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

## TL;DR

This paper explores how cadmium exposure and iron deficiency may lead to bone issues like hypophosphatemic osteomalacia, especially after intravenous iron treatment.

## Contribution

The paper provides a novel synthesis of how cadmium, anemia, and iron deficiency interact to cause bone disease following iron supplementation.

## Key findings

- Cadmium increases FGF23 expression, which may disrupt phosphate homeostasis and contribute to bone disease.
- Iron deficiency and anemia are linked to increased cadmium absorption and body burden.
- Cadmium-induced ferroptosis may play a role in osteoporosis through the HO-1/bilirubin axis and zinc deficiency.

## Abstract

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 at 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 speculated to be implicated, given that anemia, iron deficiency and inflammatory conditions are all known to increase FGF23 expression levels in osteoblasts. Additionally, early studies have demonstrated that Cd increases FGF23 expression by osteoblast-like cells and suppresses FGF23 cleavage, leading to an abrupt rise in serum FGF23, which, in turn, mediates 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 in 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. The molecular basis of Cd-induced ferroptosis in pathogenesis of osteoporosis, emphasizing heme oxygenase-1 (HO-1)/bilirubin axis and zinc deficiency, is presented.