Management of iron deficiency in primary care underwent a seismic shift in Australia 14 years ago with the advent of newer intravenous iron formulations. The molecules allow for more rapid administration of iron and have a good safety profile, making them feasible for use in primary care. Consequently, a rapid increase in use of these formulations in primary care has ensued, with a recent Healthed survey showing that over half of GPs now administer intravenous iron in their practices.1
While IV iron remains an important treatment for iron deficiency and iron‑deficiency anaemia (IDA), emerging evidence of treatment‑specific harms—most notably FCM‑associated hypophosphataemia2 and increased fracture risk3,6—requires primary care clinicians to reassess prescribing and monitoring strategies.
Four IV agents are available in Australia with two, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), commonly used in general practice. FCM has the largest market share worldwide.4 However, these agents are not without risk and cannot be considered interchangeable.
Hypophosphataemia has been reported in 47% to 75% of patients treated with FCM, compared with <10% of patients treated with FDI.5 While in most cases, this is transient and largely asymptomatic, FCM is also associated with a rare risk of severe, symptomatic hypophosphataemia.2 A 2020 TGA safety update noted that in most cases, serum phosphate levels had returned to baseline by 12 weeks after treatment.2
However, when severe hypophosphataemia does persist, it can lead to a range of symptoms including muscle weakness, lethargy, bone pain and, in the longer term, secondary hyperparathyroidism and osteomalacia.
Post‑infusion hypophosphatemia after IV iron is thought to be mediated by increases in intact fibroblast growth factor‑23 (FGF23). Elevated FGF23 enhances renal phosphate excretion and reduces production of 1,25‑dihydroxyvitamin D inhibiting. Consequently, the absorption of phosphate from the gut is impaired. The mechanism by which the intravenous iron affects the FGF 23 is not fully understood, but hypophosphataemia occurs more often with FCM, implicating the carbohydrate moiety of the molecule.5
In July, a study by Wagner et al published in the journal Blood found that FCM was an independent risk factor for fracture and osteomalacia.3
Researchers retrospectively analysed a single-hospital cohort treated with either FCM (n=172) or FDI (n=185). After 6 months there were five fractures in the FCM cohort compared with one in the FDI group (see figure 1 in Wagner et al).
The research team then validated their findings for fracture risk using the TriNetX database of 20 000 patients. This showed that significantly higher incidence of bone events (fractures and radiological signs of osteomalacia) associated with FCM persisted at seven years.
Regression analysis showed the association remained even after adjusting for age, sex, kidney function and presence of osteoporosis or osteopenia at baseline.
Intriguingly, the study showed that while hypophosphatemia was the main association with fractures, there were some fractures without documented hypophosphataemia, suggesting additional mechanisms may be contributing.
While this is a small study with inherent limitations, and the findings need to be corroborated, a previous study showed a similar trend.6
Additionally, the FCM product information states that hypophosphataemic osteomalacia and fractures have been reported in the post market setting.7 No similar statement appears in the FDI product information.8
However, while the risk of fracture is higher in the FCM treated patients, fractures have also been reported with the other agents, though the rate is much lower. Therefore, practitioners need to consider hypophosphataemia in patients who present with fracture if they have received any iv iron.
It is now imperative to determine the absolute risk for each IV iron agent, but this will need further study in representative populations with larger numbers.
Further research is needed to better understand the mechanism of action, better define high risk patients categories, and improve guidance to reduce risk and manage fracture and/or hypophosphatemia when it happens.
Iron deficiency anaemia also increases fracture risk
It’s also important to keep things in perspective. The study by Wagner et al indicates that although fracture risk after intravenous iron is higher than previously estimated, it is still small. 3
Iron deficiency is a cause of significant morbidity and mortality and IV iron remains an important treatment.
Iron deficiency can suppress normal bone turnover and iron deficiency anaemia is an independent risk for fracture that requires treatment.3,9 Notably, anaemia contributes to fracture risk through a number of mechanisms including reduced muscular performance and decreased bone mineral density.9
To date, there is no guidance to inform the choice of IV agent for particular patient groups. However, given the heightened fracture risk with FCM, it is not unreasonable to suggest choosing an alternative agent for patients who are already at higher risk of fracture. Pre-infusion testing of Vitamin D and phosphate might be considered in some cases, following an assessment of the patient’s risk.
