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.