Renal Phosphate Research Articles

Hypophosphatemia in acute liver failure of a broad range of etiologies is associated with phosphaturia without kidney damage or phosphatonin elevation

Hypophosphatemia is a common and dangerous complication of acute liver failure (ALF) of various etiologies. While various mechanisms for ALF-associated hypophosphatemia have been proposed including high phosphate uptake into regenerating hepatocytes, acetaminophen (APAP)-associated hypophosphatemia was linked to renal phosphate wasting, and APAP-induced renal tubular injury was proposed as underlying mechanism. We studied 30 normophosphatemic and 46 hypophosphatemic (serum phosphate < 2.5 mg/dL) patients from the Acute Liver Failure Study Group registry with APAP- or non-APAP-induced ALF. Since kidney injury affects phosphate excretion, patients with elevated serum creatinine (>1.2 mg/dL) were excluded. Maximal amount of renal tubular phosphate reabsorption per filtered volume (TmP/GFR) was calculated from simultaneous serum and urine phosphate and creatinine levels to assess renal phosphate handling. Instead of enhanced renal phosphate reabsorption as would be expected during hypophosphatemia of non-renal causes, serum phosphate was positively correlated with TmP/GFR in both APAP- and non-APAP-induced ALF patients (R2=0.66 and 0.46, respectively; both P < 0.0001), indicating renal phosphate wasting. Surprisingly, there was no evidence of kidney damage based on urinary markers including neutrophil gelatinase-associated lipocalin and cystatin C even in the APAP group. Additionally, there was no evidence that the known serum phosphatonins parathyroid hormone, fibroblast growth factor 23, and α-Klotho contribute to the observed hypophosphatemia. We conclude that the observed hypophosphatemia with renal phosphate wasting in both APAP- and non-APAP-mediated ALF is likely the result of renal tubular phosphate leak from yet-to-be identified factor(s) with no evidence for proximal tubular damage or contribution of known phosphatonins.

Fibroblast Growth Factor-23 Secreting Tumour Induced Osteomalacia

Tumour Induced Osteomalacia (TIO) caused by a Fibroblast-Growth- Factor-23 (FGF-23) secreting tumour is a rare paraneoplastic disorder. Patients often present with non-specific complaints of pain and stiffness however findings of hypophosphataemia and inappropriately suppressed 1,25 dihidroxyvitamin D are almost pathognemonic of this condition. We present a previously healthy 51-year-old man who presented with an 18 month history of body aches, hypophosphataemia, and an incidental finding of atraumatic foot fractures on x-ray. Technetium bone scan identified diffuse skeletal pathologic fractures. He was further found to have persistent hypophosphataemia, suppressed 1-25-dihidroxyvitamin-D, renal phosphate wasting with reduced Tubular Reabsorption of Phosphate (TRP), and an FGF-23 level more than twice the upper limit of normal. Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET), Gallium-68 Dotatate PET and magnetic resonance imaging further identified and characterised a 40 mm FDG and Dotatate-avid lesion in the right third rib. Histopathological examination of a biopsy specimen revealed phosphaturic mesenchymal tumour with positive FGF-23 immunohistochemical staining arising in a background consistent with osteomalacia. After tumour resection, the patient’s hypophosphataemia, reduced TRP and elevated FGF- 23 normalised and he made an excellent recovery with rehabilitation. This case report illustrates the importance of a diagnosis of hypophosphataemia in a patient with musculo-skeletal aches and alerts clinicians of the differential diagnosis of TIO.

The Metabolic Bone Disease X-linked Hypophosphatemia: Case Presentation, Pathophysiology and Pharmacology.

The authors present a stereotypical case presentation of X-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact fibroblast growth factor 23 (FGF23) which lead to (i) low serum phosphate levels, (ii) increased fractional excretion of phosphate, and (iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in patients with XLH is due to chronic hypophosphatemia. Additionally, patients with XLH experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.

