Effects of ferric carboxymaltose on markers of mineral and bone metabolism: A single-center prospective observational study of women with iron deficiency

Frazier, Rebecca; Hodakowski, Alexander J.; Cai, Xuan; Lee, Jung Hwa; Zakarija, Anaadriana; Stein, Brady L.; David, Véronique; Wolf, Myles; Isakova, Tamara; Mehta, Rupal

doi:10.1016/j.bone.2020.115559

Cited by 10 publications

(10 citation statements)

References 23 publications

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“…The relatively short duration of the trials precluded a determination of how long beyond day 35 hypophosphatemia and associated changes in bone and mineral metabolism persisted. While prior studies reported that hypophosphatemia persisted after a single course of FCM for 3 to 9 months in some patients ( 13 , 26-28 ), there are limited data on the long-term effects of FCM-induced hypophosphatemia on bone. Another limitation of the short duration of follow-up is that we could not assess effects on clinical outcomes, such as fractures, that have been reported in multiple case reports of patients after treatment with FCM ( 29-31 ).…”

Section: Discussionmentioning

confidence: 98%

Risk Factors for and Effects of Persistent and Severe Hypophosphatemia Following Ferric Carboxymaltose

Schaefer

Zoller

Wolf

2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Hypophosphatemia, osteomalacia and fractures are complications of certain intravenous iron formulations. Objective To investigate risk factors for incident, severe and persistent hypophosphatemia, and associated alterations in bone and mineral biomarkers following intravenous iron treatment. Design Secondary analysis of the PHOPHARE-IDA randomized clinical trials. Setting Thirty outpatient clinics in the United States. Patients 245 patients aged 18 years or older with iron deficiency anemia. Interventions Intravenous ferric carboxymaltose (FCM) versus ferric derisomaltose (FDI). Main Outcome Measures Serum phosphate, intact fibroblast growth factor-23 (iFGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), ionized calcium, parathyroid hormone (PTH), and alkaline phosphatase. Results FCM was the only consistent risk factor for incident hypophosphatemia (<2.0 mg/dl; odds ratio versus FDI: 38.37; 95% confidence interval [CI]: 16.62, 88.56; p<0.001). Only FCM-treated patients developed severe hypophosphatemia (<1.0 mg/dl; 11.3%; 13/115) or persistent hypophosphatemia (<2.0 mg/dl at study end; 40.0%; 46/115). More severe hypophosphatemia associated with significantly greater increases in iFGF23, PTH, and alkaline phosphatase, and more severe decreases in 1,25(OH)2D and ionized calcium (all p<0.05). Patients with persistent versus resolved hypophosphatemia demonstrated significantly greater changes in iFGF23, PTH, 1,25(OH)2D and N-terminal procollagen-1 peptide levels (all p<0.01), but alkaline phosphatase increased similarly in both groups. Conclusions Treatment with FCM was the only consistent risk factor for hypophosphatemia. Patients who developed severe or persistent hypophosphatemia after FCM treatment manifested more severe derangements in bone and mineral metabolism. Changes in bone biomarkers continued beyond resolution of hypophosphatemia, suggesting ongoing effects on bone that may help explain the association of FCM with osteomalacia and fractures.

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Section: Discussionmentioning

confidence: 98%

Risk Factors for and Effects of Persistent and Severe Hypophosphatemia Following Ferric Carboxymaltose

Schaefer

Zoller

Wolf

2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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“…The phosphate level after 70 days was lower than the phosphate level after 35 days [ 71 ]. Frazier et al and Wolf et al showed that intact FGF-23 increased further after administration of a second dose of FCM, and that the P i -concentration decreased further accordingly [ 56 , 57 ]. The administered dose also correlates with the nadir of hypophosphatemia—the higher the dose, the lower the nadir [ 72 , 76 ].…”

Section: Hypophosphatemia After Intravenous Ironmentioning

confidence: 99%

“…By combining both assays, the exact level of inactivated FGF-23 can be determined by comparing the results of the C-terminal assay with the results of the active assay [53]. In this way, it could be demonstrated that after the administration of FCM, the intact and active level of FGF-23 is markedly increased within 24 h [54,[56][57][58]. The mechanism behind this increase has not yet been elucidated, however it has been proposed that the carbohydrate shell of FCM might inhibit the cleavage of full-length intact FGF-23, which is upregulated in iron deficiency [53,54,56], but an alternative explanation may be the interference with gene expression.…”

Section: Clinical Relevance Mechanism Of Action and Epidemiologymentioning

confidence: 99%

“…In addition, active FGF-23 inhibits the production of active vitamin D [1.25(OH) 2 D] and stimulates the inactivation of active vitamin D. Due to the reduced level of 1.25(OH) 2 D, the production of parathyroid hormone (PTH) is no longer impaired and the increased level of PTH contributes to the severity and duration of hypophosphatemia [42,53,54,56,57,[64][65][66]. The effects of FCM on FGF-23 are presented in Fig.…”

Section: Clinical Relevance Mechanism Of Action and Epidemiologymentioning

confidence: 99%

“…This may be explained by the fact that iron deficiency upregulates FGF-23 [53,54,56]. The increase in active FGF-23, which occurs after the administration of intravenous iron, especially FCM [54,[56][57][58], may then be more pronounced. This is in concordance with the fact that in patients with autosomaldominant hypophosphatemic rickets (ADHR), who have a congenital genetic defect that impairs the degradation of intact FGF-23, iron deficiency results in an increase in renal phosphate losses [99,100].…”

Section: Intravenous Iron Formulationmentioning

confidence: 99%

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High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment

Boots

Quax

2022

Drug Saf

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The intravenous iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) offer the possibility of administering a large amount of iron in one infusion. This results in faster correction of anemia and the formulations being better tolerated than oral iron formulations. This triad of logistic advantages, improved patient convenience, and fast correction of anemia explains the fact that intravenous iron formulations nowadays are frequently prescribed worldwide in the treatment of iron deficiency anemia. However, these formulations may result in hypophosphatemia by inducing a strong increase in active fibroblast growth factor-23 (FGF-23), a hormone that stimulates renal phosphate excretion. This effect is much more pronounced with FCM than with FDI, and therefore the risk of developing hypophosphatemia is remarkably higher with FCM than with FDI. Repeated use of FCM may result in severe osteomalacia, which is characterized by bone pain, Looser zones (pseudofractures), and low-trauma fractures. Intravenous iron preparations are also associated with other adverse effects, of which hypersensitivity reactions are the most important and are usually the result of a non-allergic complement activation on nanoparticles of free labile iron—Complement Activation-Related Pseudo-Allergy (CARPA). The risk on these hypersensitivity reactions can be reduced by choosing a slow infusion rate. Severe hypersensitivity reactions were reported in < 1% of prospective trials and the incidence seems comparable between the two formulations. A practical guideline has been developed based on baseline serum phosphate concentrations and predisposing risk factors, derived from published cases and risk factor analyses from trials, in order to establish the safe use of these formulations.

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Hypophosphatemia after intravenous iron therapy: Comprehensive review of clinical findings and recommendations for management

Schaefer

Tobiasch

Wagner

et al. 2022

Bone

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Effects of ferric carboxymaltose on markers of mineral and bone metabolism: A single-center prospective observational study of women with iron deficiency

Cited by 10 publications

References 23 publications

Risk Factors for and Effects of Persistent and Severe Hypophosphatemia Following Ferric Carboxymaltose

Risk Factors for and Effects of Persistent and Severe Hypophosphatemia Following Ferric Carboxymaltose

High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment

Hypophosphatemia after intravenous iron therapy: Comprehensive review of clinical findings and recommendations for management

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