Risk factors for and effects of persistent and severe hypophosphataemia following ferric carboxymaltose: Secondary analysis of randomised clinical trials

Background Hypophosphataemia complicated by osteomalacia and fractures has been reported as an adverse effect of certain intravenous iron formulations.

Methods In this secondary analysis of pooled data from two identically designed, open-label, randomised clinical trials that compared the incidence of hypophosphataemia following treatment with ferric carboxymaltose (FCM) versus ferric derisomaltose (FDI), we investigated risk factors for hypophosphataemia – incident (serum phosphate <2·0 mg/dL); severe (≤1·0 mg/dL); persistent (<2·0 mg/dL on day 35) – and associated changes in bone and mineral metabolism.

Findings FCM was the only consistent risk factor for incident hypophosphataemia (odds ratio versus FDI: 38·37; 95 % confidence interval [CI]: 16·62, 88·56; p<0·001), and for the magnitude of maximal decrease in serum phosphate (–1·08 mg/dL; 95 % CI: –1·22, –0·94; p<0·001). Only FCM-treated patients developed severe hypophosphataemia (11·3 %; 13/115) or persistent hypophosphataemia (40·0 %; 46/115). More severe hypophosphataemia was associated with significantly greater changes in intact fibroblast growth factor-23 (iFGF23), parathyroid hormone (PTH), alkaline phosphatase, 1,25-dihydroxyvitamin D (1,25(OH)₂D) and ionised calcium levels (all p<0·05). Persistent versus resolved hypophosphataemia was associated with significantly greater changes in iFGF23, PTH, 1,25(OH)₂D and N-terminal procollagen-1 peptide levels (all p<0·01); alkaline phosphatase increased to a similar extent after FCM regardless of whether hypophosphataemia persisted or resolved.

Interpretation Besides treatment with FCM, no other factor consistently predicted increased risk for hypophosphataemia. Patients who developed more severe or persistent hypophosphataemia after treatment with FCM manifested more severe derangements in bone and mineral metabolism, which may help explain the association of FCM with osteomalacia and fractures.

Funding Pharmacosmos A/S.

Publication History

Article published online:
01 September 2021