Renal Phosphate Wasting Due to Tumor-Induced (Oncogenic) Osteomalacia

Osteomalacia is a widely prevalent bone disorder that is caused by an imbalance in body calcium and phosphate. Tumor-induced osteomalacia (TIO) is a rare form of osteomalacia that is associated with mesenchymal tumors. It is caused by overproduction of fibroblast growth factor 23 (FGF-23), a hormone involved in phosphate regulation.A 59-year-old male with a history of factor V Leiden mutation, pulmonary embolism, and deep vein thrombosis was diagnosed with oncogenic osteomalacia in 2008 following laboratory findings significant for low phosphorus and elevated FGF-23 levels. He underwent a resection of a right suprascapular notch mass with the biopsy confirming a phosphaturic mesenchymal tumor. He was maintained on oral phosphorus and calcitriol replacements with a regular follow-up with oncology and nephrology. Eight years later, the patient’s phosphorus levels started declining despite replacement. A repeat test showed FGF-23 levels once again elevated. A whole-body magnetic resonance imaging (MRI) scan showed no significant findings. The patient was continued on oral replacement therapy with a close follow-up. Two years later, urine phosphorus excretion was elevated at 2494 mg per 24 hours with low plasma phosphorus (1.2 mg/dL) and an elevated FGF-23 level of 1005 relative units (RU)/mL. A repeat MRI of the right shoulder revealed a mass in the supraspinatus muscle and another in the spinal glenoid notch. The masses were resected and the biopsy was consistent with a recurrence of the phosphaturic mesenchymal tumor. Follow-up serum phosphate levels remained in the normal range.FGF-23 plays a critical role in bone mineralization through the regulation of phosphate levels. Overproduction, as seen in mesenchymal tumors, results in hyperphosphaturia, hypophosphatemia, and low calcitriol levels. While the definitive treatment of TIO involves the resection of the mesenchymal tumor, localization of the tumor is often challenging given its small size and slow growth. This leads to delayed diagnosis and treatment. For individuals whose tumor cannot be resected or detected, burosumab is the preferred form of therapy. Interestingly, FGF-23 is shown to have a potential cardiovascular (CV) morbidity and mortality through various mechanisms like activation of myocardial FGF-23 receptors, endothelial dysfunction, inflammation, and altered phosphorus and vitamin D metabolisms. While studies have shown possible FGF-23 effects on CV outcomes in patients with chronic kidney disease, this has not been proven in cases of TIO.

Clinical and Genetic Characteristics of 153 Chinese Patients With X-Linked Hypophosphatemia.

X-linked hypophosphatemia (XLH) is caused by inactivating mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, resulting in an excess of circulating intact fibroblast growth factor-23 (iFGF-23) and a waste of renal phosphate. In the present study, we retrospectively reviewed the clinical and molecular features of 153 Chinese patients, representing 87 familial and 66 sporadic cases with XLH. A total of 153 patients with XLH presented with signs or symptoms at a median age of 18.0 months (range, 9.0 months–26.0 years). Lower-limb deformity was the most frequent clinical manifestation, accounting for 79.1% (121/153). Biochemical screening showed increased serum levels of iFGF23 in patients with XLH, with a wide variation ranging from 14.39 to 730.70 pg/ml. Median values of serum iFGF23 in pediatric and adult patients were 94.87 pg/ml (interquartile range: 74.27–151.86 pg/ml) and 72.82 pg/ml (interquartile range: 39.42–136.00 pg/ml), respectively. Although no difference in circulating iFGF23 levels between these two groups was observed (P = 0.062), the proportion of patients with high levels of circulating iFGF23 (>42.2 pg/ml) was greater in the pediatric group than in the adult group (P = 0.026). Eighty-eight different mutations in 153 patients were identified, with 27 (30.7%) being novel. iFGF23 levels and severity of the disease did not correlate significantly with truncating and non-truncating mutations or N-terminal and C-terminal PHEX mutations. This study provides a comprehensive description of the clinical profiles, circulating levels of iFGF23 and gene mutation features of patients with XLH, further enriching the genotypic spectrum of the diseases. The findings show no evident correlation of circulating iFGF23 levels with the age or disease severity in patients with XLH.

