was found (Begg’s test: 0.33, 0.99, and 0.60 and Egger’s test: 0.44, 0.91, and 0.06 for all-cause, CVD, and cancer mortality, respectively). Doseeresponse meta-analysis
Meta-analysis on dietary calcium intake and mortality Overall, 17 studies had reported data for dietary calcium intake in relation to mortality [2,3,5,6,10,14e 16,21,24,27,28,30,31,33,35,36]. Totally, 832,549 subjects aged 8 to >65 years were studied in these 17 studies. The summarized RRs from these publications revealed no significant association between dietary calcium intake
Six studies were not included in the doseeresponse metaanalysis because the dose of calcium intake [10], or the number of deaths or participants in each category were not reported [15,27,32,35,36]. In a doseeresponse metaanalysis, after adjustment for gender and duration of follow-up in the studies, dietary calcium intake was not associated with all-cause (RR: 1.00; 95% CI: 0.71e1.40;
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
Calcium intake and mortality
Figure 2
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Forest plot of the association between total calcium intake and all-cause, CVD- and cancer-mortality risk. RR stands for relative risk.
n Z seven studies), CVD (RR: 1.00; 95% CI: 0.81e1.23; n Z nine studies), or cancer mortality (RR: 1.00; 95% CI: 0.99e1.00; n Z four studies) in a linear fashion. The total calcium intake was also not related to all-cause (RR: 0.99; 95% CI: 0.82e1.21; n Z two studies) or CVD mortality (RR: 1.00; 95% CI: 0.54e1.86; n Z four studies) in a linear fashion after adjustment for confounders (Supplementary Table 1). For supplemental calcium intake, a doseeresponse meta-analysis was not possible, due to the use of supplemental calcium intake as a dichotomous variable (user vs. nonuser) in the studies [2,5,8,26], or to the lack of information about the number of deaths and participants in each category [3,14,17,21,27,32,36]. Discussion This meta-analysis of prospective cohort studies indicated a significant relationship between the total calcium intake and an increased risk of CVD mortality when the mean follow-up duration was >10 years. In addition, dietary calcium intake was protectively associated with all-cause and CVD mortality for studies with a mean follow-up duration of 10 years. Supplemental calcium intake was associated with a decreased risk of all-cause mortality. The inclusion of population-based prospective studies with large sample sizes is the strength of the current metaanalysis. In addition, we assessed the relationship between total, dietary, and supplemental calcium intake with allcause, CVD, and cancer mortality in the current metaanalysis. Subgroup analysis based on follow-up duration and study location might also provide further information. In the present meta-analysis of observational studies, no significant relationship between total, dietary, or
supplemental calcium intake and the risk of CVD mortality was found. However, findings from a meta-analysis of 11 randomized clinical trials (RCTs) (n Z 11,921, mean duration Z 4.0 years) showed that calcium supplements (without co-administered vitamin D) were associated with a modest increase in the risk of CVD (RR for myocardial infarction: 1.27; 95% CI: 1.01e1.59) [42]. The same conclusion was also reached in the Women’s Health Initiative (WHI) calciumevitamin D (CaeD) study [43]. On the other hand, in a meta-analysis of RCTs, calcium supplementation led to a significant decrease in systolic blood pressure [44]. In addition, a significant decrease in serum low density lipoprotein (LDL)echolesterol levels was observed with calcium and vitamin D supplementations during a weight-loss intervention in healthy, overweight, or obese women [45]. Differences in the amount of calcium intake, the duration of intervention and follow-up, as well as the existence of several confounders in observational studies may explain the inconsistencies in findings from the meta-analysis of observational studies and RCTs. Although previous investigations proposed the hypothesis that the safety of calcium for CVD outcomes in the elderly was questionable [46], in a recent RCT, a 3-year calcium supplementation did not increase either carotid artery intimal medial thickness or carotid atherosclerosis [47]. Also, in the WHI trial, the calcium carbonateevitamin D3 supplementation versus placebo did not alter coronaryartery-calcified plaque burden among postmenopausal women [48]. Findings from this meta-analysis also revealed no significant association between total calcium intake and all-cause and CVD mortality; however, when the analyses were performed based on the duration of follow-up, we observed a significant positive association
