Cadmium, Iron Deficiency Anemia and Hypophosphatemic Osteomalacia Due to Intravenous Iron Supplementation

Cadmium (Cd) is a ubiquitous environmental pollutant that enters the circulation from the lungs and gastrointestinal tract. For most people, staple foods form the main route of Cd exposure. Current evidence suggests that Cd may increase the prevalence of iron deficiency and anemia in environmentally exposed people. Concerningly, intravenous iron administration to treat iron deficiency anemia has resulted in adverse bone outcomes in a higher-than-expected frequency; for which reasons remain unclear. The bone-derived hormone, fibroblast growth factor 23 (FGF23), the regulator of vitamin D and phosphate homeostasis, has been speculatively implicated, given that anemia, iron deficiency and inflammatory conditions all are known to increase FGF23 expression levels in osteoblasts. Additionally, early studies demonstrated that Cd increased FGF23 expression by osteoblast-like cells and suppressed FGF23 cleavage leading to an abrupt rise in serum FGF23, which, in turn, mediated an effect of Cd on tubular phosphate reabsorption. In this review, experimental breakthrough studies showing Cd-induced iron deficiency, and a reduction in iron absorption by Cd are summarized together with intestinal absorption of Cd, and an increment of Cd uptake and Cd body burden in those with low body iron stores. Potential contributions of Cd, anemia and iron deficiency in the context of hypophosphatemic osteomalacia development after intravenous iron supplementation, are discussed. Mechanism of Cd-induced ferroptosis in pathogenesis of osteoporosis, emphasizing heme oxygenase-1 (HO-1)/bilirubin axis and zinc deficiency are presented.