Osteomalacia as a Complication of Intravenous Iron Infusion: A Systematic Review of Case Reports

ABSTRACT 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. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Introduction P hosphate is one of the main components of the mineral bone compartment, and adequate serum levels are required for normal mineralization. Severe malnutrition and increased renal loss of phosphate are common causes of chronic phosphate depletion. Persistent hypophosphatemia leads to osteomalacia, a lack of mineralization of bone matrix. (1,2) Clinically, osteomalacia presents as muscle weakness and bone pain, biochemically as elevated alkaline phosphatase activity (ALP), and radiologically as Looser's zones (pseudofracture). (2) Physiologically, fibroblast growth factor 23 (FGF-23) is a key positive regulator of renal phosphate excretion in response to elevated phosphate levels. Inappropriately elevated intact FGF-23 activity is associated with phosphate depletion and adverse bone and neuromuscular outcomes. (2) Hypophosphatemic diseases, such as X-linked hypophosphatemia and tumor-induced osteomalacia, are characterized by high levels of FGF-23. In X-linked hypophosphatemia, FGF-23 is not properly regulated because of a mutation on the PHEX gene, resulting in FGF-23 overactivity. Conversely, in the rare tumor-induced osteomalacia, FGF-23-and occasionally other phosphatonins-is produced by mesenchymal phosphaturic tumors. In recent randomized controlled trials of up to 5 weeks duration, intravenous iron therapy with ferric carboxymaltose (FCM) was shown to increase the concentration of circulating intact FGF23 (iFGF-23), (3)(4)(5) but the long-term effects of repeated iron infusions and prolonged hypophosphatemia have not been investigated. These abnormalities could adversely affect the skeleton, but the epidemiology and pathophysiology remain incompletely understood. Several previous case reports have reported adverse effects on the skeleton after repeated iron intravenous infusions. To characterize these adverse effects, we conducted a systematic review of case reports addressing the question: Is osteomalacia observed in adults receiving iron infusions for anemia treatment?

Search strategy and selection criteria
This review was conducted in line with the principles from the Cochrane Handbook and the Centre for Reviews Dissemination Handbook. (6) This report followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). (7) The protocol was registered in PROSPERO CRD42021243237.
MEDLINE, Embase, Web of Science, and Cochrane databases were searched on March 22, 2021 combining terms for iron infusion and outcomes such as "hypophosphatemia," "osteomalacia," "fractures," and "pseudofractures" and other bone-related features. We used relevant MeSH and free text terms with no search limits. Reference lists of key articles, (1,8) a list of references on hypophosphatemia associated with iron infusions collated by Pharmacosmos, and experts in the field were also consulted. The full search strategy can be found in Supplemental Material S1.
We included case reports or case report series of osteomalacia associated with hypophosphatemia in people older than 16 years who received any form of intravenous iron infusion. We excluded randomized controlled trials, conference abstracts, studies not written in English, Danish, Norwegian, Spanish, Portuguese, or French, studies that only reported abnormalities not related to the skeletal system, and studies where bone abnormalities were not associated with hypophosphatemia. We conducted a narrative synthesis, including tabulation of study characteristics, and a description of the available data. We grouped studies by clinical criteria (presence of pseudofractures/fractures) because these are the main clinical outcomes of osteomalacia.
We defined osteomalacia as musculoskeletal pain, fractures, and/or pseudofractures associated with low phosphate. Serum phosphate levels in mg/dL were converted in mmol/L; serum 25OH vitamin D levels on ng/mL were converted to nmol/L, and serum calcium levels in mg/dL were converted in mmol/L using standard formulas. Some articles reported "insufficiency fractures." In patients with biochemical changes suggesting hypophosphatemic osteomalacia, such as bone pain and low phosphate, if there were signs of a fracture without displacement it was considered a pseudofracture. If there was a displacement of the two ends of the fracture, then we referred to it as a "fracture." (9) Data analysis We uploaded retrieved records into Endnote and removed duplicates. Two reviewers independently conducted the data extraction, the quality assessment, and the data checking using standardized and piloted forms (Supplemental Material S2 and S3). For each study, we extracted the information about the author, date, country, age, sex, clinical features of the condition that led to iron deficiency, details about iron infusion (iron formulation, dose, and frequency), phosphate levels, clinical, imaging, and laboratory features after iron infusion, details of hypophosphatemia management, and patient outcome. Disagreements at any step were resolved through discussion or involvement of a third reviewer.