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
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Table 2 Subgroup analysis for total, dietary, and supplemental calcium intake and all-cause and CVD mortality in prospective cohort studies. Total calcium intake and CVD mortality (Ref)
Effect sizes
Overall [14,15,21,31,34,36] 8 Duration 10 years [14,15,31] 3 <10 years [21,34,36] 5 Gender Female [21,31,34,36] 4 Male [14,34,36] 3 Both [15] 1 Dietary assessment tools FFQ [14,15,21,31,34] 6 Food recall [36] 2 Location United States [14,21,36] 4 Non-US [15,31,34] 4 Dietary calcium intake and all-cause mortality (Ref) Overall [5,6,15,16,24,28,31,33] 10 Duration 10 years [15,24,31,33] 5 <10 years [5,6,16,28] 5 Gender Female [6,28,31,33] 4 Male [6,16,33] 3 Both [5,15,24] 3 Dietary assessment tools FFQ [5,6,15,16,28,31] 7 Food recall [24,33] 3 Dietary calcium intake and CVD mortality (Ref) Overall [2,3,5,6,10,14,16,21,24,31,35,36] 17 Duration 10 years [2,3,14,15,24,31,35] 9 <10 years [5,6,10,16,21,36] 8 Gender Female [6,28,31,33] 6 Male [6,16,33] 7 Both [5,15,24] 4 Dietary assessment tools FFQ [2,5,6,10,14e16,21,31] 10 Food recall [3,24,35,36] 7 Location United States [3,14,21,36] 6 Non-US [2,5,6,10,15,16,24,31,35] 11 Supplemental calcium intake and CVD mortality (Ref) Overall [2,3,5,8,14,21,36] 9 Duration 10 years [2,3,8,14] 5 <10 years [5,21,36] 4 Gender Female [3,8,21,36] 4 Male [3,14,36] 3 Both [2,5] 2 Dietary assessment tools FFQ [25,14] 2 Food recall [2,3,8,21,36] 7 Location United States [3,8,14,21,36] 7 Non-US [2,5] 2
between total calcium intake and CVD mortality for cohort studies with a mean follow-up duration of >10 years, while a protective association was seen between dietary calcium intake and all-cause and CVD mortality for cohort studies with a mean follow-up duration of 10 years. In addition, in a previous meta-analysis, no significant association was found between serum concentrations of calcium and all-cause mortality in individuals with chronic
I2
Q-test
RR (95% CI)
60.8
0.01
1.05 (0.83e1.34)
21.8 0.5
0.28 0.40
1.35 (1.09e1.68) 0.88 (0.71e1.08)
82 0 e
0.001 0.89
1.02 (0.66e1.58) 1.04 (0.81e1.34) 1.31 (0.52e3.29)
70.2 0
0.005 0.73
1.08 (0.81e1.42) 0.90 (0.54e1.50)
27.6 26.9
0.25 0.24
0.88 (0.66e1.215) 1.28 (1.01e1.61)
79.6
<0.001
0.89 (0.75e1.04)
77.7 78.5
0.001 0.001
0.95 (0.70e1.29) 0.84 (0.70e1.00)
75.1 0 0
0.007 0.65 0.42
1.07 (0.87e1.32) 0.79 (0.70e0.90) 0.71 (0.60e0.84)
85.5 0
<0.001 0.81
0.91 (0.74e1.11) 0.81 (0.67e0.96)
42.4
0.03
0.97 (0.88e1.06)
45.7 0
0.06 0.46
1.04 (0.93e1.17) 0.88 (0.78e0.99)
37.5 45.6 50.4
0.16 0.09 0.11
1.06 (0.91e1.24) 0.92 (0.80e1.06) 0.84 (0.58e1.22)
49.7 37.8
0.04 0.14
0.98 (0.84e1.15) 0.97 (0.87e1.09)
0 51.8
0.42 0.02
1.03 (0.97e1.09) 0.92 (0.78e1.09)
73.9
<0.001
0.95 (0.82e1.10)
85.7 0
<0.001 0.66
0.99 (0.83e1.18) 0.83 (0.66e1.06)
72.8 59.7 18.7
0.101 0.08 0.27
0.93 (0.80e1.08) 0.98 (0.59e1.64) 0.78 (0.45e1.33)
0 77.6
0.94 <0.001
0.60 (0.39e0.94) 0.99 (0.85e1.15)
79.2 18.7
<0.001 0.27
0.96 (0.83e1.12) 0.78 (0.45e1.33)
P between 0.001
0.64
e
0.33
0.002
0.006
<0.001
0.14
0.006
0.26
0.62
0.15
0.31
0.001
0.05
0.44
kidney disease [20]. However, another meta-analysis showed a significant relationship between higher-thanreferent levels of serum calcium and mortality in patients with end-stage renal disease [19]. Total, dietary, and supplemental calcium intake in the current meta-analysis were not related to the risk of cancer mortality. This finding needs to be interpreted with caution as events (n Z 5294) from three studies
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
Calcium intake and mortality
Figure 3
9
Forest plot of the association between dietary calcium intake and all-cause, CVD- and cancer-mortality risk. RR stands for relative risk.
