<p>Hypophosphatemia Associated with Intravenous Iron Therapies for Iron Deficiency Anemia: A Systematic Literature Review</p>

Abstract

Background: Iron deficiency anemia (IDA) is a prevalent yet underdiagnosed condition with a significant impact on quality of life. Oral iron supplementation is often poorly tolerated or yields inadequate response, requiring the use of intravenous iron (IVI) in some patients. Administration of certain IVI preparations has been associated with decreases in serum phosphate levels and clinically significant hypophosphatemia, which has been reported to lead to adverse events including serious fatigue and osteomalacia. Objective: The purpose of this study was to systematically assess the prevalence, clinical consequences, and reporting of treatment-emergent hypophosphatemia within literature investigating IVI therapies marketed in the United States (US). Methods: A systematic literature review (SLR) was conducted using the PubMed database to identify publications reporting serum phosphate levels or rates of hypophosphatemia within adult IDA patient populations receiving current US-marketed IVIs. Results: The SLR yielded 511 unique publications, with 40 records meeting the final inclusion criteria. Most studies did not report phosphate monitoring methodology or an explicit definition of hypophosphatemia. Hypophosphatemia rates ranged from 0.0% to 92.1% for ferric carboxymaltose (FCM), 0.0% to 40.0% for iron sucrose, 0.4% for ferumoxytol, and 0.0% for low-molecular-weight (LMW) iron dextran. Randomized controlled studies described hypophosphatemia as "asymptomatic" or did not report on other associated sequelae. Eleven case reports detailed treatment-emergent hypophosphatemia in patients treated with FCM. Patients with acute hypophosphatemia primarily developed severe fatigue; those with repeated FCM dosing developed chronic hypophosphatemia associated with osteomalacia and bone deformities. Conclusion: Studies analyzed in this SLR reported a range of hypophosphatemia rates, with the highest consistently seen in patients treated with FCM. Across the clinical literature, there appeared to be minimal standardization of phosphate monitoring and definitions of hypophosphatemia. Although multiple cases have documented serious clinical consequences of hypophosphatemia associated with certain IVIs, current trials neither consistently nor adequately assess the frequency and severity of treatment-emergent hypophosphatemia and may underestimate its prevalence.

A Pooled Analysis of Serum Phosphate Measurements and Potential Hypophosphataemia Events in 45 Interventional Trials with Ferric Carboxymaltose

“…The effect of serum PO 4 3− lowering following administration of FCM has been frequently observed in interventional, observational, and retrospective studies [20,[36][37][38][39][40][41][42]. This effect has been seen at 2 weeks following FCM administration, and persistence of laboratory HP at Weeks 5 and 6 has been noted [39][40][41].…”

“…Given that fully functional kidneys have the capacity to modulate excess phosphate in the blood, compromised kidneys (as with CKD patients and heart failure patients with eGFR < 65 mL/min/1.73 m 2 ) may have a reduced capacity for renal excretion and therefore are hyperphosphataemic and are at a decreased risk of developing HP following FCM treatment [20]. It has been noted elsewhere that patients with gynaecological causes of iron-deficiency anaemia tend to have higher HP rates, which may explain the higher-than-anticipated incidence of HP following their treatment with FCM [40,42]. Chronic HP has a number of different potential aetiologies, including genetic mutations, altered immunity, tumour induction, and renal disease [57].…”

Severe osteomalacia with multiple insufficiency fractures secondary to intravenous iron therapy in a patient with Rendu-Osler-Weber syndrome

“…Despite the heterogeneous methodology of the studies and the different definition of hypophosphatemia, FCM is the form of IV iron most frequently associated with this complication. In a recent systematic literature review hypophosphatemia associated to IV iron therapies was reported in 19 randomized control trials ( Glaspy et al, 2020 ). This complication has been observed in 0.0–92.1% patients treated with FCM (18 studies), 0.0–40.0% treated with iron sucrose (5 studies), 0.4% treated with ferumoxytol (1 study), and 0.0% treated with low-molecular-weight iron dextran (1 study).…”

“…Ferric carboxymaltose (FCM) is an iron formulation increasingly prescribed due to its effectiveness and fast infusion time. FCM can cause hypophosphatemia secondary to fibroblast growth factor 23 (FGF23) dysregulation ( Glaspy et al, 2020 ).…”

Hypophosphataemia, fibroblast growth factor 23 and third-generation intravenous iron compounds: a narrative review

“…Hypophosphataemia rates were found to be 0.0–92.1% for FCM, 0.0–40.0% for iron sucrose, 0.4% for ferumoxytol and 0.0% for low-molecular-weight iron dextran. 31 All of the RCTs in the systematic review reported hypophosphataemia to be transient, while the case reports included (exclusively involving FCM) described severe fatigue associated with acute hypophosphataemia and osteomalacia and fractures in cases of chronic hypophosphataemia linked to repeated i.v. iron infusions.…”