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Radioisotope whole-body bone scan. (a) Increased focal uptake consistent with multiple rib fractures as well as increased metabolic activity involving the right distal radius, ribs, ankles, right inferior pubic ramus and sacral ala. (b) Increased focal uptake consistent with multiple fractures as well as enhanced metabolic activity affecting the scapulae, spine, sternum, proximal and distal ends of the tibiae and distal femora. There are also degenerative changes of the hands, feet as well as spine.
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Iron-induced hypophosphataemic osteomalacia remains under-recognized as a potential complication of parenteral iron therapy. We here report two cases of symptomatic hypophosphataemic osteomalacia with multiple insufficiency fractures in the context of chronic gastrointestinal blood loss, necessitating monthly iron polymaltose infusions over prolong...
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Oncogenic osteomalacia is a rare condition, with overproduction of fibroblast growth factor 23, leading to hypophosphatemia, phosphaturia. If it is associated with benign mesenchymal tumor, then resection of tumor is curable. Thus, detection and localization of the lesion are of utmost importance. We report a case, where18F-FDG PET/CT scan was usef...
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... Medication history should be carefully assessed for iatrogenic causes of hypophosphatemia (Table 1) [45][46][47]. ...
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.
Graphical Abstract
... First described in the late 1980s [2] with the former, it has since been reported in more cases, induced by the latter [1] although clear timelines associated with development, time to nadir, and duration to resolution are less clear. While it is transient and self-limiting in most cases, it can be symptomatic and long lasting, requiring aggressive treatment and supplementation in other instances [3][4][5]. ...
... Hypophosphatemia has been increasingly reported following therapy with parenteral iron formulations recently [6]. Certain formulations like ferric carboxymaltose and saccharated ferric oxide are implicated at a higher frequency than others [1,4,6]. ...
Hypophosphatemia is a less known complication of parenteral iron use, particularly after the use of certain iron formulations. We report the case of a young male with inflammatory bowel disease and iron deficiency anemia, who developed severe symptomatic hypophosphatemia after his third exposure to iron carboxymaltose with no evidence of the same occurring upon prior exposures to the compound. Investigations revealed serum phosphorous levels of 0.7 mg/dl, corrected serum calcium of 8–9.5 mg/dl, alkaline phosphatase of 50 U/L (38–126), 25 hydroxy vitamin D level of 40.2 ng/ml, and intact PTH elevated to 207 pg/ml. Urine studies indicated renal phosphate wasting. Presentation was not in keeping with refeeding syndrome. Intact fibroblast growth factor 23 level, measured after the initiation of treatment was within the normal range at 179 RU/mL (44–215). 1,25 dihydroxy vitamin D level, also measured after the initiation of treatment, was normal at 26.3 pg/ml (19.9–79.3). The patient was treated with calcitriol and aggressive oral and intravenous phosphorous repletion. Symptoms then resolved and the patient was discharged on an oral regimen. This phenomenon is postulated to occur due to an increase in the level and activity of FGF23 and decreased cleavage of the same, due to anemia as well as use of specific iron formulations. This is the first instance, in our literature review, of this complication known to occur, not after initial exposure to an implicated iron formulation but occurring on subsequent exposure.
... To date, several cases have been published that showed that repeated use of FCM leads to a severe form of osteomalacia, characterized by bone pain, Looser zones (pseudofractures) and low-trauma fractures [66,[118][119][120][121][122][123][124][125]. Similar results have been reported for another intravenous iron formulation, ironpolymaltose (Maltofer ® , Vifor Pharma, Switzerland), the use of which is less common [126,127]. In addition, in Japan, [131]; however, since osteomalacia has been reported with a comparable formulation to IS and hypophosphatemia may also occur with FDI, it seems likely that repeated use of FDI may also lead to osteomalacia. ...
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.
... The vast majority (n = 26) were single case reports, (11)(12)(13)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(32)(33)(34)(35)(36)(37)(38) and two manuscripts reported two cases. (14,31) The case reports were published between 1993 and 2020. Half of the case reports were from Europe (n = 14), (11)(12)(13)15,17,20,21,23,25,26,28,30,32,34) eight from Japan, (18,22,27,29,31,(36)(37)(38) and three from both Australia (14,16,24) and the United States. ...
... (14,31) The case reports were published between 1993 and 2020. Half of the case reports were from Europe (n = 14), (11)(12)(13)15,17,20,21,23,25,26,28,30,32,34) eight from Japan, (18,22,27,29,31,(36)(37)(38) and three from both Australia (14,16,24) and the United States. (19,33,35) The main characteristics of the patients in the case reports are shown in Table 1. ...