[8,27,32] reported that the relationships might result in such finding. In the Iowa Women’s Health Study [8], with 4828 incident of cancer mortality, the use of calcium supplements was inversely related to cancer mortality (RR: 0.89; 95% CI: 0.83e0.94), while a metaanalysis of 10 RCTs (n Z 10,496) revealed that calcium supplementation, for a mean duration of 3.9 years, did not alter the risk of total cancer (RR: 0.95; 95% CI: 0.76e1.18), or cancer-related mortality (RR: 0.96; 95% CI: 0.74e1.24) [49]. It seems that concentrations of serumionized calcium might influence gene polymorphisms [50]. Another proposed mechanism by which supplemental calcium intake has been suggested to affect cancer is by downregulating the synthesis of 1,25dihydroxyvitamin D, the bioactive vitamin D metabolite involved in regulating cellular differentiation and proliferation of epithelia [51]. We found no significant association between dietary calcium intake and all-cause and CVD mortality for studies that had a mean follow-up duration of >10 years, while a significant inverse association was seen between dietary calcium intake and all-cause as well as CVD mortality for studies with a mean follow-up duration of 10 years. In line with ours, a recent meta-analysis showed no significant association between dietary calcium intake and coronary artery disease or stroke [52]. Some studies have also shown no association between dietary calcium intake and breast cancer risk in postmenopausal women [53,54], while others found an inverse association between high calcium intake [55] and high serum calcium levels [56], and the risk of breast cancer. In contrast with our meta-
analysis, dietary calcium intake was inversely associated with stroke in populations with low to moderate calcium intake as well as in Asian populations [57]. Several lines of evidence have pointed to a beneficial effect of dietary calcium on a decreased risk of all-cause mortality. The influence of dietary calcium on blood pressure, serum cholesterol levels, and plasma glucose might explain the beneficial effects of dietary calcium intake on reduced mortality [16]. We did not find a doseeresponse association between total or dietary calcium and all-cause, CVD, or cancer mortality. However, Michaëlsson et al. [31] suggested a nonlinear relationship between both total and dietary calcium intake and mortality outcomes, with higher rates concentrated around the highest total intake (1400 mg/ day) as well as the higher death rate with a low dietary calcium intake (<600 mg/day), compared with the intake between 600 and 1000 mg/day [31]. Regarding the use of random- and fixed-effects models in the analysis, some investigators believe that the heterogeneity is better to be examined using the randomeffects modeling [58]; others have suggested that the fixed-effects model, which assumes that a single common (or “fixed”) effect underlies every study, should be used to summarize the associations across studies in the metaanalysis, as the random-effects models give larger weights to small extreme studies [59]. We used the random-effects model in the assessment of heterogeneity; however, when we repeated the analysis by using the fixed-effects model, CIs became relatively narrow, but the results did not change significantly.
Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008
10
Z. Asemi et al.
Figure 4 Forest plot of the association between supplemental calcium intake and all-cause, CVD- and cancer-mortality risk. RR stands for relative risk.
In conclusion, we found a significant relationship between the total calcium intake and an increased risk of CVD mortality for studies with a long follow-up time, while a significant protective association was seen between dietary calcium intake and all-cause and CVD mortality for studies with a mean follow-up of 10 years. In addition, supplemental calcium intake was associated with a decreased risk of all-cause mortality. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.numecd.2015.03.008.
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Please cite this article in press as: Asemi Z, et al., Total, dietary, and supplemental calcium intake and mortality from all-causes, cardiovascular disease, and cancer: A meta-analysis of observational studies, Nutrition, Metabolism & Cardiovascular Diseases (2015), http://dx.doi.org/10.1016/j.numecd.2015.03.008