There is no standard quality assessment tool to assess the quality of case report studies. We used a tool proposed by Murad and colleagues, which assesses eight items categorized in four domains: selection, ascertainment, causality, and reporting. (10)

Quality assessment
To assess the quality of the case reports, we used a tool proposed by Murad and colleagues, which assesses eight items categorized in four domains: selection, ascertainment, causality, and reporting. (10) Results are reported in Table 2.For the selection, the tool asks if the patient represents the whole experience of the center on the disease. None of the case reports included in this review reported that this was their whole experience on bone adverse outcomes associated with hypophosphatemia. In regard to the ascertainment of the exposure and the outcome, all the case reports were based on clinical records, which is the highest possible quality of ascertainment.  Alternative causes that could explain the observation were clearly ruled out in 22 of the case reports. (11,(13)(14)(15)(18)(19)(20)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)34,36) Only 5 case reports reported a re-challenge with the same iron infusion, resulting in hypophosphatemia again. (13,17,29,32,34) Because the bone adverse events seem to be associated with chronic hypophosphatemia, we considered the worsening of signs and symptoms with cumulative dose as a dose-response effect. This was reported in 21 of the 30 case reports. (11,13,14,16,(18)(19)(20)23,24,(26)(27)(28)(29)(30)(31)(32)34,36,38) Because we only included case reports that reported signs or symptoms of osteomalacia associated with hypophosphatemia, the follow-up was long enough in all cases.  Finally, we considered that enough details were reported in 21 of the 30 cases. (12)(13)(14)(15)(16)(18)(19)(20)(22)(23)(24)(26)(27)(28)(29)32,34,(36)(37)(38) Discussion This is the first systematic review of case reports of osteomalacia as a complication of intravenous iron infusion. We found 30 cases of ostemalacia associated with repeated iron infusions. In the vast majority of the patients, gastrointestinal diseases were the cause of iron deficiency, and in a few cases, iron deficiency was caused by gynecological bleeding. We observed osteomalacia in patients who received certain iron formulations (FCM, SFO, IPM) that have previously been linked to hypophosphatemia in randomized controlled trials and observational studies. (1,40) The mechanism seems to be an increase in FGF-23. (3) FGF-23 leads to renal phosphate loss and decreased activation of vitamin D. The clinical picture was bone pain, fractures, and pseudofractures. (2,41) Most of the cases had an increase in ALP, and all isotope bone scans reported were abnormal. Treatment with phosphate and active forms of vitamin D seems to be of limited benefit, while discontinuing or switching iron preparation was the most effective intervention. Abnormalities in FGF-23 metabolism mediate hypophosphatemia associated with repeated iron infusions. (3,5,41,42) Experimental data suggest that iron deficiency increases FGF-23 expression through action on hypoxia-inducible factors (HIFs), HIF1a and HIF1b. (43,44) The increase in the production of intact FGF-23 (iFGF-23) is usually followed by an increase in the cleavage and generation of c-FGF23 and N-terminal fragments and has no impact on phosphate levels. However, some iron preparations (FCM, SFO, IPM) seem to decrease the physiological cleavage of iFGF-23, resulting in high levels of iFGF-23 and hypophosphatemia. (45) The resulting hypophosphatemia might last for weeks to months. (3,5,46) ) Some patients with severe iron deficiency require repeated infusions, which could lead to prolonged hypophosphatemia. In this review, most patients with osteomalacia had more than five infusions, suggesting that persistent hypophosphatemia is likely required for the development of osteomalacia.
Hypophosphatemia (mostly moderate or severe) was associated with other abnormalities in the phosphate homeostasis axis. The cut-offs of 0.8, 0.6, and 0.3 mmol/L categorize mild, moderate, or severe hypophosphatemia. (47) In our case series, the lowest phosphate levels reported were between 0.16 and 0.77 mmol/L, and 1 patient had mild, 20 had moderate, and 8 had severe hypophosphatemia (1 was not reported). RCTs that investigated the effects of FCM in phosphate metabolism have reported an increase in iFGF-23, renal phosphate wasting, and PTH and a decrease in 1,25OHD and calcium. (5) An observational study reported similar findings after IPM, except for the decrease in calcium levels. (40) Case reports do not describe data systematically, but an increase in iFGF-23 and phosphate wasting was found when measured. In addition, in 11 of 17 cases, 1,25OHD was decreased, in half of the cases when PTH was measured it was high, and serum calcium levels were low in 10 of 26 cases. Noteworthily, in the case reports, we were not able to capture variations in the blood tests within the normal range. For example, it is possible that PTH has increased in some patients, without becoming high. Therefore, similar findings were reported in RCTs, observational studies, and this review of case reports. The consistency of the findings suggests a strong association between the iron infusions and the phosphate homeostasis abnormalities and the resulting osteomalacia.
