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Dietary calcium intake in relation to blood lipids and lipoproteins profiles: A systematic review and meta-analysis of epidemiologic studies

  • Zahra Hajhashemy
    Affiliations
    Students' Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran

    Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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  • Parisa Rouhani
    Affiliations
    Students' Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran

    Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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  • Parvane Saneei
    Correspondence
    Corresponding author. Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, PO Box 81745-151 Iran. Fax: +98 3136681378.
    Affiliations
    Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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      Highlights

      • We performed a systematic review and meta-analysis on epidemiologic studies to evaluate the relation of dietary calcium intake with serum lipid profiles.
      • A systematic search was performed for epidemiological studies that considered dietary Ca intake as the exposure and reported risk of dyslipidemia or serum lipid concentrations as the outcomes of interest in adults.
      • This meta-analysis demonstrated that individuals with the highest dietary calcium intake had lower serum TG, LDL-c, and higher HDL-c concentrations, compared to those with the lowest Ca intake. However, the linkage between dietary calcium intake with odds of hyperlipidemia or dyslipidemia was not significant. Further prospective studies are needed to affirm these findings.

      Abstract

      Aims

      Findings of prior investigations on the association between calcium intake and lipid profiles were inconsistent. We performed a systematic review and meta-analysis on epidemiologic studies to evaluate the relationship of dietary calcium intake with blood lipids and lipoproteins.

      Data synthesis

      A systematic search up to April 2021 was performed in different electronic databases, including MEDLINE (PubMed), Scopus, Web of Science (ISI), and Google Scholar for epidemiological studies that considered dietary calcium intake as the exposure and reported risk of dyslipidemia or blood lipids and lipoproteins concentrations (as mean ± SD or mean ± SE or median (Inter Quartile Range) as the outcomes of interest in adult populations from both genders (18 years or older), regardless of their health status. Nineteen cross-sectional studies were included in the analysis. Combining estimates from 11 studies (including 33,304 subjects) revealed that individuals in the highest category of calcium intake, compared to the lowest one, had 5.94 mg/dL lower circulating triglyceride (TG) concentration (weighted mean difference (WMD): −5.94; 95% CI: −8.27, −3.62), 4.02 mg/dL lower circulating low-density lipoprotein cholesterol (LDL-c) levels (WMD: −4.02; 95% CI: −7.08, −0.95), and 1.56 mg/dL higher blood high-density lipoprotein cholesterol (HDL-c) (WMD: 1.56; 95% CI: 0.81, 2.30). Although meta-analysis on 13 studies (including 38,714 participants) did not reveal a significant relationship between dietary calcium intake and odds of dyslipidemia or hyperlipidemia in the whole population, the highest vs. lowest level of calcium intake was related to 42% decreased odds of low blood HDL-c levels in females (95% CI: 0.40, 0.84) and 41% increased odds in males (95% CI: 1.21, 1.65).

      Conclusions

      This meta-analysis demonstrated that individuals with the highest dietary calcium intake might have lower blood TG, LDL-c, and higher HDL-c concentrations as compared to those with the lowest calcium intake. However, the linkage between dietary calcium intake with odds of hyperlipidemia or dyslipidemia was not significant. Because of the cross-sectional nature of included studies, causality could not be proven. Further prospective studies are needed to affirm these findings.

      Keywords

      1. Introduction

      Dyslipidemia is a prevalent metabolic disorder that increases in an alarming rate worldwide. Evidence has suggested a significant relationship between dyslipidemia and insulin resistance, type 2 diabetes (T2D), and obesity [
      • Taskinen M.-R.
      Diabetic dyslipidemia.
      ]. Moreover, epidemiologic studies demonstrated that dyslipidemia is a major risk factor for arterial disease, atherosclerotic cardiovascular disease (CVD), myocardial infarction (MI), ischemic cerebrovascular accident, CVD mortality, and all-cause mortality [
      • Vodnala D.
      • Rubenfire M.
      • Brook R.D.
      Secondary causes of dyslipidemia.
      ,
      • Orozco-Beltran D.
      • Gil-Guillen V.F.
      • Redon J.
      • Martin-Moreno J.M.
      • Pallares-Carratala V.
      • Navarro-Perez J.
      • et al.
      Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: the ESCARVAL-RISK study.
      ]. Therefore, the identification and management of risk factors are worthy to prevent the abnormality in serum lipid profiles. Besides age, sex, genetics, and race that are known risk factors of dyslipidemia, lifestyle, physical activity, education, and dietary intake play important roles in dyslipidemia incidence [
      • Vekic J.
      • Zeljkovic A.
      • Stefanovic A.
      • Jelic-Ivanovic Z.
      • Spasojevic-Kalimanovska V.
      Obesity and dyslipidemia.
      ,
      • Phan B.A.P.
      • Toth P.P.
      Dyslipidemia in women: etiology and management.
      ].
      Dietary nutrients intake has an important role in the prevention and management of the disorder. Calcium (Ca) is a well-known nutrient because of its effect on bone and dental health. In addition, it was illustrated that Ca intake is related to the incidence of CVD [
      • Yang C.
      • Shi X.
      • Xia H.
      • Yang X.
      • Liu H.
      • Pan D.
      • et al.
      The evidence and controversy between dietary calcium intake and calcium supplementation and the risk of cardiovascular disease: a systematic review and meta-analysis of cohort studies and randomized controlled trials.
      ], stroke [
      • Larsson S.C.
      • Orsini N.
      • Wolk A.
      Dietary calcium intake and risk of stroke: a dose-response meta-analysis.
      ], multiple sclerosis [
      • Goldberg P.
      Multiple sclerosis: vitamin D and calcium as environmental determinants of prevalence: (A viewpoint) part 2. biochemical and genetic factors.
      ], insulin resistance, and T2D [
      • Pittas A.G.
      • Lau J.
      • Hu F.B.
      • Dawson-Hughes B.
      The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis.
      ]. It has also been suggested that calcium could play a role in serum lipid profile abnormalities. Some epidemiologic studies indicated a significant inverse relationship between Ca intake and risk of high TG [
      • Shin S.K.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Chun BY, Choi BY: the cross-sectional relationship between dietary calcium intake and metabolic syndrome among men and women aged 40 or older in rural areas of Korea.
      ] and low HDL-c [
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ]. However, some other studies did not confirm significant relations between Ca intake and risk of abnormalities in serum lipid profiles [
      • Moore-Schiltz L.
      • Albert J.M.
      • Singer M.E.
      • Swain J.
      • Nock N.L.
      Dietary intake of calcium and magnesium and the metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001-2010 data.
      ,
      • Aritici G.
      • Bas M.
      Metabolic syndrome and calcium: the effects on body composition and biochemical parameters among premenopausal women.
      ]. Although the results of prior investigations were inconsistent [
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ,
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ,
      • Kim M.H.
      • Bu S.Y.
      • Choi M.K.
      Daily calcium intake and its relation to blood pressure, blood lipids, and oxidative stress biomarkers in hypertensive and normotensive subjects.
      ,
      • Cherne M.
      What is the relationship between dietary calcium intake and CVD risk factors in a college-age population?.
      ], there was no previous review that systematically summarized the relationship between dietary Ca intake and serum lipid profiles or lipid abnormalities in epidemiologic studies. Therefore, we performed a systematic review and meta-analysis on epidemiologic studies to investigate the relationship of dietary calcium intake with serum lipid profiles in epidemiologic studies.

      2. Materials

      2.1 Search strategy

      A systematic search was performed in electronic databases, including MEDLINE (PubMed), Scopus, Web of Science (ISI), and Google scholar, for all published articles up to April 2021. No limitation in language or publication year was applied. Details of the applied MeSH and non-MeSH keywords used in the systematic search are presented in Supplemental Table 1. Moreover, to identify additional studies, bibliographies of the relevant articles were manually searched. In the present analysis, we conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline (PRISMA). We also conformed to AMSTAR 2, a tool for assessing particular domains and the overall quality of a systematic review. The study was registered at Prospero (no. CRD42021244368).

      2.2 Inclusion criteria

      The systematic review and meta-analysis included published articles that met the following criteria: (1) they were observational studies including cross-sectional, case–control, or cohort studies; (2) they were conducted on the adult population (18 years or older), regardless of their health status; (3) they considered dietary Ca intake from all food groups (not supplements or particular foods) as the exposure and reported dyslipidemia or blood lipids and lipoproteins values as the outcome of interest; and (4) they investigated the relationship between dietary Ca intake and dyslipidemia by reporting odds ratios (ORs), hazard ratios (HR), and relative risks (RRs) with corresponding 95% CIs, or sufficient data to calculate these values or provide blood lipid values (as mean ± SD or mean ± SE or median (Inter Quartile Range)) in different levels of dietary Ca intake. Additionally, in the case of studies that reported median and interquartile range for dietary calcium intake, the mean and standard deviation (SD) were calculated using the previously proposed formulas [
      • Hozo S.P.
      • Djulbegovic B.
      • Hozo I.
      Estimating the mean and variance from the median, range, and the size of a sample.
      ].

