Persistent Hypophosphatemia after Ferric Carboxymaltose Is Associated with Persistent Changes in Biomarkers of Bone Metabolism

Introduction

High-dose intravenous (IV) iron formulations are used to correct iron-deficiency anemia in patients when there is a clinical need to deliver iron rapidly or to treat patients who do not tolerate or fail to respond to oral iron. Hypophosphatemia is an important adverse effect of some IV iron formulations. Persistent hypophosphatemia is associated with bone complications, including osteomalacia. In two recent head-to-head trials, ferric carboxymaltose (FCM) induced marked increases in the phosphaturic hormone fibroblast growth factor 23 (FGF23), which led to significantly higher rates of incident and persistent hypophosphatemia than in patients treated with ferric derisomaltose (FDI) (Wolf et al. JAMA. 2020;323:432-43). Here, we present a post hoc analysis of patients with incident hypophosphatemia in which we investigated predictors of persistent hypophosphatemia and tested whether persistent hypophosphatemia was associated with persistent changes in biomarkers of bone metabolism, which could help explain bone complications that have been linked to FCM in numerous case reports.

Methods

We analyzed pooled data from two open-label, randomized clinical trials that compared the US dosing of FCM (2 doses of 750mg administered 1 week apart; N=117) to FDI (1 dose of 1000mg; N=125). In this analysis only patients who developed incident hypophosphatemia (serum phosphate <2.0 mg/dL) after treatment were included. This subgroup was then classified according to their serum phosphate at the end of the trials' observation period on day 35 as either 'recovered' (≥2.0 mg/dL) or 'persistent' (<2.0 mg/dL). We used multivariate logistic regression analyses with forward stepwise selection to identify baseline predictors of persistent hypophosphatemia. To better understand the effects of persistent hypophosphatemia on bone health, we compared changes in biomarkers of bone metabolism in patients who developed persistent hypophosphatemia with those who recovered from hypophosphatemia.

Results

Overall, 90 patients (FDI, n=8; FCM, n=82) who developed incident hypophosphatemia were classified as 'recovered' or 'persistent'. All 8 patients who developed hypophosphatemia after FDI recovered. In the FCM group, hypophosphatemia recovered in 43% of patients (n=35) and persisted in 57% (n=47). Besides FCM use, no baseline predictor could independently distinguish patients who developed hypophosphatemia and recovered from patients who experienced persistent hypophosphatemia.

Within the FCM group, patients who developed persistent hypophosphatemia had greater increases in intact FGF23 on day 8 compared to patients who recovered (mean change from baseline to day 8 [95% CI]: 471.3 pg/mL [402.7 to 539.9] vs 228.3 pg/mL [186.8 to 269.9]). Compared to patients who recovered from hypophosphatemia, patients in whom hypophosphatemia persisted also had significant and persistent differences in multiple biomarkers at study end on day 35 (mean change from baseline to day 35 [95% CI]): increased intact FGF23 (58.7 pg/mL [40.8 to 76.5] vs -0.1 pg/mL [-6.7 to 6.5); increased parathyroid hormone (38.6 pg/mL [26.6 to 50.5] vs 14.5 pg/mL [4.5 to 24.5]); decreased 1,25-(OH)₂-vitamin D (-35.1 pg/mL [-39.1 to -30.9] vs -3.4 pg/mL [-8.5 to 1.7]); and decreased N-terminal pro-peptide of type 1 collagen (-22.5 ng/mL [-26.3 to -18.6] vs -6.1 ng/mL [-11.1 to -1.1]).

Conclusion

Persistent hypophosphatemia developed only in patients who received FCM. Baseline characteristics could not discern whether patients with incident hypophosphatemia would remain persistently hypophosphatemic or go on to recover by study end. Persistent hypophosphatemia resulted in similarly persistent changes in biomarkers of bone metabolism. These findings suggest that treatment with FCM may affect bone health, especially in patients with persistent hypophosphatemia, and may help explain the association of FCM with osteomalacia and fractures that has been described in several case reports.