Intravenous Iron-Induced Hypophosphatemia: An Emerging Syndrome.

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.

FC 018HIGH DIETARY PHOSPHATE INTAKE AND INTRA-CARDIAC SYNTHESIS OF FIBROBLAST GROWTH FACTOR 23 SYNERGISTICALLY WORSEN CARDIAC FUNCTION

Abstract Background and Aims Left ventricular hypertrophy (LVH) is a major complication of CKD and associates with increased levels of the phosphaturic hormone fibroblast growth factor (FGF) 23. FGF23 induces hypertrophic growth of cardiac myocytes in vitro and LVH in rodents, suggesting that FGF23 can directly affect the heart. Besides the bone, cardiac myocytes express FGF23, too, and recent studies demonstrate that its expression is increased in cardiac and kidney injury, suggesting that cardiotoxicity of FGF23 may be at least partly due to the paracrine effects of heart-derived FGF23. However, it is still questioned whether elevated FGF23 per se is able to induce pathologic alterations in the heart or whether additional factors in CKD, such as Klotho deficiency or hyperphosphatemia are required for FGF23 to tackle the heart. By generating a mouse model with cardiac-specific overexpression of FGF23 via myocardial gene transfer using adeno-associated virus (AAV), we elucidated the cardiotoxic properties of elevated FGF23 in (1) unchallenged mice, unbiased of alterations usually associated with CKD, and (2) in the presence of high dietary phosphate intake, mimicking the exposure of enhanced serum phosphate. Method First, an adeno-associated virus that expresses murine Fgf23 (AAV-Fgf23) under the control of the cardiac troponin T promotor was injected subcutaneously into eight-week-old male C57BL/6 wildtype mice. After four months, cardiac function and geometry was assessed by cardiac magnetic resonance imaging (MRI) and echocardiography and heart tissue was analysed by qPCR, immunoblot and histological analyses. The biological activity of AAV-Fgf23-derived cardiac Fgf23 was determined using isolated neonatal rat ventricular myocytes (NRVM) in vitro. Second, AAV-Fgf23 and control mice were fed a 2% high phosphate diet (HPD) or a 0.8% normal phosphate diet (NPD) and cardiac phenotype was investigated after six months. Results AAV-Fgf23 mice showed increased cardiac-specific Fgf23 expression and synthesis of intact Fgf23 (iFgf23) protein in the heart resulting in enhanced circulating iFgf23 compared to control. Serum of AAV-Fgf23 mice stimulated hypertrophic growth of isolated NRVM and induced pro-hypertrophic gene expression in vitro, indicating that cardiac iFgf23 is biologically active. Likewise, AAV-Fgf23 mice revealed an activation of renal FGFR1/Klotho/MAPK signalling and subsequent down-regulation of renal sodium phosphate transporters NaPi-2a and NaPi-2c, causing reduced tubular phosphate reabsorption. Nevertheless, in unchallenged AAV-Fgf23 mice, impaired cardiac function, LVH and LV fibrosis were lacking. In contrast, HPD stimulated the bone expression of Fgf23 in both AAV-Fgf23 and Ctrl mice, while intra-cardiac Fgf23 mRNA levels were only increased in both AAV-Fgf23 groups irrespective of NPD or HPD. However, HPD in AAV-Fgf23 mice promoted O-glycosylation of cardiac iFgf23, suggesting stabilization of biologically active Fgf23 protein. Echocardiography showed impaired cardiac function in AAV-Fgf23 on HPD compared to its NPD group, demonstrated by enhanced end-systolic and end-diastolic volumes, increased systolic and diastolic LV diameters as well as enlarged LV inner diameters, respectively. Pressure-volume analysis using Millar catheter showed higher end-systolic and end-diastolic blood pressure (ESP, EDP) in AAV-Fgf23 mice on HPD compared to NPD. HPD in Ctrl only enhanced EDP, although this did not reach the level of statistical significance. Conclusion Chronic exposure to biologically active cardiac iFgf23 per se does not tackle the heart, while high intra-cardiac Fgf23 synthesis in the presence of high dietary phosphate promotes cardiotoxicity of Fgf23, which could pose a significant health risk to the general population.