      2.3 Exclusion criteria

      Details of excluding more relevant studies are provided in Supplemental Table 2. We excluded studies if they (1) considered dietary Ca intake as the outcome and dyslipidemia or blood lipids and lipoproteins profiles as the exposure; (2) reported Ca intake for individuals with and without hyperlipidemia; (3) reported standard regression coefficient (β) or un-standard regression coefficient (B) for blood lipids and lipoprotein profiles in various categories of dietary Ca intake and did not provide unprocessed data of circulating lipid profile values in Ca categories; (4) reported changes in circulating lipid profiles after a follow-up period; and (5) reported correlation coefficients between dietary calcium consumption and blood lipids or lipoproteins and did not provide unprocessed data of blood lipid profiles in Ca categories. In addition, we excluded studies with overlapped populations. We had two reports from Multi-Rural Communities Cohort (MR Cohort 2005–2011) [
      • Shin S.K.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Chun BY, Choi BY: the cross-sectional relationship between dietary calcium intake and metabolic syndrome among men and women aged 40 or older in rural areas of Korea.
      ,
      • Woo H.W.
      • Lim Y.H.
      • Kim M.K.
      • Shin J.
      • Lee Y.H.
      • Shin D.H.
      • et al.
      Choi BY: prospective associations between total, animal, and vegetable calcium intake and metabolic syndrome in adults aged 40 years and older.
      ] which reported OR for dyslipidemia, and two reports that were part of Korean Genome and Epidemiology Study (KoGES 2005–2011) [
      • Oh J.M.
      • Woo H.W.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Choi BY: dietary total, animal, vegetable calcium and type 2 diabetes incidence among Korean adults: the Korean Multi-Rural Communities Cohort (MRCohort).
      ,
      • Kim K.
      • Yang Y.J.
      • Kim K.
      • Kim M.K.
      Interactions of single nucleotide polymorphisms with dietary calcium intake on the risk of metabolic syndrome.
      ], which reported circulating lipid values in categories of Ca intake. For both cases, just publications with a larger sample size (MR Cohort 2005–2010 [
      • Shin S.K.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Chun BY, Choi BY: the cross-sectional relationship between dietary calcium intake and metabolic syndrome among men and women aged 40 or older in rural areas of Korea.
      ] and KoGES 2005–2011 [
      • Oh J.M.
      • Woo H.W.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Choi BY: dietary total, animal, vegetable calcium and type 2 diabetes incidence among Korean adults: the Korean Multi-Rural Communities Cohort (MRCohort).
      ]) were included in the analysis. Although the full text of unavailable articles was obtained by requesting the authors, it was not provided for two papers, even though the request from the authors. Hence, we could not include them in the current analysis [
      • Teran-Garcia M.
      • Mosley M.
      • Aradillas-Garcia C.
      • Andrade F.C.D.
      • Grp U.
      Daily calcium intake and prevalence of metabolic syndrome (MetS) risk factors in Mexican college student applicants.
      ,
      • Lee Y.K.
      • Hyun T.
      • Lyu E.S.
      • Oh S.Y.
      • Park H.
      • Ro H.K.
      • et al.
      Serum calcium is associated with dyslipidemia in Korean adults: a cross-sectional study.
      ]. Overall, 818 published articles were obtained in the initial systematic search; 145 of them were duplicate and excluded. Then, two investigators independently screened the title and abstract of 675 remaining studies. Afterward, the full text of 100 papers was carefully assessed. Finally, 19 eligible studies were included in the current analysis. All processes of search strategy were independently performed by two researchers (Z.H. and P.R.). In case of any disagreement, the principal investigator (P.S.) was consulted. The details of the search strategy and study selection are presented in Fig. 1.
      Figure 1
      Figure 1Flow diagram of search strategy and study selection.

      2.4 Data extraction

      General characteristics of eligible studies were extracted, including first authors’ last name, year of publication, study design, study location (longitude, latitude, and development status), representativeness of the study population, recruitment source of population, mean age, sex of participants, sample size, health status of participants, the prevalence of dyslipidemia in dietary Ca intake levels, ORs, HRs, RRs with 95% CIs for dyslipidemia or blood lipids and lipoproteins abnormality, mean ± SD or mean ± SE or median (Inter Quartile Range) for circulating lipid values in different categories of dietary Ca intake, method of dietary Ca intake assessment, Ca intake levels, the definition of dyslipidemia and measurement method of circulating lipid profiles, adjustments for confounders, and quality score of included studies. Notably, we extracted the most comprehensive adjusted risk estimates for lipid abnormalities. Data extraction was independently conducted by two researchers (Z.H. and P.R.). The principal investigator (P.S.) was consulted in the case of any disagreement. To ensure accuracy, the authors extracted data twice and then cross-checked them.

      2.5 Quality assessment of studies

      The quality of included studies was assessed based on Newcastle–Ottawa Scale (NOS) [
      • Wells G.A.
      • Tugwell P.
      • O'Connell D.
      • Welch V.
      • Peterson J.
      • Shea B.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses.
      ] for epidemiologic studies. According to NOS, each cross-sectional study was given a maximum score of 10, including five for selection subjects (representativeness of study population, description of non-respondents, satisfaction of sample size, and ascertainment of dietary Ca intake as the exposure), two for comparability (adjustment for confounders including age and sex), and three scores for outcomes assessment (using an appropriate statistical test for the analysis and validated assessment of dyslipidemia or blood lipids and lipoproteins values as the outcome). In addition, NOS assigned a maximum of 9 points to each cohort study: four for selection participants (selection of the non-exposed cohort, representativeness of the exposed cohort, ascertainment of dietary Ca intake as the exposure, and demonstration that dyslipidemia was not present at the start of the study), two for comparability (adjustment for confounders including age and sex), and three for assessment of outcomes (adequacy of cohort follow-up, adequate duration of follow-up for incidence of dyslipidemia, and validated assessment of dyslipidemia as the outcome). The process of quality assessment of eligible studies is depicted in Supplemental Table 3. In the current meta-analysis, studies with a quality score of 7 (median score) or more were determined as “high quality,” and others were considered as “low quality”. Discrepancies were resolved through discussion.

      2.6 Statistical analysis

      The reported ORs and their 95% CIs for dietary Ca intake–dyslipidemia relation were used to calculate log ORs and their standard errors. We manually calculated the ORs for studies that did not report ORs but provided the number of participants with and without dyslipidemia in each category of dietary Ca intake. First, we separately computed the odds of dyslipidemia in each level of dietary Ca intake, such that the number of cases with dyslipidemia was divided into the number of participants without dyslipidemia in each group. After that, we calculated the OR of dyslipidemia for each level of dietary Ca intake by dividing the odds of dyslipidemia in that level by odds of dyslipidemia in the lowest dietary Ca intake as the reference group [
      • Uemura H.
      • Katsuura-Kamano S.
      • Yamaguchi M.
      • Nakamoto M.
      • Hiyoshi M.
      • Arisawa K.
      Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.
      ,
      • Liu S.
      • Song Y.
      • Ford E.S.
      • Manson J.E.
      • Buring J.E.
      • Ridker P.M.
      Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women.
      ,
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ,
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ,
      • Delavar M.A.
      • Sann L.M.
      • Lin K.G.
      • Hassan S.
      • Hanachi P.
      Total calcium intake and metabolic syndrome in middle aged women, Babol, Iran.
      ,
      • Chae M.
      • Jang J.
      • Park K.
      Association between dietary calcium intake and the risk of cardiovascular disease among Korean adults.
      ].
      We did two meta-analyses: mean differences and their SDs were used as the effect sizes in the first analysis, and ORs and their 95% CIs were assumed as the effect sizes in the second analysis. We computed the overall effect size through the use of a random-effects model that takes between-study variation into account. Cochran's Q test and I2 were used to examine the between-study heterogeneity. When the between-study heterogeneity was significant, subgroup analyses were conducted based on age (<50 year, ≥ 50), sex, developmental status of countries, assessment tools for Ca intake, quality of studies, measurement methods of circulating lipid profiles, the health status of participants, and representativeness of the study population and study location (Asian vs. non-Asian countries) to find the possible sources of heterogeneity. To determine the probable effect of continuous variables (including mean/median of Ca intake of the reference group, latitude, longitude, quality of studies, and mean age of participants) on the overall estimate, a meta-regression analysis was conducted. In addition, we examined the linear dose–response relationship of dietary Ca intake and odds of hyperlipidemia/dyslipidemia through random-effects meta-regression analysis. OR and 95% CI of different categories of calcium intake compared with the reference group were extracted and converted to log OR (SE). The corresponding medians or means of calcium intake (mg/d) in each category were also used in this meta-regression. In addition, since the extreme categories of Ca intake might be inconsistent, we transformed the odds of dyslipidemia/hyperlipidemia to compare the top versus the bottom third of the dietary Ca in all eligible studies, using the method previously described by Danesh et al. [
      • Danesh J.
      • Collins R.
      • Appleby P.
      • Peto R.
      Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.
      ]. Assuming a normal distribution for log OR, we used the following conversions: log OR was multiplied to the factor of (1) 2.18 divided by 1.59, for conversion of the top vs. bottom halves; (2) 2.18 divided by 2.54, for conversion of the top vs. bottom quartiles; (3) 2.18 divided by 2.80, for conversion of the top vs. bottom quintiles; (4) 2.18, for studies that reported odds of dyslipidemia for one SD increase in dietary Ca intake. In this way, we converted all categories (including halves, quartiles, quintiles, one SD increase) to the third tertile vs. the first tertile of dietary Ca intake. The standard error of the log OR was computed through confidence limits and then converted in the same way. In Pannu et al.'s study [
      • Pannu P.K.
      • Soares M.J.
      • Piers L.S.
      • Zhao Y.
      • Ansari Z.
      The association of vitamin D status and dietary calcium intake with individual components of the metabolic syndrome: a population-based study in Victoria, Australia.
      ], a linear relationship for each 500 mg/day dietary Ca intake was reported, but SD of Ca intake was not provided. Thus, we could not calculate OR for highest vs. lowest or T3 vs. T1 category of Ca intake. Therefore, this study was included only in the systematic review and could not be included in the meta-analysis. Sensitivity analysis was performed to evaluate the extent to which inferences might depend on an individual study. We examined the publication bias through the use of visual inspection of Begg's funnel plot asymmetry and Begg's test. STATA version 14.0 (STATA Crop, college station, TX, USA) was used to perform statistical analyses. We considered P-values <0.05 as statistically significant for all tests, including Cochran's Q test.