... Ages ranged from 28 to 80 years (median 50 years), with 6 patients younger than 40 years, (11,12,29,32,34,35) 20 patients between 40 and 70 years, (13)(14)(15)17,19,(21)(22)(23)(24)(25)(26)(27)(28)30,31,33,36,38) and 3 older than 70 years old. (16,18,37) In one case report, the age of the patient was not reported. ...
Randomised control trials (RCTs) have shown that certain intravenous iron preparations can induce high levels of 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 following repeated iron infusions. To characterise 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 Murad et al tool. 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). Most patients (n = 18) received ferric carboxymaltose (FCM) while eight received saccharated ferric oxide (SFO) and three received iron polymaltose (IPM). All but two cases had more than five infusions (range 2–198, median 17). The lowest phosphate levels ranged from 0.16 to 0.77 mmol/L (median 0.36 mmol/L). iFGF‐23 was high when measured. Serum 25OH vitamin D was low in 10 out of 21 cases measured and 1,25(OH)2 vitamin D in 12 out of 18. Alkaline phosphatase was high in 18 out of 22 cases. Bone or muscle pain was reported in 28 out of the 30 cases. Twenty patients had pseudofractures, nine had fractures and, six 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 pseudo‐fractures 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. This article is protected by copyright. All rights reserved.
... While FGF23-mediated hypophosphataemia occurs in virtually all patients with TIO, it is non-specific with similar biochemical profiles being found as a result of some other inherited or acquired disorders, as shown in Table 2 [4,6,7,[65][66][67]. Although the mechanism is not fully known, acquired FGF23-mediated hypophosphatemia can develop from repeated treatment with some forms of parenteral iron, the subject now of an extensive number of case reports and case series in the literature [68][69][70]. Recent evidence suggests that iron carboxymaltose may impair FGF23 cleavage [71]. ...
... Evolving evidence shows that 68 Ga-DOTA-Phe 1 -Tyr 3 -Thr 8 -octreotate ( 68 Ga-DOTATATE) PET/computed tomography (CT) is superior to older SRS techniques (e.g. 111 In-pentetreotide [OctreoScan™]) and to 18 Ffluorodeoxyglucose ( 18 F-FDG) PET/CT in locating PMTs [78][79][80][81][82][83][84]. This is likely due to the higher affinity of 68 Ga-DOTATATE binding to SSTR2 combined with the advantages of PET [85]. ...
... This is likely due to the higher affinity of 68 Ga-DOTATATE binding to SSTR2 combined with the advantages of PET [85]. Based on pooled values from two recent meta-analyses, the detection rate of culprit PMTs using 68 Ga-DOTATATE-PET/CT is 88-90% [83,84]. Other SSTR binding ('DOTA') radiopharmaceuticals have now been developed, and a recent retrospective study indicated a 94.1% sensitivity and 90.5% accuracy of PMT detection using 68 Ga-DOTA-NOC PET/CT [81]. ...
Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease that is challenging to diagnose and treat. TIO is characterized by hypophosphatemia resulting from excess levels of tumor-secreted fibroblast growth factor 23 (FGF23), one of the key physiological regulators of phosphate metabolism. Elevated FGF23 results in renal phosphate wasting and compromised vitamin D activation, ultimately resulting in osteomalacia. Patients typically present with progressive and non-specific symptoms, including bone pain, multiple pathological fractures, and progressive muscle weakness. Diagnosis is often delayed or missed due to the non-specific nature of complaints and lack of disease awareness. Additionally, the disease-causing tumors are often difficult to detect and localize because they are often small, lack localizing symptoms and signs, and dwell in widely variable anatomical locations.
One of the current unmet needs in TIO that causes a delay in diagnosis is the measurement of fasting serum phosphate, which should be an inherent diagnostic component when assessing otherwise unexplained osteomalacia, fractures, and weakness. In cases of hypophosphatemia with inappropriate (sustained) phosphaturia and inappropriately normal or frankly low 1,25-dihydroxy vitamin D, differentiation of the potential causes of renal phosphate wasting should include measurement of FGF23, and TIO should be considered.
Patients experience severe disability without treatment but complete excision of the tumor is typically curative and results in a dramatic reversal of symptoms. Two additional key current unmet needs in optimizing TIO management are: (1) the considerable delay in diagnosis and consequent delay between the onset of symptoms and surgical resection; and (2) alternative management. These may be addressed by raising awareness of TIO, and taking into consideration the accessibility and variability of different healthcare infrastructures. By recognizing the challenges associated with the diagnosis and treatment of TIO and by applying a stepwise approach with clear clinical practice guidelines, patient care and outcomes will be improved in the future.