Intravenous iron is indicated for the treatment of iron deficiency (ID) and/or iron deficiency anemia (IDA). ID/IDA is commonly caused by gastrointestinal (GI) blood loss, inflammatory bowel disease (IBD), heavy uterine bleeding, and postpartum hemorrhage. (47) A systematic review and meta-analysis of prospective studies with FCM and ferric derisomaltose (FDI) suggested that the risk factors for hypophosphatemia are the type of iron preparation (higher with FCM), the degree of iron deficiency (more likely if ferritin or transferrin saturation are low), and kidney function (more likely if renal function is normal). (47) FCM, SFO, and IPM were prescribed in 18, 8, and 3 cases (62%, 28%, and 10%), respectively, three forms of iron preparation previously associated with hypophosphatemia. (1) Another systematic review reported increased rates of hypophosphatemia for FCM and iron sucrose but not iron dextran or ferumoxytol. (48) The rising concerns in regard to osteomalacia associated with intravenous iron preparations have led to the inclusion of a warning on hypophosphatemic osteomalacia in FCM product information and a safety update by the Medicines and Healthcare Products Regulatory Agency (MHRA) on the risk of osteomalacia after FCM in the United Kingdom. (49) In this review, there were no cases of osteomalacia associated with chronic kidney disease (CKD). Because CKD prevents hypophosphatemia, the increase in FGF-23 associated with iron infusion is not followed by hypophosphatemia and osteomalacia associated with hypophosphatemia after repeated iron infusion is not observed.
Patients with comorbidities that could have detrimental effects on bone homeostasis such as malabsorption, corticosteroid use, and vitamin D deficiency might be at higher risk of osteomalacia. In this review, osteomalacia was associated with gastrointestinal disease in 23 of 30 cases. Low vitamin D status was reported in 10 of 21 cases (48%). The definition of low was left to the author; if we had used the threshold by the Institute of Medicine of 50 nmol/L, then 8 of 19 would have been low. (50) This might have contributed to the low phosphate through secondary hyperparathyroidism. Several of the patients with low vitamin D had other biochemical features of vitamin D deficiency, such as low serum calcium and high ALP and PTH. ALP is usually high in osteomalacia, but osteomalacia with normal ALP have been previously reported in patients with malabsorption, often associated with low calcium. (51) ALP was high in 18 of the 22 cases in which it was reported (82%). In the 4 cases where ALP was normal, 2 had abnormal bone scans (24,36) and the other 2 had rib pseudofractures. (14,32) Therefore, osteomalacia might be present with normal ALP. Two of these cases had  malabsorption and low calcium. (24,32) We found IBD associated with osteomalacia in 30% of cases; IBD is likely to be associated with malabsorption of calcium and phosphate and vitamin D deficiency, all of which would likely increase the risk of osteomalacia. IBD is often treated with glucocorticoids, and 2 patients were in use of corticosteroids when osteomalacia was reported, which may have contributed to bone fragility, if not osteomalacia. Osteomalacia presented as pain, fractures, and pseudofractures. Pseudofractures (or Looser's zones) are the radiological hallmark of osteomalacia, and these can go onto complete fracture. As expected, a large proportion of patients had either pseudofractures or fractures, and these were the likely sources of the bone pain. Pseudofractures are best identified by the isotope bone scan. This scan was performed in 15 cases and all of these showed focal increased uptake that can be due to pseudofractures or fractures. There were 7 patients who had pain but no fracture or pseudofractures. However, in every case, there was no imaging to test for fractures, so non-diagnosed fractures cannot be ruled out.
Some patients were reported to have osteopenia (n = 3) and osteoporosis (n = 8). Although bone mineral density was reported to be low, it is important to highlight that osteomalacia could have contributed to these findings, due to the unmineralized osteoid matrix. This is confirmed by the increase in BMD observed after the recovery from hypophosphatemia reported in 2 cases.