      3. Results

      3.1 Study characteristics

      In total, 19 epidemiologic studies were included in this systematic review, and 18 studies were included in the analysis; details of all eligible studies are presented in Table 1. These researches were published between 2003 and 2020; almost all of them had cross-sectional design, except one cohort study with a 9-year follow-up [
      • Fumeron F.
      • Lamri A.
      • Emery N.
      • Bellili N.
      • Jaziri R.
      • Porchay-Balderelli I.
      • et al.
      Dairy products and the metabolic syndrome in a prospective study, DESIR.
      ], which reported both cross-sectional and prospective relationships. Only the baseline data of this cohort study (as a cross-sectional investigation) was included in the analysis. Hence, all included articles in the current analysis had cross-sectional design. In total, 73,954 participants were investigated in the included studies. Five eligible studies (26%) were done in Korea [
      • Shin S.K.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Chun BY, Choi BY: the cross-sectional relationship between dietary calcium intake and metabolic syndrome among men and women aged 40 or older in rural areas of Korea.
      ,
      • Oh J.M.
      • Woo H.W.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Choi BY: dietary total, animal, vegetable calcium and type 2 diabetes incidence among Korean adults: the Korean Multi-Rural Communities Cohort (MRCohort).
      ,
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ,
      • Chae M.
      • Jang J.
      • Park K.
      Association between dietary calcium intake and the risk of cardiovascular disease among Korean adults.
      ,
      • Shin B.R.
      • Choi Y.K.
      • Kim H.N.
      • Song S.W.
      High dietary calcium intake and a lack of dairy consumption are associated with metabolic syndrome in obese males: the Korean National Health and Nutrition Examination Survey 2010 to 2012.
      ], 4 (21%) in Brazil [
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ,
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ,
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ,
      • Leite L.H.M.
      • Sampaio A.
      Dietary calcium, dairy food intake and metabolic abnormalities in HIV-infected individuals.
      ], 3 (16%) in the USA [
      • Moore-Schiltz L.
      • Albert J.M.
      • Singer M.E.
      • Swain J.
      • Nock N.L.
      Dietary intake of calcium and magnesium and the metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001-2010 data.
      ,
      • Liu S.
      • Song Y.
      • Ford E.S.
      • Manson J.E.
      • Buring J.E.
      • Ridker P.M.
      Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women.
      ,
      • Dibaba D.T.
      • Xun P.C.
      • Fly A.D.
      • Bidulescu A.
      • Tsinovoi C.L.
      • Judd S.E.
      • et al.
      Calcium intake and serum calcium level in relation to the risk of ischemic stroke: findings from the REGARDS study.
      ], 2 (11%) in Turkey [
      • Aritici G.
      • Bas M.
      Metabolic syndrome and calcium: the effects on body composition and biochemical parameters among premenopausal women.
      ,
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ], and the remaining (26%) in Canada [
      • Jacqmain M.
      • Doucet E.
      • Després J.P.
      • Bouchard C.
      • Tremblay A.
      Calcium intake, body composition, and lipoprotein-lipid concentrations in adults.
      ], Australia [
      • Pannu P.K.
      • Soares M.J.
      • Piers L.S.
      • Zhao Y.
      • Ansari Z.
      The association of vitamin D status and dietary calcium intake with individual components of the metabolic syndrome: a population-based study in Victoria, Australia.
      ], Japan [
      • Uemura H.
      • Katsuura-Kamano S.
      • Yamaguchi M.
      • Nakamoto M.
      • Hiyoshi M.
      • Arisawa K.
      Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.
      ], Iran [
      • Delavar M.A.
      • Sann L.M.
      • Lin K.G.
      • Hassan S.
      • Hanachi P.
      Total calcium intake and metabolic syndrome in middle aged women, Babol, Iran.
      ], and France [
      • Fumeron F.
      • Lamri A.
      • Emery N.
      • Bellili N.
      • Jaziri R.
      • Porchay-Balderelli I.
      • et al.
      Dairy products and the metabolic syndrome in a prospective study, DESIR.
      ]. Nine studies (47%) were done in Asian countries, and 10 others (53%) were from non-Asian regions. To examine the amount of dietary Ca intake, the eligible studies have used different tools, including food frequency questionnaires (FFQs) in 11 reports (58%), food recalls in 7 articles (37%), and food records in the last study (5%). Fifteen studies (79%) were conducted on apparently healthy subjects; however, four studies (21%) were performed on patients with T2D [
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ], renal transplant recipients [
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ], hypertension [
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ], and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) [
      • Leite L.H.M.
      • Sampaio A.
      Dietary calcium, dairy food intake and metabolic abnormalities in HIV-infected individuals.
      ]. Thirteen studies (68%) have randomly selected their subjects, so their samples were representative of the general adult population. Nevertheless, six others (32%) did not use a random sampling method. Among the cross-sectional studies, seven articles (37%) received a score of 7 or more; therefore, they were considered as high-quality studies, and the remaining (63%) were deemed to be low quality.
      Table 1Main characteristics of the included studies that examined the association between Ca intake and lipid profiles in adults.
      First author, year (reference)Study design

      /name study
      CountryAge range/mean ageSexNo. participantsMethod of calcium intake assessment (exposure)No. caseCalcium intake levels, mg/dayOR or RR (95% CI)Outcome (definition, unite: mg/dL)Sample (serum or plasma)Method of circulating lipids profile assessment (outcome)SubjectAdjustments∗Quality score
      Chae, 2020 [
      • Chae M.
      • Jang J.
      • Park K.
      Association between dietary calcium intake and the risk of cardiovascular disease among Korean adults.
      ]
      Cross-sectional (based on Ansung–Ansan cohort 2011–2012)Korea40–69Both9186Validated FFQ49Median

      Q5: 737.9 vs. Q1: 222.1
      OR (95% CI)

      0.61 (0.25, 1.48)
      Dyslipidemia medication useNRAdults7
      Aritici, 2018 [
      • Aritici G.
      • Bas M.
      Metabolic syndrome and calcium: the effects on body composition and biochemical parameters among premenopausal women.
      ]
      Cross-sectionalTurkey19–52/34.59Female1563-day self-reported21Highest vs. LowestOR (95% CI)

      1.86 (0.59, 1.11)
      TG ≥ 150Plasma lipid profileAuto-analyzerPremenopausal women1–56
      79Highest vs. Lowest0.36 (0.61, 1.69)HDL-c <50
      Pannu, 2017 [
      • Danesh J.
      • Collins R.
      • Appleby P.
      • Peto R.
      Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.
      ]
      Cross-sectional (based on VHM survey)Australia18–75/49Both3387Five-pass 24-h diet recall711Every 500 mg/day increment in dietary Ca intakeOR (95% CI)

      1.05 (0.84,1.31)
      TG ≥ 150Serum lipid profileGPO Trinder reagent setAdults1–159
      474Every 500 mg/day increment in dietary Ca intake0.80 (0.61,1.05)HDL-c <40 in men and <50 in womenElimination/catalase method
      Shin, 2015 [
      • Shin S.K.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Chun BY, Choi BY: the cross-sectional relationship between dietary calcium intake and metabolic syndrome among men and women aged 40 or older in rural areas of Korea.
      ]
      Cross-sectional (based on MR Cohort, part of KoGES 2005–2010)Korea40≤

      /61.5
      Male2331Validated FFQ886Median, range

      Q4: 525.4 (430.9, 1369.8) vs.

      Q1: 188.4 (37.5236.3)
      OR (95% CI)

      0.62 (0.45, 0.85)
      TG ≥ 150Plasma lipid profileAutomatic analyzerAdults calcium and multinutrient non-users12, 18-209
      883Q4: 525.4 (430.9, 1369.8) vs.

      Q1: 188.4 (37.5236.3)
      1.55 (1.31, 2.12)HDL-c <40 in men
      Female34731147Q4: 506.9 (406.8, 1140.2) vs.

      Q1: 161.9 (32.2206.0)
      0.91 (0.68,1.22)TG ≥ 1501, 5, 8, 11, 12, 16-20
      2344Q4: 506.9 (406.8, 1140.2) vs.

      Q1: 161.9 (32.2206.0)
      0.97 (0.72,1.30)HDL-c <50 in women
      Shin, 2016 [
      • Shin B.R.
      • Choi Y.K.
      • Kim H.N.
      • Song S.W.
      High dietary calcium intake and a lack of dairy consumption are associated with metabolic syndrome in obese males: the Korean National Health and Nutrition Examination Survey 2010 to 2012.
      ]
      Cross-sectional (based on KNHANES V

      2010–2012)
      Korea20≤

      /44.4
      Male5946Single 24-h food recall3228Range (716.7–5049.1) vs. (30.9–333.8)OR (95% CI)

      1.20 (0.84, 1.72)
      TG ≥ 150 or medicationPlasma lipid profileAuto-analyzerAdults1-5, 7, 8, 11, 20-239
      2974(716.7–5049.1) vs. (30.9–333.8)1.65 (1.10, 2.46)HDL-c <40 or medication
      Moore-Schiltz, 2015 [
      • Moore-Schiltz L.
      • Albert J.M.
      • Singer M.E.
      • Swain J.
      • Nock N.L.
      Dietary intake of calcium and magnesium and the metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001-2010 data.
      ]
      Cross-sectional (based on NHANES 2001–2010)USA20≤

      /50
      Male454924-h recallsNRQ4: (>1224) vs. Q1: (<572)OR (95% CI)

      1·28 (0·95, 1·73)
      TG ≥ 150 or medicationSerum lipid profileTG: enzymatically after hydrolyzation to glycerol