MO1034PHOSPHATE EQUIVALENT (PEQ) EDUCATION SYSTEM: AN EFFICIENT SELF-ADJUSTMENT PHOSPHATE BINDER DOSAGE TOOL IN DIALYSIS PATIENTS

Abstract Background and Aims Hyperphosphatemia is common in end-stage renal disease (ESRD) because of impaired renal phosphate excretion and is treated by dietary measures, dialysis techniques and the use of phosphate binder medication. It is one of the most important cardiovascular risk factors for dialysis patients. Our goal was to involve dialysis patients in the achievement of phosphate targets by self-adjusting the dose of Phosphate Binders (PB) on a meal-to-meal basis, according to the individual dietary P intake Method We conducted an interventional prospective single-arm study with a pre-post design. The inclusion criteria were patients with ESRD who had been receiving dialysis for more than three months, with dialysis schedule for four hours per session, three times per week, and who were older than 18 years of age. The primary endpoints of the study were the number of patients who reached the goal of serum phosphate before and after the training program and the weekly mean serum phosphate levels evaluated after the intervention period and compare them with the pre-intervention baseline levels. The secondary end-point was the burden of PB daily. All patients were trained in a self-administer PB program. A self-adjusted PB dose card was developed based on the phosphate food content list published by the National Technical University of Athens. The aim was to allow patients to immediately calculate the iP content of any food they consume easily. Phosphate Equivalent (PEQ) was defined as the weight of phosphorus having the same phosphate impact as a given weight of food. One PEQ corresponded in 100 mg of inorganic phosphorous and to one tablet of PB (one tablet of 800 mg of sevelamer). After 4 weeks (weeks 1-4) of washout from previous phosphate binders, eligible patients with serum phosphorus concentrations ≥ 6 mg/dl were included in the study. All patients received standard dietary phosphate counseling and a fixed dosing regimen of sevelamer PB was prescribed according to KDIGO and dialysis unit protocols for eight weeks (weeks 5-12 – pre-intervention period) In the 13th week, patients were asked to practice the self-administer PB program for eight more weeks. Results A total of 97 patients were screened for the study. 21 patients were excluded. 74 patients completed the study. The percentage of patients with uncontrolled phosphate levels reduced from 56.76% (42 out of 74) to 36.48 % (27 out of 74) in the post-intervention period. Of 9 patients who initially had a serum phosphorus level ≥9 mg/dl, 8 were reverted to phosphorus levels &amp;lt; 6 mg/dl at the end of the PEQ intervention period. There was a significant reduction of phosphate levels (prePEQ 7.42 ± 1.43 mg/dl vs. postPEQ 5.59 ± 1.82 mg/dL, p=0.036) and Ca × P levels (prePEQ: 67.1 ± 11.5 mg2/dL2; postPEQ: 51.9 ± 13.4 mg2/dL2, p=0.021) after patient education. There was a non-significant increase on serum calcium (pre PEQ: 8.13 ± 1.18 mg/dL; post PEQ: 8.56 ± 0.83mg/dL, p=0.515) and iPTH (prePEQ: 411 ± 376 pg/mL; postPEQ: 381 ± 321 pg/mL,p=0.13) Conclusion Our work shows that providing the patients with a relatively simple tool about the use of phosphate binders as PEQ is, we had a positive effect on the dialysis patients’ knowledge about the use of PB, phosphate content of their meals, and increase their sense of the necessity of the treatment and it was proved more effective than the standard fixed dose method. Using the PEQ education system was rewarding in an additional 20% of the patients with previous uncontrolled hyperphosphatemia. The PEQ education system is an efficient self-adjustment phosphate binder dosage tool in dialysis patients in reducing the serum phosphate level in our hemodialysis patients.