... Multiple IV iron formulations have been implicated, including saccharated iron oxide [7] and ferric carboxymaltose (FCM) [7][8][9][10], which is responsible for most of the cases in the European Union and North America. Initially, IV iron-induced hypophosphatemia was thought to be asymptomatic, selflimited, and not associated with adverse events or clinical sequelae [10][11][12][13][14]; however, evidence is accumulating that this is not always the case [7, [15][16][17][18][19][20][21]. ...
Some, but not all, intravenous iron formulations have been recognized to induce renal phosphate wasting syndrome. Most commonly this has been reported following treatment of iron deficiency anemia (IDA) with ferric carboxymaltose (FCM). A search of PubMed identified relevant randomized controlled trials (RCTs), and case studies evaluating hypophosphatemia (HPP) resulting from intravenous iron treatment. While more recent larger comparative RCTs have confirmed that the majority of patients receiving FCM, especially those with normal renal function, may experience severe HPP, complete documentation is hampered by inconsistent reporting of serum phosphate in such trials. Similarly, while case series and RCTs have documented the persistence of HPP for several weeks or even months, the lack of studies lasting beyond 5-6 weeks has constrained full understanding of the duration of effect. Clinical trials have established that the mechanism involves the bone/metabolic axis with the elevation of intact fibroblast growth factor 23 playing the central role. Reports continue to accumulate of the clinical consequences of severe HPP which are, most commonly, bone abnormalities following repetitive dosing. Case reports and studies, however, have also shown that symptomatic hypophosphatemia can occur after a single FCM dose. The frequency of such events remains unknown, in part due to lack of awareness of hypophosphatemia coupled with the fact that the most common acute symptoms of HPP (fatigue and weakness) are the same for IDA and for many of the chronic diseases that cause IDA. Changes to US and European prescribing information for FCM should raise awareness of the potential for HPP and need to monitor patients at risk for it.
... Importantly, while oral iron supplementation in iron-deficient ADHR patients is recommended, intravenous iron administration could be detrimental. This is because, for reasons that are not yet understood, some intravenous iron formulations given to iron-deficient patients can trigger an acute and prolonged rise in intact FGF23 and resultant hypophosphatemia [64][65][66][67][68][69]. Remember that FGF23 gene expression is elevated in the setting of iron deficiency, even among patients without FGF23 mutations. ...
... Remember that FGF23 gene expression is elevated in the setting of iron deficiency, even among patients without FGF23 mutations. Several case reports and now multiple prospective clinical trials have clearly demonstrated that intravenous iron in this setting can cause an acute rise in intact FGF23, which is thought to be due to some other factor, possibly the carbohydrate moiety of the iron infusion, impairing cleavage of FGF23 [64][65][66][67][68][69]. Indeed, the propensity to develop hypophosphatemia after intravenous iron varies with the formulation, with most reports citing iron carboxymaltose or iron polymaltose. ...
Great strides over the past few decades have increased our understanding of the pathophysiology of hypophosphatemic disorders. Phosphate is critically important to a variety of physiologic processes, including skeletal growth, development and mineralization, as well as DNA, RNA, phospholipids, and signaling pathways. Consequently, hypophosphatemic disorders have effects on multiple systems, and may cause a variety of nonspecific signs and symptoms. The acute effects of hypophosphatemia include neuromuscular symptoms and compromise. However, the dominant effects of chronic hypophosphatemia are the effects on musculoskeletal function including rickets, osteomalacia and impaired growth during childhood. While the most common causes of chronic hypophosphatemia in children are congenital, some acquired conditions also result in hypophosphatemia during childhood through a variety of mechanisms. Improved understanding of the pathophysiology of these congenital conditions has led to novel therapeutic approaches. This article will review the pathophysiologic causes of congenital hypophosphatemia, their clinical consequences and medical therapy.
... The most common formulation of intravenous iron causing hypophosphatemia is ferric carboxymaltose. The incidence of hypophosphatemia after iron infusion varies from 2.1 to 86% [111]. The precise mechanism remains unclear, but intravenous iron formulations are suspected to have an effect on the intracellular metabolism of FGF23. ...