      HDL-c: direct immunoassay
      Adults1, 7, 8, 11–13, 24, 259
      Q4: (>1224) vs. Q1: (<572)1·23 (0·96, 1·57)HDL-c <40 medication
      Female4599NRQ4: (>1109) vs. (Q1: <524)1·22 (0·96, 1·55)TG ≥ 150 or medication
      Q4: (>1109) vs. (Q1: <524)0·87 (0·70, 1·08)HDL-c <50 or medication
      Uemura, 2014 [
      • Uemura H.
      • Katsuura-Kamano S.
      • Yamaguchi M.
      • Nakamoto M.
      • Hiyoshi M.
      • Arisawa K.
      Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.
      ]
      Cross-sectional (based on J-MICC 2009–2012)Japan35–69/25Male535Validated FFQQ4 (>497·3)/Q1 (≤351·8)Mean ± SD:

      5·56 ± 0·78/5·44 ± 0·93
      TC1Serum lipid profiledirect methodAdults7
      Q4 (>497·3)/Q1 (≤351·8)1·46 ± 0·33/1·45 ± 0·29HDL-c
      mmol/L.
      Q4 (>497·3)/Q1 (≤351·8)Median (IQR)

      1·31 (0·93, 1·90)/1·29 (0·89, 1·83)
      TG
      mmol/L.
      216Q4 (>497·3) vs. Q1 (≤351·8)OR (95% CI)

      1.13 (0.69, 1.87)
      TC ≥ 220 or medication
      24Q4 (>497·3) vs. Q1 (≤351·8)0.70 (0.21, 2.29)HDL-c <40 or medication
      164Q4 (>497·3) vs. Q1 (≤351·8)1.28 (0.76, 2.15)TG ≥ 150 or medication
      da Silva Ferreira, 2013 [
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ]
      Cross-sectionalBrazil18–50Female76Validated FFQ(≥600)/(<600)Mean ± SEM

      1920·0 ± 68·3/1860·9 ± 52·3
      TC
      mg/L.
      Serum lipid profileAutomated analyzerHealthy premenopausal women9
      (≥600)/(<600)586·3 ± 18·4/529·3 ± 21·6HDL-c
      mg/L.
      (≥600)/(<600)1105·9 ± 58·3/1129·6 ± 49·9LDL-c
      mg/L.
      (≥600)/(<600)1082·5 ± 86·8/1001·2 ± 71·3TG
      mg/L.
      27(≥600) vs. (<600)OR (95% CI)

      2·48 (0·73, 8·41)
      TC ≥ 2000
      mg/L.
      1, 3, 11, 26-28
      22(≥600) vs. (<600)1·23 (0·33, 4·56)LDL-c ≥ 1300
      mg/L.
      48(≥600) vs. (<600)0·11 (0·03, 0·41)HDL-c <600
      mg/L.
      Delavar, 2008 [
      • Delavar M.A.
      • Sann L.M.
      • Lin K.G.
      • Hassan S.
      • Hanachi P.
      Total calcium intake and metabolic syndrome in middle aged women, Babol, Iran.
      ]
      Cross-sectionalBabol, Iran30–50Female984Validated FFQ293Q4 vs. Q1OR (95% CI)

      0.65 (0.43, 0.97)
      TC ≥ 200Serum lipid profileAuto-analyzerMiddle-aged women7
      178Q4 vs. Q10.88 (0.54, 1.43)LDL-c ≥ 1300
      382Q4 vs. Q10.25 (0.16, 0.38)HDL-c <50
      308Q4 vs. Q10.21 (0.14, 0.32)TG ≥ 150
      Liu, 2005 [
      • Liu S.
      • Song Y.
      • Ford E.S.
      • Manson J.E.
      • Buring J.E.
      • Ridker P.M.
      Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women.
      ]
      Cross-sectionalUSA≥45Female10,066Validated FFQ2999Q5 (1005–2596) vs. Q1 (223–561)OR (95% CI)

      0.88 (0.78, 1.006)
      HDL-c <50Blood sampleDirect measurement assaysMiddle-aged and older6
      1648Q5 (1005–2596) vs. Q1 (223–561)0.84 (0.73, 0.97)TG ≥ 150
      Dibaba, 2019 [
      • Dibaba D.T.
      • Xun P.C.
      • Fly A.D.
      • Bidulescu A.
      • Tsinovoi C.L.
      • Judd S.E.
      • et al.
      Calcium intake and serum calcium level in relation to the risk of ischemic stroke: findings from the REGARDS study.
      ]
      Cross-sectional (based on REGARDS study)USA64.82Both19,553Modified FFQ957.9 ± 421.7/317.1 ± 90.3Mean ± SD:

      193.3 ± 37.9/192.3 ± 41.1
      TCBlood sampleSpectrophotometryBlack and white people6
      957.9 ± 421.7/317.1 ± 90.355.7 ± 16.7/51.1 ± 15.7HDL-c
      957.9 ± 421.7/317.1 ± 90.3111.8 ± 32.9/115.6 ± 35.8LDL-c
      957.9 ± 421.7/317.1 ± 90.3130.7 ± 85.5/129.1 ± 78.2TG
      Oh, 2017 [
      • Oh J.M.
      • Woo H.W.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Choi BY: dietary total, animal, vegetable calcium and type 2 diabetes incidence among Korean adults: the Korean Multi-Rural Communities Cohort (MRCohort).
      ]
      Cross-sectional (based on MR Cohort, part of KoGES 2005–2011)Korea40≤

      61.37
      Male3033Validated FFQ(Median, range)

      T3:462 (370, 1278)/T1:197 (37, 251)
      Mean ± SD

      152 ± 3.4/162 ± 3.4
      TGBlood sampleAutomatic analyzerAdults19
      T3:462 (370, 1278)/T1:197 (37, 251)45.2 ± 0.4/44.7 ± 0.4HDL-c
      Female5280T3:458 (363,1232)/T1:180 (38,234)138 ± 2.0/145 ± 2.0TG
      T3:458 (363,1232)/T1:180 (38,234)47.3 ± 0.3/45.6 ± 0.3HDL-c
      Gulmez, 2016 [
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ]
      Cross-sectionalTurkey19–56Male100Questionnaires for the 24-h food consumption(>1000)/(<600)Mean ± SD

      73.3 ± 17.0/145.8 ± 103.2
      TGSerum lipid profileAuto-analyzerAdults7
      (>1000)/(<600)145.6 ± 17.2/175.6 ± 39.7TC
      (>1000)/(<600)37.3 ± 1.1/40.8 ± 8.5HDL-c
      (>1000)/(<600)93.7 ± 15.9/105.3 ± 27.3LDL-c
      (>1000)/(<600)14.6 ± 3.4/29.1 ± 20.6VLDL
      32(>600) vs. (<600)OR (95% CI)

      0.84 (0.35, 2.03)
      TG ≥ 150
      15(>600) vs. (<600)0.37 (0.9, 1.42)TC ≥ 200
      54(>600) vs. (<600)1.69 (0.74, 3.88)HDL-c <40
      Female100(>1000)/(<600)Mean ± SD

      64.6 ± 22.8/77.0 ± 39.8
      TG
      (>1000)/(<600)161.2 ± 10.6/156.2 ± 28.6TC
      (>1000)/(<600)53.2 ± 7.0/51.8 ± 11.6HDL-c
      (>1000)/(<600)95.0 ± 10.8/89.0 ± 25.0LDL-c
      (>1000)/(<600)12.9 ± 4.5/15.6 ± 8.2VLDL
      8(>600) vs. (<600)OR (95% CI)

      0.85 (0.19, 3.78)
      TG ≥ 150
      6(>600) vs. (<600)0.70 (0.12, 4.04)TC ≥ 200
      19(>600) vs. (<600)1.05 (0.38, 2.91)HDL-c <40
      Kim, 2013 [
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ]
      Cross-sectional (based on cohort study)Korea35–80/59Female509Validated FFQMean ± SD

      889.1 ± 295.2/404.9 ± 107.5
      Mean ± SD

      198.1 ± 42.7/198.3 ± 43.5
      TCSerum lipid profileAuto-analyzerFemale patients with type 2 diabetes8
      889.1 ± 295.2/404.9 ± 107.5135.7 ± 75.5/146.6 ± 88.4TG
      889.1 ± 295.2/404.9 ± 107.552.9 ± 13.3/49.5 ± 11.9HDL-c
      889.1 ± 295.2/404.9 ± 107.5117.8 ± 37/119.3 ± 39.1LDL-c
      165(889.1 ± 295.2) vs.

      (404.9 ± 107.5)
      0.94 (0.65, 1.37)Hyperlipidemia medication
      112(889.1 ± 295.2) vs.

