Randomized control trials (RCTs) have shown that certain intravenous iron preparations can induce high levels of fibroblast growth factor 23 (FGF-23) and persistent hypophosphatemia. Repeated iron infusions may lead to prolonged hypophosphatemia and osteomalacia events not captured by RCTs. Several previous case reports have described skeletal adverse effects after repeated iron infusions. To characterize these effects, we conducted a systematic review of case reports. MEDLINE, Embase, Web of Science, and Cochrane databases were searched in March 2021. We selected case reports of patients ≥16 years old. Study quality was assessed using the tool from Murad and colleagues. We report the results in a narrative summary. We identified 28 case reports, reporting 30 cases. Ages ranged from 28 to 80 years (median 50 years). Most patients (n = 18) received ferric carboxymaltose (FCM), whereas 8 received saccharated ferric oxide (SFO) and 3 received iron polymaltose (IPM). All but 2 cases had more than five infusions (range 2 to 198, median 17). The lowest phosphate levels ranged from 0.16 to 0.77 mmol/L (median 0.36 mmol/L). Intact FGF-23 (iFGF-23) was high when measured. Serum 25OH vitamin D was low in 10 of 21 cases measured and 1,25(OH) 2 vitamin D in 12 of 18. Alkaline phosphatase was high in 18 of 22 cases. Bone or muscle pain was reported in 28 of the 30 cases. Twenty patients had pseudofractures, 9 had fractures, and 6 patients had both. All 15 available bone scans showed focal isotope uptake. Case reports tend to report severe cases, so potential reporting bias should be considered. Osteomalacia is a potential complication of repeated iron infusion, especially in patients with gastrointestinal disorders receiving prolonged therapy. Pain and fractures or pseudofractures are common clinical findings, associated with low phosphate, high iFGF-23, high alkaline phosphatase, and abnormal isotope bone scan. Discontinuing or switching the iron formulation was an effective intervention in most cases.