Several strategies were used to treat hypophosphatemia and its consequences. Oral or intravenous phosphate and active metabolites of vitamin D (calcitriol or alfacalcidol) were often prescribed, but they were not able to normalize serum phosphate. Care needs to be taken with the active metabolites of vitamin D as they can cause hypercalcemia and hypercalciuria with nephrocalcinosis and nephrolithiasis. The latter could be of clinical importance in patients with IBD as they may have enteric hyperoxaluria and so be prone to calcium oxalate kidney stones. Vitamin D deficiency should be corrected by the administration of vitamin D3.
The most efficient intervention for recovery was discontinuing the intravenous iron infusions. That was not always possible, and sometimes the iron preparation was switched. This was followed by improvement in hypophosphatemia in most cases. In one case, hypophosphatemia persisted and osteomalacia progressed despite switching the iron preparation. That was a patient with severe Crohn's disease who received FCM, FDI, and then burosumab. There is not much data on the sequential use of iron preparations. In an observational study, 32 patients received FCM and FDI. FCM caused a greater reduction in serum phosphate than FDI and the median of phosphate levels returned to baseline after 5 weeks with FDI and 10 weeks after FCM. (52) We do need further research on the effect of switching between iron preparations on serum phosphate. Burosumab is an antibody to FGF-23 and when it was used, the symptoms improved along with serum phosphate. However, this treatment is not licensed for this indication. Finally, bisphosphonates are not indicated for osteomalacia. (1) MHRA UK recommends to monitor serum phosphate levels in patients treated with multiple high-dose administrations or those on long-term treatment and in those with preexisting risk factors for hypophosphatemia, and reevaluate FCM treatment in patients with persistent hypophosphatemia. (49) Based on these recommendations and the findings of this review, we would propose the management algorithm shown in Fig. 2 for patients receiving repeated iron infusions. Our recommendation is to check phosphate levels at 2 and 5 weeks after infusion (based on data from the RCTs) and perform skeletal imaging if bone pain develops, also after the 5-week period. In those cases, also recheck phosphate levels.
Recently, a review has discussed the iron-phosphate axis and the complications of intravenous iron-induced hypophosphatemia, including osteomalacia. (41) Differences in the results between the two reviews are probably associated with differences in the methodology applied; the review by Schaefer and colleagues is a narrative review; (41) this is a PROSPERO registered and prespecified systematic review, which included only peerreviewed manuscripts.
This study has limitations. Case reports are reported according to local practice. Therefore, different teams might assess the patients in different ways, using different tests and management. There is no standardization of how the case is investigated, conducted, or reported. Because there is no systematic approach, in the absence of some information, it is impossible to know if this was a negative finding not reported or if it was not investigated. For example, in the many cases that did not report fractures, it is impossible to know if there were no fractures or if fractures were not investigated. In addition, case reports tend to describe severe cases and mild forms are less likely to be reported, which might lead to a publication bias. Case reports are considered low-grade evidence. Because this is a systematic review of case reports, caution should be taken while interpreting the results. However, case reports are the first line of information and can suggest associations. Moreover, consistent findings in multiple case reports might suggest a pattern and help to understand the potential underlying mechanisms. Finally, several case reports might help to draw a bigger picture and to plan further research steps using appropriate methodology.
We conducted a systematic review of case reports of osteomalacia after repeated iron infusion. We found 30 cases of osteomalacia characterized by musculoskeletal pain, fractures, and pseudofractures. Not all cases presented high alkaline phosphatase, but iFGF-23 and isotope bone scans were abnormal whenever reported. Osteomalacia was associated with FCM, SFO, and IPM, iron formulations that have been shown to increase iFGF-23 and lead to significant hypophosphatemia. Phosphate supplementation and active forms of vitamin D were used for treatment, but the most effective intervention was discontinuing or switching intravenous iron preparation. In patients receiving repeated iron infusions, musculoskeletal pain can be a symptom of osteomalacia and it should be investigated. review process, the selection of studies for inclusion, the data interpretation, or the recommendations made in the article.
Authors' roles: Conceptualization: TV, BA, and RE. Methodology: TV, NV, and CS. Analysis: TV, NV, BA, and RE. Data curation: TV, NV, and CS. Writing-original draft: TV. Writing-review and editing: all authors. Funding: BA and RE.

DATA AVAILABILITY STATEMENT
Data derived from public domain resources