Bone marker response to intravenous iron treatment - an in vitro model

Background Iron deficiency is the most frequent cause of anemia in Europe. Treatment of iron deficiency requires supplementation with oral or intravenous (i.v.) formulations of the metal. Over 50 % of patients treated with the i.v. formulation ferric carboxymaltose (FCM) develop hypophosphatemia, which appears not to be a class effect, but specific to this drug. Repeated dosing with FCM can even result in severe complications including muscle weakness, bone fractures and osteomalacia.

Methods We identified a retrospective cohort of 81 patients treated with FCM or ferric derisomaltose (FDI) with serum phosphate concentrations measured before and after iron therapy. Biochemical markers of bone turnover and mineral metabolism were analyzed in stored serum samples in a subgroup of 34 patients. An in vitro osteogenic differentiation model was established, using the osteoblastic MC3T3E1 cells. The effect of exposure to i.v. iron on osteogenic differentiation was investigated by qRT-PCR for bone marker gene expression, Alizarin Red S- and Masson Gold Trichrome staining.

Results Hypophosphatemia developed in 13 of 29 FCM treated patients (45 %), and 0 of 5 patients treated with IIM with stored serum samples available. At baseline, mean procollagen type 1 N-terminal propeptide (P1NP) concentration was significantly lower in patients developing hypophosphatemia when compared to those not developing hypophosphatemia (31.7 vs 88.7 ng/ml; p = 0.032). In both subgroups, P1NP further decreased after FCM treatment. The same pattern was found for carboxy-terminal collagen crosslinks (CTX) at baseline, which did not decrease after FCM treatment. These findings were replicated in a MC3T3E1 cell model, where impaired osteogenic differentiation was found when cultivated in the presence of i.v. iron formulations.

Conclusion I.v. iron induced hypophosphatemia can result in a dysregulation of bone markers similar to steroid induced osteoporosis and appears to reduce bone turnover. These changes can be reproduced in an in vitro model of osteogenic differentiation.

Publication History

Article published online:
01 September 2021