Phosphate homeostasis involves several major organs that are the skeleton, the intestine, the kidney, and parathyroid glands. Major regulators of phosphate homeostasis are parathormone, fibroblast growth factor 23, 1,25-dihydroxyvitamin D, which respond to variations of serum phosphate levels and act to increase or decrease intestinal absorption and renal tubular reabsorption, through the modulation of expression of transcellular transporters at the intestinal and/or renal tubular level. Any acquired or genetic dysfunction in these major organs or regulators may induce hypo- or hyperphosphatemia. The causes of hypo- and hyperphosphatemia are numerous. This review develops the main causes of acquired and genetic hypo- and hyperphosphatemia.
... Although replenishing iron stores appears to reduce the production of FGF23, IV iron preparations such as FCM may potentially inhibit the proteolytic cleavage of FGF23, thereby increasing the circulating levels of iFGF23 [25], which in a downward cascade, may have an impact on phosphate homeostasis causing phosphaturia. The exact mechanisms mediating iFGF23 increase by FCM is unknown [26]. FCM has been studied extensively in both the clinical trial and real-world settings (>12 million patient-years of post-marketing exposure) [27] and is an effective and generally well-tolerated treatment to rapidly replenish iron stores and correct anaemia in patients with iron deficiency of various aetiologies [28]. ...
Ferric carboxymaltose (FCM) has been shown to achieve rapid replenishment of iron stores and correction of anaemia in various populations with iron deficiency. A decrease in serum phosphate (PO43−) levels, which in most cases is asymptomatic, has been reported with IV iron preparations. Hypophosphataemia (HP) is a known adverse drug reaction with FCM. This post hoc pooled analysis investigates the frequency, duration, risk factors, and clinical signs of HP as reported in interventional clinical trials with FCM. Pooled data from subjects enrolled across 45 clinical trials in different therapy areas were included. A three-step adjudication process was utilised to identify adverse events of HP. Stratified analyses by therapy group and stepwise logistic regression analysis were used to identify predictors of HP. This pooled analysis confirms that FCM is associated with increased rates of serum PO43− lowering, but mean serum PO43− values were seen to recover at Week 4 and further recover at Week 8. Among all subjects receiving FCM therapy (n = 6879), 41.4% (n = 2847) reached a PO43− nadir value <2.5 mg/dL at any point on study and 0.7% (n = 49) reached a nadir <1 mg/dL. Although gastroenterology and women’s health subjects were identified to be at higher risk, occurrence of severe HP (<1 mg/dL [0.3 mmol/L]) following FCM administration was not observed to be common among subjects in these studies. Furthermore, there was no correlation between laboratory serum PO43− values and the occurrence of reported adverse events related to low PO43− levels.
... The parathormone may be normal or elevated in the context of hyperparathyroidism secondary to the vitamin D deficiency. 1 All of these findings are associated with the production of FGF23 by the tumor cells, affecting the renal tubules and increasing the phosphate kidney excretion, in addition to reducing the production of 1.25(OH)-D. 4 However, as a result of the analytical findings, a differential diagnosis should be made with other causes of hereditary or acquired hypophosphatemic osteomalcia, 5 including toxins (alumina, arsenic), medications (IV iron, nucleotide-analogue antiretrovirals) and Fanconi syndrome, 1,6,7 which were all ruled out in this patient following the study of aminoaciduria, glucosuria and arterial blood gases, which were all normal. Other hereditary conditions resulting from excessive FGF23, such as autosomal dominant hypophosphatemic osteomalacia, chromosome Xrelated HO or the autosomal recessive type, all present identical biochemical findings to OO, 4 but the onset of the disease in adulthood, the symptoms of proximal muscle weakness and pain in the lower extremities, as well as the absence on family history or prior metabolic disorders, ruled out this possibility in our case. ...
Oncogenic osteomalacia is a paraneoplastic metabolic syndrome characterised by a low phosphates in the blood due to renal phosphate losses with inadequately normal or low vitamin D levels. This disorder is associated with the release of tumour cell-secreted phosphaturic factor, most notably fibroblast growth factor 23 (FGF-23). The neoplasms related to oncogenic osteomalacia are usually small tumours of mesenchymal lineage, and they may be difficult to locate in the physical examination in some cases, due to their size and inaccessible location. The case is presented of a patient who developed vertebral and hip fractures due to oncogenic osteomalacia associated with a phosphaturic mesenchymal tumour of the deep fat tissue in the sole of the foot. This was finally diagnosed after 3 years of the onset of symptoms after being located by bone scintigraphy with Indium 111-labelled pentetreotide and magnetic resonance imaging.