      (404.9 ± 107.5)
      1.39 (0.91, 2.13)Dyslipidemia medication
      Torres, 2011 [
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ]
      Cross-sectionalBrazil>18/47.3Both7424-h recalls≥600/<600Mean ± SE

      204.34 ± 7.90/203.64 ± 6.31
      TCSerum lipid profileNRRenal transplant recipients

      1, 5, 11, 29-31
      7
      ≥600/<60055.00 ± 8.0/40.25 ± 2.21HDL-c
      ≥600/<600119.70 ± 31.10

      /135.1 ± 24.52
      LDL-c
      ≥600/<600167.52 ± 18.05

      /176.17 ± 13.36
      TG
      48(≥600) vs. (<600)OR (95% CI)

      0.59 (0.12, 2.84)
      Dyslipidemia (TC ≥ 200; LDL-c ≥ 130; TG ≥ 150; or use of lipid-reducing drugs.)
      Torres, 2011 [
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ]
      Cross-sectionalBrazil25–70/56.9Both57Validated FFQ(≥800)/(<800)Mean ± SE

      210.97 ± 7.08/212.08 ± 7.60
      TCSerum lipid profileAutomated analyzerHypertensive patients7
      (≥800)/(<800)48.03 ± 2.05/49.61 ± 2.02HDL-c
      (≥800)/(<800)131.61 ± 6.09/133.22 ± 6.4LDL-c
      (≥800)/(<800)145.13 ± 16.52/146.12 ± 14.91TG
      37(≥800) vs. (<800)OR (95% CI)

      1.06 (0.98,1.16)
      Dyslipidemia1, 2, 5, 11, 29, 32, 33
      Leite, 2010 [
      • Leite L.H.M.
      • Sampaio A.
      Dietary calcium, dairy food intake and metabolic abnormalities in HIV-infected individuals.
      ]
      Cross-sectionalBrazil22–65/41.78Both10024-h dietary recall(>700)/(<350)Mean ± SD

      210.0 ± 167.8/229.96 ± 159.5
      TGNRNRIndividuals with HIV/AIDS4
      (>700)/(<350)38.08 ± 7.24/3762 ± 10.2HDL-c
      (>700)/(<350)192.58 ± 52.2/183.55 ± 35.35TC
      Fumeron, 2011 [
      • Fumeron F.
      • Lamri A.
      • Emery N.
      • Bellili N.
      • Jaziri R.
      • Porchay-Balderelli I.
      • et al.
      Dairy products and the metabolic syndrome in a prospective study, DESIR.
      ]
      Cross-sectional (based on baseline data of DESIRFrance30–65Both3417Validated FFQ(Ca intake/1000 Kcal)

      Q4/Q1
      Mean ± SEM

      1.65 ± 0.01/1.64 ± 0.01
      HDL-c
      mmol/L.
      Serum lipid profileDAX 24Adults8
      Q4/Q1Geometric means (95% CI)

      0.95 (0.92,0.98)/0.98 (0.95,1.01)
      TG
      mmol/L.
      Cohort (DESIR)

      9-year follow-up
      Q4/Q1Mean ± SEM

      1.53 ± 0.01/1.51 ± 0.01
      HDL-c
      mmol/L.
      6
      Q4/Q1Geometric means (95% CI)

      1.02 (0.99,1.05)/1.13 (1.09,1.16)
      TG
      mmol/L.
      Jacqmain, 2003 [
      • Jacqmain M.
      • Doucet E.
      • Després J.P.
      • Bouchard C.
      • Tremblay A.
      Calcium intake, body composition, and lipoprotein-lipid concentrations in adults.
      ]
      Cross-sectional (based on Québec Family Study 1991–1998)Canada20–65Male2353-d dietary record(>1000)/(<600)Mean ± SEM

      1.11 ± 0.03/1.06 ± 0.05
      HDL-c
      mmol/L.
      Serum lipid profileCommercial kit CHOD-PAP from Boehringer and A-GENT kitAdults7
      (>1000)/(<600)3.08 ± 0.08/3.43 ± 0.15LDL-c
      mmol/L.
      (>1000)/(<600)1.61 ± 0.09/1.86 ± 0.17TG
      mmol/L.
      (>1000)/(<600)4.88 ± 0.09/5.32 ± 0.17TC
      mmol/L.
      (>1000)/(<600)4.64 ± 0.13/5.23 ± 0.23TC/HDL-c
      Female235(>1000)/(<600)1.37 ± 0.04/1.29 ± 0.05HDL-c
      mmol/L.
      (>1000)/(<600)2.88 ± 0.10/3.27 ± 0.13LDL-c
      mmol/L.
      (>1000)/(<600)1.24 ± 0.07/1.43 ± 0.09TG
      mmol/L.
      (>1000)/(<600)4.80 ± 0.12/5.19 ± 0.16TC
      mmol/L.
      (>1000)/(<600)3.69 ± 0.11/4.16 ± 0.14TC/HDL-c
      Adjustments∗: 1-Age, 2-BMI, 3-alcohol intake, 4-cigarette smoking, 5-exercise, 6- country of birth, 7-income, 8- education, 9- BMI, 10- season, 11- energy intake,12- fiber intake, 13-magnesium intake, 14-zinc intake, 15-remaining MetS components, 16-farmer, 17-marital status, 18-GL, 19-fat intake, 20-residential area, 21- eGFR, 22–25 (OH) D, 23-dietary supplements, 24-ethnicity, 25-Ca intake, 26-protein, 27-carbohydrates, 28-lipids, 29-gender, 30-time from transplantation, 31-dose of prednisone, 32-antihypertensive agents, and 33-WC.
      Abbreviations: BMI: body mass index; DESIR: Data from an Epidemiological Study on the Insulin Resistance Syndrome; eGFR: estimated glomerular filtration rate; EAR: estimated average requirement; FFQ: food frequency questionnaire; GL: glycemic load; HIV/AIDS: human immunodeficiency virus/acquired immunodeficiency syndrome; HDL-c, high-density lipoprotein cholesterol; J-MICC: Japan Multi-Institutional Collaborative Cohort; KoGES: Korean Genome and Epidemiology Study; KNHANES: Korea national health and nutrition examination survey; LDL, low-density lipoprotein cholesterol; MR Cohort: Multi-Rural Communities Cohort; MetS: metabolic syndrome; NHANES: National Health and Nutrition Examination Surveys; Ref: reference; REGARDS: Reasons for Geographic And Racial Differences in Stroke; TC: total cholesterol; TG, triglyceride; VLDL: very low-density lipoprotein; VHM: Victorian Health Monitor; WC: waist circumference; 25 (OH) D: serum 25-hydroxyvitamin D level.
      a mmol/L.
      b mg/L.

      3.2 Findings from mean difference of circulating TG concentration between the highest and lowest category of Ca intake as well as odds ratio (OR) for hypertriglyceridemia in relation to dietary Ca intake

      A total of 11 relevant studies (including 33,304 subjects) reporting the mean ± SD of blood lipids in highest vs. lowest category of dietary Ca intake was included in this analysis, and the results are presented in Table 2. Meta-analysis of 14 effect sizes from 11 studies [
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ,
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ,
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ,
      • Oh J.M.
      • Woo H.W.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Choi BY: dietary total, animal, vegetable calcium and type 2 diabetes incidence among Korean adults: the Korean Multi-Rural Communities Cohort (MRCohort).
      ,
      • Uemura H.
      • Katsuura-Kamano S.
      • Yamaguchi M.
      • Nakamoto M.
      • Hiyoshi M.
      • Arisawa K.
      Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.
      ,
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ,
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ,
      • Fumeron F.
      • Lamri A.
      • Emery N.
      • Bellili N.
      • Jaziri R.
      • Porchay-Balderelli I.
      • et al.
      Dairy products and the metabolic syndrome in a prospective study, DESIR.
      ,
      • Leite L.H.M.
      • Sampaio A.
      Dietary calcium, dairy food intake and metabolic abnormalities in HIV-infected individuals.
      ,
      • Dibaba D.T.
      • Xun P.C.
      • Fly A.D.
      • Bidulescu A.
      • Tsinovoi C.L.
      • Judd S.E.
      • et al.
      Calcium intake and serum calcium level in relation to the risk of ischemic stroke: findings from the REGARDS study.
      ,
      • Jacqmain M.
      • Doucet E.
      • Després J.P.
      • Bouchard C.
      • Tremblay A.
      Calcium intake, body composition, and lipoprotein-lipid concentrations in adults.
      ] (3 additional effect sizes were from studies that separately reported ORs for males and females) demonstrated that individuals in the highest category of Ca intake, in comparison with the lowest one, had 5.94 mg/dL lower blood TG concentration (mean difference: −5.94 mg/dL; 95% CI: −8.27, −3.62) (Fig. 2) (Table 2). The between-study heterogeneity was high (I2 = 96.6%, P < 0.001); hence, we performed subgroup analysis based on study location (Asian vs. non-Asian countries) to find the source of heterogeneity. Highest vs. lowest dietary Ca intake was significantly associated with lower circulating TG concentration in Asian countries (mean difference: −8.81 mg/dL; 95% CI: −11.66, −5.95). However, we could not find a significant mean difference of blood TG concentration in highest vs. lowest level of Ca intake in non-Asian countries (mean difference: −1.09 mg/dL; 95% CI: −4.57, 2.40) (Fig. 2). Although the between-study heterogeneity disappeared in non-Asian countries (I2 = 15.5%, P = 0.30), it was significant in the Asian countries subgroup (I2 = 98.6%, P < 0.001). Therefore, subgroup analyses were conducted based on several other confounders, and the results are presented in Supplemental Table 4. Although higher dietary Ca intake was associated with lower blood TG concentration in most subgroups, heterogeneity was still significant in some of them.
      Table 2Results of analysis for mean difference of serum lipid concentration between the highest and lowest category of Ca intake in adults.
      No. of effect sizesMean difference, (mg/dL)