In a comment published alongside the Wagner study, Finberg and Auerbach go further, stating that “FCM-associated hypophosphatemia, secondary hyperparathyroidism, and its incipient skeletal morbidity may be avoided through use of the other three available iron formulations, which have been reported to have no disadvantage in safety, efficacy, or cost in prospective, randomized, and double-blind trials.”10
Children will pose a particular dilemma for clinicians. FDI is not approved in Australia for people under 18, limiting the choice of iron agent. As Finberg and Auerbach observe, because there is a is a paucity of data on the incidence of hypophosphatemia and clinical outcomes in this cohort clinicians need to be cautious.10
Minimise the number of infusions
One consistent observation from the studies is that multiple infusions with FCM increase hypophosphataemia risk.2,9 Therefore, it is important to minimise the number of infusions. This also underscores the importance of determining the underlying cause of the iron deficiency, and correcting or managing it to preserve the iron stores for longer.
Identify and manage the underlying cause of iron deficiency
The safety concerns highlight the imperative to have an appropriate indication for intravenous iron. Furthermore, a thorough assessment and management plan for the underlying cause of iron deficiency are crucial, as is a good risk assessment that includes fracture risk prior to intravenous iron administration.
Ensure patients provide informed consent
The decision to treat with intravenous iron requires consideration of both risk and benefit. Further research and data will help determine the absolute risk of fractures and high risk patient cohort. Meanwhile, it is important to discuss fracture risk with all patients before infusions, contextualising this new research and incorporating into written consent forms – but also to keep things in perspective and reassure patients since iron deficiency and IDA have their own risks.
The TGA’s perspective
To date, the TGA said it has no plans to update existing product information or issue additional warnings, noting it has investigated safety signals for iron infusions, including FCM, that could be associated with increased risk of fractures, including hypophosphataemia, hypophosphataemic osteomalacia, and interaction with denosumab, potentially resulting in hypophosphataemia and hypocalcaemia.
“Our investigations have found that many of these risks are already adequately addressed in the Product Information (PI) for these products, but we are continuing to monitor the safety of iron infusions and will work with sponsors to make updates where appropriate. The TGA recommends that health professionals maintain awareness of the information in the current PIs,” a spokesperson for the TGA said.
Healthed also reached out to CSL Seqirus, which sponsors Ferinject (ferric carboxymaltose) in Australia, but they declined to comment for this article.
1 Healthed. GP iron infusions are a growing trend. 2021. Available at: https://www.healthed.com.au/clinical_articles/gp-iron-infusions-are-a-growing-trend
2 Therapeutic Goods Administration. Ferric carboxymaltose and low blood phosphorous. 2020 Feb 27. Available from: https://www.tga.gov.au/news/safety-updates/ferric-carboxymaltose-and-low-blood-phosphorous
3 Wagner SA, et al. Ferric carboxymaltose increases fracture risk in patients and reduces bone formation in mice with iron deficiency anemia. Blood. 2026;148(1):15‑30. https://doi.org/10.1182/blood.2025031806
4 Dominguez Rieg JA et al. Distinct roles of ferric carboxymaltose and ferric derisomaltose on phosphate homeostasis in iron deficiency anemia. Eur J Pharm Sci. 2025;214:107265 https://doi.org/10.1016/j.ejps.2025.107265
5 Martens KL, Wolf M. Incidence, mechanism, and consequences of IV iron‑induced hypophosphatemia. Hematology Am Soc Hematol Educ Program. 2023;(1):636-639. https://doi.org/10.1182/hematology.2023000521
6 Zoller H et al. Incidence of fractures after intravenous iron: retrospective analysis comparing ferric carboxymaltose and ferric derisomaltose. Blood. 2023;142(Suppl 1):3838. https://doi.org/10.1182/blood-2023-174508.
7 CSL Seqirus. Ferinject (ferric carboxymaltose) product information. 2024 Apr. Available from: https://www.cslseqirus.com.au/-/media/seqirus-australia/products/product-information/au-ferinject-pi-apr24.pdf
8 Fresenius Kabi. Monofer (ferric derisomaltose) product information. Available from: https://rss.medsinfo.com.au/fk/pi.cfm?product=fkpmonoi
9 von Brackel FN, Oheim R. Iron and bones: effects of iron overload, deficiency and anemia treatments on bone. JBMR Plus.2024;8(8):ziae064. https://doi.org/10.1093/jbmrpl/ziae064
10 Finberg KE, Auerbach M. A bone to pick with ferric carboxymaltose. Blood. 2026;148(1):1‑2. https://doi.org/10.1182/blood.2026033929
Listen to expert interviews.
Click to open in a new tab
Browse the latest articles from Healthed.
Once you confirm you’ve read this article you can complete a Patient Case Review to earn 0.5 hours CPD in the Reviewing Performance (RP) category.
Select ‘Confirm & learn‘ when you have read this article in its entirety and you will be taken to begin your Patient Case Review.
