Effect of calcium intake on iron absorption and hematologic status: A systematic review and dose-response meta-analysis of randomized trials and case-cross-over studies

Background The interaction between dietary (and supplementary) divalent ions has been a long- standing issue in human nutrition research. Developing optimal calcium and iron supplementation recommendation needs detailed knowledge of the potential trade-offs between: a) the clinical effects of concurrent intake on iron absorption and hematological indices, and b) the potentially negative effects of separated ingestion on adherence to either or both iron and calcium supplements. Human clinical studies have examined the effects of calcium intake on iron status, but there are no meta-analyses or recent reviews summarizing the findings. Objective We aimed to summarize the literature on the effect of calcium consumption from meals and supplements on iron indices in humans, and quantify the pooled effects. Design Peer-reviewed randomized and case-cross-over studies were included in this review. Result The negative effect of calcium intake was statistically significant in short-term iron absorption studies but the effect magnitude was low (weighted mean difference (WMD) = -5.57%, (95% CI: -7.09, -4.04)). The effect of calcium on iron status was mixed. There was a quadratic dose-response relationship between calcium intake and serum ferritin concentration. Higher daily calcium intake was associated with a modest reduction in serum ferritin concentration. There was, however, no reduction in hemoglobin concentration (WMD = 1.22g/L, 95% CI: 0.37, 2.07). Conclusion The existing body of studies is insufficient to make recommendations with high confidence due to heterogeneity in design, limitations of ferritin as an iron biomarker and lack of intake studies in pregnant women. Prescribing separation of prenatal calcium and iron supplements in free living individuals is unlikely to affect the anemia burden. There is a need for effectiveness trials comparing the effects of prescribing separated intake to concurrent intake, with functional end-points as primary outcomes, and adherence to each supplement as intermediate outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement No funding was received for this work at all. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a meta-analysis of publicly available studies, and would not warrant an IRB review or exemption. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The datasheet for the meta-analysis are available upon request * AIC : Akaike Information Criteria CI : Confidence Interval CINAHL : Current Nursing and Allied Health Literature LMIC : Low- and middle-income countries MeSH : Medical Subject Headings PRISMA : Preferred Reporting Items for Systematic Reviews and Meta-analysis RCT : Randomized controlled trial RR : Relative risk SD : Standard deviation se : Standard error WHO : World Health Organization WMD : Weighted mean differences