      95% CI
      P within
      P for heterogeneity, within subgroup.
      I2 (%)
      TG14−5.94 (−8.27, −3.62)<0.00196.6
      HDL-c141.56 (0.81, 2.30)<0.00199.6
      TC11−1.00 (−5.37, 3.37)0.0153
      LDL-c9−4.02 (−7.08, −0.95)0.3015.5
      Abbreviations: HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; TG, triglyceride; TC, total cholesterol.
      a P for heterogeneity, within subgroup.
      Figure 2
      Figure 2Forest plots of the mean difference of serum TG value between highest and lowest category of Ca intake in adults, stratified by Asian vs. non-Asian countries.
      A total of 13 studies (including 38,714 participants) reporting the odds for abnormality in circulating lipid profiles in the highest vs. lowest category of dietary Ca intake was included in the analysis, and the results are presented in Table 3. Combining 11 ORs from 8 studies [
      • Shin S.K.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Chun BY, Choi BY: the cross-sectional relationship between dietary calcium intake and metabolic syndrome among men and women aged 40 or older in rural areas of Korea.
      ,
      • Moore-Schiltz L.
      • Albert J.M.
      • Singer M.E.
      • Swain J.
      • Nock N.L.
      Dietary intake of calcium and magnesium and the metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001-2010 data.
      ,
      • Aritici G.
      • Bas M.
      Metabolic syndrome and calcium: the effects on body composition and biochemical parameters among premenopausal women.
      ,
      • Uemura H.
      • Katsuura-Kamano S.
      • Yamaguchi M.
      • Nakamoto M.
      • Hiyoshi M.
      • Arisawa K.
      Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.
      ,
      • Liu S.
      • Song Y.
      • Ford E.S.
      • Manson J.E.
      • Buring J.E.
      • Ridker P.M.
      Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women.
      ,
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ,
      • Delavar M.A.
      • Sann L.M.
      • Lin K.G.
      • Hassan S.
      • Hanachi P.
      Total calcium intake and metabolic syndrome in middle aged women, Babol, Iran.
      ,
      • Shin B.R.
      • Choi Y.K.
      • Kim H.N.
      • Song S.W.
      High dietary calcium intake and a lack of dairy consumption are associated with metabolic syndrome in obese males: the Korean National Health and Nutrition Examination Survey 2010 to 2012.
      ] (3 additional effect sizes were for studies that separately analyzed males and females) showed no significant OR for hypertriglyceridemia relation to Ca intake (OR: 0.91, 95% CI: 0.68, 1.23) (Fig. 3) (Table 3). The between-study heterogeneity was significant (I2 = 88.8%, P < 0.001); therefore, subgroup analysis was conducted based on study location (Asian vs. non-Asian countries) to explain the source of heterogeneity. However, between-study heterogeneity remained significant in both Asian (I2 = 90.9%, P < 0.001) and non-Asian countries (I2 = 81.4%, P = 0.005) (Fig. 3). Then, subgroup analyses were conducted by other cofounding variables, and the results are presented in Supplemental Table 5. Almost all subgroups did not show significant relations between Ca intake and odds of high TG, except the subgroup of studies that used food recall. Unexpectedly, the higher Ca intake related to 32% increased odds of high TG in this subgroup (OR: 1.32, 95% CI: 1.11, 1.58).
      Table 3Results of OR for hyperlipidemia/dyslipidemia in relation to dietary Ca intake in adults.
      No. of effect sizesOR (95% CI)P within
      P for heterogeneity, within subgroup.
      I2 (%)
      High TG110.91 (0.68, 1.23)<0.00188.8
      Low HDL-c120.83 (0.62, 1.11)<0.00188.1
      High TC50.77 (0.41, 1.42)<0.00184.2
      Dyslipidemia41.07 (0.89, 1.30)0.3115.8
      High LDL-c20.92 (0.58, 1.45)0.630.0
      Abbreviations: HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; TG, triglyceride; TC, total cholesterol.
      a P for heterogeneity, within subgroup.
      Figure 3
      Figure 3Forest plots of OR for hypertriglyceridemia in relation to dietary Ca intake in adults, stratified by Asian vs. non-Asian countries.

      3.3 Finding from mean difference of serum LDL-c concentration between highest and lowest category of Ca intake

      Combining 9 effect sizes from 7 studies [
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ,
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ,
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ,
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ,
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ,
      • Dibaba D.T.
      • Xun P.C.
      • Fly A.D.
      • Bidulescu A.
      • Tsinovoi C.L.
      • Judd S.E.
      • et al.
      Calcium intake and serum calcium level in relation to the risk of ischemic stroke: findings from the REGARDS study.
      ,
      • Jacqmain M.
      • Doucet E.
      • Després J.P.
      • Bouchard C.
      • Tremblay A.
      Calcium intake, body composition, and lipoprotein-lipid concentrations in adults.
      ] showed that participants in the highest vs. lowest category of Ca intake had 4.02 mg/dL lower blood LDL-c concentration (mean difference: −4.02 mg/dL; 95% CI: −7.08, −0.95), with no significant between-study heterogeneity (I2 = 15.5%, P = 0.30) (Table 2). Furthermore, when we excluded 3 studies with patient participants [
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ,
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ,
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ], six effect sizes from four publications on healthy populations demonstrated an overall marginally significant inverse association among highest vs. lowest dietary Ca intake and blood LDL-c concentration (mean difference: −5.49 mg/dL; 95% CI: −11.02, 0.04).

      3.4 Finding from mean difference of blood HDL-c concentration between the highest and lowest category of Ca intake as well as odds ratio (OR) for low circulating HDL-c in relation to dietary Ca intake

      Meta-analysis of 14 effect sizes from 11 studies [
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ,
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ,
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ,
      • Oh J.M.
      • Woo H.W.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Choi BY: dietary total, animal, vegetable calcium and type 2 diabetes incidence among Korean adults: the Korean Multi-Rural Communities Cohort (MRCohort).
      ,
      • Uemura H.
      • Katsuura-Kamano S.
      • Yamaguchi M.
      • Nakamoto M.
      • Hiyoshi M.
      • Arisawa K.
      Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.
      ,
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ,
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ,
      • Fumeron F.
      • Lamri A.
      • Emery N.
      • Bellili N.
      • Jaziri R.
      • Porchay-Balderelli I.
      • et al.
      Dairy products and the metabolic syndrome in a prospective study, DESIR.
      ,
      • Leite L.H.M.
      • Sampaio A.
      Dietary calcium, dairy food intake and metabolic abnormalities in HIV-infected individuals.
      ,
      • Dibaba D.T.
      • Xun P.C.
      • Fly A.D.
      • Bidulescu A.
      • Tsinovoi C.L.
      • Judd S.E.
      • et al.
      Calcium intake and serum calcium level in relation to the risk of ischemic stroke: findings from the REGARDS study.
      ,
      • Jacqmain M.
      • Doucet E.
      • Després J.P.
      • Bouchard C.
      • Tremblay A.
      Calcium intake, body composition, and lipoprotein-lipid concentrations in adults.
      ] (3 additional effect sizes were from studies that separately reported ORs for males and females) illustrated that participants with the highest Ca intake had 1.56 mg/dL higher blood HDL-c in comparison with those with the lowest intake (mean difference: 1.56 mg/dL; 95% CI: 0.81, 2.30) (Fig. 4) (Table 2). As the between-study heterogeneity was significant, subgroup analysis was conducted based on gender. We found a significant mean difference of HDL-c between highest vs. lowest Ca intake level in females (mean difference: 2.08 mg/dL; 95% CI: 1.18, 2.98); but the difference was not significant in subgroups of males (mean difference: −0.33 mg/dL; 95% CI: −2.42, 1.76) and both genders together (mean difference: 1.92 mg/dL; 95% CI: −1.31, 5.15) (Fig. 4). In addition, the between-study heterogeneity was eliminated only in subgroup of females (I2 = 13.6%, P = 0.32), but not in males (I2 = 72.0%, P = 0.01) and both genders together (I2 = 92.0%, P < 0.001). Therefore, subgroup analyses were conducted based on other covariates, as shown in Supplemental Table 6.
      Figure 4
      Figure 4Forest plots of the mean difference of serum HDL-c value between highest and lowest category of Ca intake in adults, stratified by sex.
      Combining 12 ORs from 9 studies [
      • Shin S.K.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Chun BY, Choi BY: the cross-sectional relationship between dietary calcium intake and metabolic syndrome among men and women aged 40 or older in rural areas of Korea.
      ,
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ,
      • Moore-Schiltz L.
      • Albert J.M.
      • Singer M.E.
      • Swain J.
      • Nock N.L.
      Dietary intake of calcium and magnesium and the metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001-2010 data.
      ,
      • Aritici G.
      • Bas M.
      Metabolic syndrome and calcium: the effects on body composition and biochemical parameters among premenopausal women.
      ,
      • Uemura H.
      • Katsuura-Kamano S.
      • Yamaguchi M.
      • Nakamoto M.
      • Hiyoshi M.
      • Arisawa K.
      Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.
      ,
      • Liu S.
      • Song Y.
      • Ford E.S.
      • Manson J.E.
      • Buring J.E.
      • Ridker P.M.
      Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women.
      ,
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ,
      • Delavar M.A.
      • Sann L.M.
      • Lin K.G.
      • Hassan S.
      • Hanachi P.
      Total calcium intake and metabolic syndrome in middle aged women, Babol, Iran.
      ,
      • Shin B.R.
      • Choi Y.K.
      • Kim H.N.
      • Song S.W.
      High dietary calcium intake and a lack of dairy consumption are associated with metabolic syndrome in obese males: the Korean National Health and Nutrition Examination Survey 2010 to 2012.
      ] (3 additional effect sizes were for studies that separately analyzed males and females) did not show a significant relationship between dietary Ca intake and low blood HDL-c (OR: 0.83; 95% CI: 0.62, 1.11). The between-study heterogeneity was significant (I2 = 88.1%, P < 0.001) (Fig. 5) (Table 3); hence, subgroup analysis was applied according to gender. Higher Ca intake related to 42% decreased odds of low circulating HDL-c in females (OR: 0.58; 95% CI: 0.40, 0.84), although the heterogeneity remained significant (I2 = 88.2%, P < 0.001). Unexpectedly, higher Ca intake was linked to a 41% increased odds of low circulating HDL-c in males (OR: 1.41; 95% CI: 1.21, 1.65), without significant between-study heterogeneity (I2 = 0.0%, P = 0.42). Subgroup analyses based on other confounders were also conducted, and the findings are presented in Supplemental Table 7.
      Figure 5
      Figure 5Forest plots of OR for low serum level HDL-c in relation to dietary Ca intake in adults, stratified by sex.

      3.5 Findings from mean difference of circulating TC concentration between the highest and lowest category of Ca intake as well as odds ratio (OR) for hypercholesterolemia and dyslipidemia in relation to dietary Ca intake

      Meta-analysis of 11 effect sizes from 9 studies [
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ,
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ,
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ,
      • Uemura H.
      • Katsuura-Kamano S.
      • Yamaguchi M.
      • Nakamoto M.
      • Hiyoshi M.
      • Arisawa K.
      Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.
      ,
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ,
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ,
      • Leite L.H.M.
      • Sampaio A.
      Dietary calcium, dairy food intake and metabolic abnormalities in HIV-infected individuals.
      ,
      • Dibaba D.T.
      • Xun P.C.
      • Fly A.D.
      • Bidulescu A.
      • Tsinovoi C.L.
      • Judd S.E.
      • et al.
      Calcium intake and serum calcium level in relation to the risk of ischemic stroke: findings from the REGARDS study.
      ,
      • Jacqmain M.
      • Doucet E.
      • Després J.P.
      • Bouchard C.
      • Tremblay A.
      Calcium intake, body composition, and lipoprotein-lipid concentrations in adults.
      ] (2 additional effect sizes were from studies that separately reported ORs for males and females) did not find a significant difference in TC levels between highest and lowest category of Ca intake (mean difference: −1.00 mg/dL; 95% CI: −5.37, 3.37) (Table 2). Because of significant between-study heterogeneity (I2 = 53.0%, P = 0.01), subgroup analysis was conducted based on other confounders (Supplemental Table 8). In almost all subgroups, no significant difference was found, except in the subgroup of studies that used food record questionnaires to assess Ca intake (mean difference: −16.10 mg/dL; 95% CI: −26.61, −5.59).
      Combining five ORs from 4 studies [
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ,
      • Uemura H.
      • Katsuura-Kamano S.
      • Yamaguchi M.
      • Nakamoto M.
      • Hiyoshi M.
      • Arisawa K.
      Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.
      ,
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ,
      • Delavar M.A.
      • Sann L.M.
      • Lin K.G.
      • Hassan S.
      • Hanachi P.
      Total calcium intake and metabolic syndrome in middle aged women, Babol, Iran.
      ] (one additional effect size was from the study that separately reported ORs for males and females) revealed no significant relationship between high blood TC and dietary Ca intake (OR: 0.77; 95% CI: 0.41, 1.42) (Table 3), with significant between-study heterogeneity (I2 = 84.2%, P < 0.001). Because of the low number of effect sizes, subgroup analysis could not be performed; therefore, we examined the effect of each study on heterogeneity by excluding each study from the analysis. After excluding the study of Gulmez et al. [
      • Gulmez M.O.
      • Inanc N.
      • Oguzhan A.
      • Soylu M.
      • Kaner G.
      • Erez R.
      The relationship between dietary calcium intake and serum lipoprotein levels and anthropometric measurements.
      ] on male population, there was no significant heterogeneity anymore (I2 = 49.2%, P = 0.116). Combining 4 effect sizes from 4 studies [
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ,
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ,
      • Kim J.
      • Hwang J.Y.
      • Kim K.N.
      • Choi Y.J.
      • Chang N.
      • Huh K.B.
      Relationship between milk and calcium intake and lipid metabolism in female patients with type 2 diabetes.
      ,
      • Chae M.
      • Jang J.
      • Park K.
      Association between dietary calcium intake and the risk of cardiovascular disease among Korean adults.
      ] resulted in no significant relationship between dyslipidemia and dietary Ca intake (OR: 1.07; 95% CI: 0.89, 1.30), with no significant between-study heterogeneity (I2 = 15.8%, P = 0.31) (Table 3).

      3.6 Finding from odds ratio (OR) for hyperlipidemia/dyslipidemia in relation to top vs. bottom thirds of dietary Ca intake

      As shown in Supplemental Table 9, the odds of hyperlipidemia/dyslipidemia were not significant for those in the top tertile of dietary Ca intake in comparison with subjects in the bottom tertile of intake.

      3.7 Finding from meta-regression, sensitivity analysis, and publication bias

      Meta-regression analyses based on mean/median of calcium intake of the reference group, mean age of subjects, latitude, the longitude of the study location, and quality score of the included studies were conducted, and the findings are presented in Supplemental Tables 10 and 11. Results revealed no significant effect for almost all of these covariates, except for latitude that would inversely affect the mean difference of TC (β = −0.668, P = 0.029, I2 residual = 26.01%) (Supplemental Table 10). Additionally, most of the included studies did not provide enough information for us to do dose–response analysis. Hence, we conducted meta-regression for the dosage of all levels dietary Ca intake (mg/d) with dyslipidemia/hyperlipidemia; nevertheless, results revealed no significant linear relation between dosage of dietary Ca intake with odds of high TG (β = 0.00014, P = 0.26, I2 residual = 62.25%), low HDL-c (β = −0.00015, P = 0.29, I2 residual = 68.31%), high TC (β = −0.00172, P = 0.20, I2 residual = 58.34%), and dyslipidemia (β = 0.00050, P = 0.28, I2 residual = 0.0%). Sensitivity analysis showed that none of the studies significantly influenced the overall effect. There was no significant publication bias based on Begg's funnel plot, Begg's test, and Egger's test.

      4. Discussion

      In the current meta-analysis, we demonstrated that individuals with the highest Ca intake had lower serum TG and LDL-c compared to those with the lowest Ca intake. In addition, HDL-c concentration was higher in individuals with the highest Ca intake. In almost all subgroups, these relations were significant; however, the relations between Ca intake with odds of high TG, TC, LDL-c, low HDL-c, and dyslipidemia were insignificant. Although the relationship was insignificant in most subgroups, highest vs. lowest Ca intake was related to 42% decreased odds of low HDL-c in females and 41% increased odds in males.
      Dyslipidemia is a well-known risk factor for atherosclerotic CVD, CVD mortality, and all-cause mortality [
      • Chen S-c
      • Tseng C.-H.
      Dyslipidemia, kidney disease, and cardiovascular disease in diabetic patients.
      ,
      • Kopin L.
      • Lowenstein C.J.
      Dyslipidemia.
      ,
      • Garg A.
      • Simha V.
      Update on dyslipidemia.
      ]. The Coronary Artery Risk Development in Young Adults (CARDIA) study documented that abnormal lipid levels in the young adulthood period could increase the odds of atherosclerosis later in life [
      • Pletcher M.J.
      • Bibbins-Domingo K.
      • Liu K.
      • Sidney S.
      • Lin F.
      • Vittinghoff E.
      • et al.
      Nonoptimal lipids commonly present in young adults and coronary calcium later in life: the CARDIA (Coronary Artery Risk Development in Young Adults) study.
      ]. Therefore, prevention strategies to manage serum lipid abnormalities could receive great attention. People with the age of 20–35 years should be aware of what they eat and how much they exercise; although they have a low risk for a heart attack in the short term, they should adhere to healthy eating and an appropriate exercise activity until middle age [
      • Pletcher M.J.
      • Bibbins-Domingo K.
      • Liu K.
      • Sidney S.
      • Lin F.
      • Vittinghoff E.
      • et al.
      Nonoptimal lipids commonly present in young adults and coronary calcium later in life: the CARDIA (Coronary Artery Risk Development in Young Adults) study.
      ]. In the current analysis, we found that highest vs. lowest Ca intake might relate to lower serum TG and LDL-c and higher HDL-c levels. Our findings of the cross-sectional studies could be informative and hypothesis-generating for future investigations. Thus, it could be clinically recommended for people to improve their Ca intake to decrease the risk of dyslipidemia and consequent disorders.
      The meta-analysis study of Wang et al. [
      • Wang X.
      • Chen H.
      • Ouyang Y.
      • Liu J.
      • Zhao G.
      • Bao W.
      • et al.
      Dietary calcium intake and mortality risk from cardiovascular disease and all causes: a meta-analysis of prospective cohort studies.
      ], which was conducted on prospective cohort studies, documented a U-shaped relation between Ca intake and CVD mortality. For all-cause mortality, they found a threshold effect at Ca intake around 900 mg/day, but the risk did not decrease further at intakes more than 900 mg/day. However, a similar meta-analysis could not find a significant relationship between Ca intake and risk of CVD, risk of coronary heart disease (CHD), and MI [
      • Yang C.
      • Shi X.
      • Xia H.
      • Yang X.
      • Liu H.
      • Pan D.
      • et al.
      The evidence and controversy between dietary calcium intake and calcium supplementation and the risk of cardiovascular disease: a systematic review and meta-analysis of cohort studies and randomized controlled trials.
      ]. Nevertheless, it was suggested that Ca from supplements might raise the risk of CHD and MI [
      • Yang C.
      • Shi X.
      • Xia H.
      • Yang X.
      • Liu H.
      • Pan D.
      • et al.
      The evidence and controversy between dietary calcium intake and calcium supplementation and the risk of cardiovascular disease: a systematic review and meta-analysis of cohort studies and randomized controlled trials.
      ]. However, two meta-analyses of randomized controlled trials (RCTs) documented that Ca supplementation had a favorable effect on LDL-c concentration, especially in individuals without dyslipidemia [
      • Derakhshandeh-Rishehri S.-M.
      • Ghobadi S.
      • Akhlaghi M.
      • Faghih S.
      The effect of calcium supplement intake on lipid profile: a systematic review and meta-analysis of randomized controlled clinical trials.
      ] and in overweight and obese participants [
      • Heshmati J.
      • Sepidarkish M.
      • Namazi N.
      • Shokri F.
      • Yavari M.
      • Fazelian S.
      • et al.
      Impact of dietary calcium supplement on circulating lipoprotein concentrations and atherogenic indices in overweight and obese individuals: a systematic review.
      ]. In another meta-analysis of RCTs [
      • de Goede J.
      • Geleijnse J.M.
      • Ding E.L.
      • Soedamah-Muthu S.S.
      Effect of cheese consumption on blood lipids: a systematic review and meta-analysis of randomized controlled trials.
      ], cheese consumption, compared to butter consumption, decreased both serum LDL-c and HDL-c concentration. It seems that increasing Ca intake from diet would be safe and have a little adverse effect on health parameters such as lipid profile, compared to supplementation. In the current analysis, we could only examine the relation of dietary Ca intake from all food groups (not supplements or particular foods) on serum lipid profile in adults.
      In the current analysis, we documented that highest vs. lowest Ca intake was related to lower circulating TG and LDL-c levels and higher serum HDL-c concentrations. Nevertheless, we did not find significant odds for hyperlipidemia or dyslipidemia in different categories of Ca intake. In this case, some points might affect the significance status of the results that should be considered. First, the number of effect sizes in the analysis investigating odds of hyperlipidemia or dyslipidemia was lower than those in the analysis assessing mean difference of serum lipid concentrations. Second, just a few included studies [
      • Shin S.K.
      • Kim M.K.
      • Lee Y.H.
      • Shin D.H.
      • Shin M.H.
      Chun BY, Choi BY: the cross-sectional relationship between dietary calcium intake and metabolic syndrome among men and women aged 40 or older in rural areas of Korea.
      ,
      • da Silva Ferreira T.
      • Torres M.R.
      • Sanjuliani A.F.
      Dietary calcium intake is associated with adiposity, metabolic profile, inflammatory state and blood pressure, but not with erythrocyte intracellular calcium and endothelial function in healthy pre-menopausal women.
      ,
      • Moore-Schiltz L.
      • Albert J.M.
      • Singer M.E.
      • Swain J.
      • Nock N.L.
      Dietary intake of calcium and magnesium and the metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001-2010 data.
      ,
      • Aritici G.
      • Bas M.
      Metabolic syndrome and calcium: the effects on body composition and biochemical parameters among premenopausal women.
      ,
      • Torres M.R.S.G.
      • Gioseffi C.
      • Cardoso L.G.
      • Barroso S.G.
      • Sanjuliani A.F.
      • Souza E.
      A Pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients.
      ,
      • Torres M.R.
      • Ferreira Tda S.
      • Carvalho D.C.
      • Sanjuliani A.F.
      Dietary calcium intake and its relationship with adiposity and metabolic profile in hypertensive patients.
      ,
      • Pannu P.K.
      • Soares M.J.
      • Piers L.S.
      • Zhao Y.
      • Ansari Z.
      The association of vitamin D status and dietary calcium intake with individual components of the metabolic syndrome: a population-based study in Victoria, Australia.
      ,
      • Shin B.R.
      • Choi Y.K.
      • Kim H.N.
      • Song S.W.
      High dietary calcium intake and a lack of dairy consumption are associated with metabolic syndrome in obese males: the Korean National Health and Nutrition Examination Survey 2010 to 2012.
      ] made adjustments for potential confounders when exploring the odds of dyslipidemia in relation to dietary Ca intake. Third, different cut-off points were used in eligible studies to define dyslipidemia or hyperlipidemia. However, in case of mean differences of lipid values in Ca intake levels, reported means of serum lipid profiles in the highest vs. lowest category of Ca intake were used in the analysis, without using any cut-off point. It is also worth noting that our stratified analysis by the health status of participants revealed significant mean difference values for lipid profiles between the highest and lowest category of Ca intake in healthy population but not in patients.
      We found that highest vs. lowest Ca intake was significantly related to higher serum HDL-c concentration just in females, but the relation was not significant in males and both genders together. Furthermore, higher Ca intake was related to the reduced odds of low serum HDL-c in females and increased odds of low serum HDL-c in males. Previous studies suggested some mechanisms to clarify this different finding between males and females. In premenopausal women (at reproductive age), estrogen hormone would increase Ca absorption and its bioavailability [
      • Heaney R.P.
      • Recker R.R.
      • Stegman M.R.
      • Moy A.J.
      Calcium absorption in women: relationships to calcium intake, estrogen status, and age.
      ]. Furthermore, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) had a protective effect on serum HDL-c levels. On the other hand, it has been demonstrated that estradiol might lead to an increased risk of atherogenic lipid profiles [
      • Wranicz J.K.
      • Cygankiewicz I.
      • Rosiak M.
      • Kula P.
      • Kula K.
      • Zareba W.
      The relationship between sex hormones and lipid profile in men with coronary artery disease.
      ]. Therefore, the association of Ca intake with lipid profiles might be different in men and women. Stratified analysis by gender in future prospective studies has been suggested to shed light on these associations.
      In the current analysis, we illustrated that highest vs. lowest dietary Ca intake was significantly associated with lower serum TG levels only in Asian countries, and the result for non-Asian regions was insignificant. In this case, it must be considered that Asian countries are more exposed to sunshine; therefore, the synthesis of vitamin D and consequently absorption and bioavailability of dietary Ca intake in Asian people might be higher than the non-Asian population.
      Several mechanisms have been suggested for the relationship between Ca intake and improved lipid profiles. First, high dietary Ca intake plays an important role in attenuating lipid accretion in adipocytes and in increasing lipolysis and thermogenesis maintenance through caloric restriction [
      • Shi H.
      • DiRienzo D.
      • Zemel M.B.
      Effects of dietary calcium on adipocyte lipid metabolism and body weight regulation in energy-restricted aP2-agouti transgenic mice.
      ]. Second, an increase in intracellular Ca leads to the inhibition of lipolysis through the activation of phosphodiesterase enzyme and a consequent decrease in cyclic adenosine monophosphate (AMP) and hormone-sensitive lipase phosphorylation [
      • Xue B.
      • Greenberg A.G.
      • Kraemer F.B.
      • Zemel M.B.
      Mechanism of intracellular calcium ([Ca2+] i) inhibition of lipolysis in human adipocytes.
      ]. Third, high Ca intake may decrease the bioavailability of bile acids that are necessary for fat absorption and micelle formation. In addition, calcium could bind to saturated fatty acids and make calcium soap which is excreted in feces. Therefore, calcium might decrease fat absorption through the primary local intestinal effects [
      • Fleischman A.I.
      • Yacowitz H.
      • Hayton T.
      • Bierenbaum M.L.
      Long-term studies on the hypolipemic effect of dietary calcium in mature male rats fed cocoa butter.
      ].
      To our knowledge, this is the first meta-analysis that examined the relationship between Ca intake and serum lipid profiles. In the current study, two different analyses on mean difference of serum lipid values and ORs for lipid abnormalities were conducted to assess the relationship. This study was performed on a large population of adults, and subgroup analyses were applied based on several covariates. However, some limitations should be considered. First, only a few included studies have separately reported dietary, supplemental, plant-based, and animal-based Ca intake; therefore, we could only consider dietary Ca intake as the exposure. Future studies are proposed to separately report the linkage between Ca from different sources (food sources vs. supplements) and lipid profiles. Second, some included studies did not consider the effect of confounders. Third, the levels of Ca intake in eligible studies were different, such that, for some studies, the lowest group had almost the same mean/median calcium intake as the highest group in other studies. Thus, the reference groups were quite different among the studies. Furthermore, the effects of confounding variables in epidemiological studies are unavoidable; therefore, the overall estimate from unadjusted mean values might be imprecise. These limitations could increase between-study heterogeneity, which was not completely removed, even after meta-regression analyses based on continuous covariates (such as dosage of dietary Ca intake in the reference group) and subgroup analyses based on qualitative variables. Furthermore, there was not enough information to perform linear and non-linear dose–response analysis; hence, we could not define the threshold of dietary Ca intake that would have a favorable effect on serum lipid profiles. However, we conducted meta-regression analyses to examine the linear relationship between the dosage of all levels of dietary Ca intake and odds of dyslipidemia/hyperlipidemia. Moreover, as all the included research in the analysis had a cross-sectional design, we could not define the causality of the relationship. Although we illustrated that people with the highest dietary Ca intake had more desirable serum lipid, this relation would be inversely interpreted; more prospective studies are needed to determine a causal relationship.
      In conclusion, this meta-analysis of epidemiologic studies demonstrated that individuals with the highest Ca intake might have lower blood TG and LDL-c and higher HDL-c concentrations compared to those with the lowest Ca intake. Because of the cross-sectional nature of included studies, causality could not be proven. Further prospective studies are needed to affirm these findings.

      Sources of support

      The financial support for conception, design, data analysis, and manuscript drafting come from Isfahan University of Medical Sciences, Isfahan, Iran.

      Disclosure Statement

      None of the authors had any personal or financial conflicts of interest.

      Authors’ contribution

      ZH, PR, and PS contributed in conception, design, statistical analyses, data interpretation, and manuscript drafting. All authors approved the final manuscript for submission.

      Financial Support

      The financial support for this study comes from Isfahan University of Medical Sciences , Isfahan, Iran. Isfahan University of Medical Sciences had no role in the design/conduct of the study, collection/analysis/interpretation of the data, and preparation/review/approval of the manuscript.

      Declaration of competing interest

      The authors declared no personal or financial conflicts of interest.

      Acknowledgments

      We wish to thank Dr. Mi-Kyeong Choi, who kindly responded to our request and sent the PDF of his study.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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