FC 004PHOSPHATE FACILITATES PHOSPHATURIA BY PIT-2-MEDIATED ACTIVATION OF ERK1/2 SIGNALLING INTERNALIZING NAPI-2A FROM THE APICAL BRUSH BORDER MEMBRANE INDEPENDENT OF FGF23

Abstract Background and Aims Increased phosphate load stimulates the secretion of fibroblast growth factor (FGF) 23 in the bone leading to decreased phosphate reabsorption in the kidney. FGF23 activates FGFR1/Klotho/ERK1/2 signalling in proximal tubule cells to suppress type II sodium phosphate transporters NaPi-2a and NaPi-2c in the apical brush border membrane (BBM) resulting in lower serum phosphate levels. The type III sodium-dependent phosphate transporters PiT-1 and PiT-2 are expressed in key organs of phosphate regulation and were shown to activate ERK1/2 in osseous cells in the presence of high extracellular phosphate. Furthermore, PiT-2 was shown to be responsible for the phosphate-dependent FGF23 secretion in bone cells. Whether phosphate itself can be sensed by kidney cells and stimulate its own excretion remains unknown. The aim of our study was to examine the molecular mechanism regulating renal phosphate transport in the setting of chronic oral phosphate loading in mice and to analyse phosphate sensing as well as phosphaturic actions of phosphate itself independent of FGF23. Method First, eight-week-old male C57BL/6 wildtype mice were fed a 2% high phosphate diet (HPD) or a 0.8% normal phosphate diet (NPD). Mice were sacrificed after six months and blood and urine were collected to determine parameters of phosphate homeostasis. Kidneys were isolated to evaluate the HPD-induced regulation of phosphate transporters by qPCR, immunoblot and histological analyses. Second, murine proximal tubule (mPT) cells were stimulated with either phosphate or FGF23 in the presence or absence of Foscarnet, as an inhibitor of phosphate transporters, to verify the molecular mechanism of phosphate sensing. Results Although, HPD caused significantly elevated circulating levels of intact FGF23 which resulted in hyperphosphaturia, serum phosphate levels were still enhanced compared to NPD-fed mice. Renal Klotho protein expression was significantly reduced in HPD mice and histological staining demonstrated lower Klotho accumulation in proximal and distal tubule cells, while FGFR1 was not altered. The FGF23/Klotho/FGFR1 downstream pathway revealed neither a clear activation of the ERK1/2 signalling pathway nor induction of the transcription factor Egr-1 due to HPD. Nevertheless, NaPi-2a mRNA expression was significantly reduced in HPD-fed mice compared to NPD group and NaPi-2c was unchanged. The amount of NaPi-2a protein in isolated BBM vesicles of HPD-fed mice was lower compared to NPD and immunofluorescent staining confirmed the internalisation of NaPi-2a from the apical BBM. Among the type III sodium-dependent phosphate cotransporters, renal PiT-1 mRNA expression was not altered in HPD-fed mice, but PiT-2 was significantly increased compared to NPD group and immunofluorescent staining revealed an enhanced localization of PiT-2 on the basolateral membrane of proximal tubule cells. Stimulation of mPTs with phosphate or FGF23 increased the expression of PiT-2, induced the phosphorylation of ERK1/2 and decreased NaPi-2a in vitro. The pre-treatment with Foscarnet blunted the phosphate-mediated activation of ERK1/2 signalling pathway, but not the FGF23-induced effects, suggesting a direct phosphate transporter-regulating mechanism of high phosphate in renal proximal tubule cells. Conclusion A chronic high dietary intake of phosphate results in downregulation of renal Klotho causing hyperphosphatemia, suggesting in part a renal resistance of FGF23/Klotho signalling pathway. However, HPD-induced internalization NaPi-2a from the apical BBM pointing to an FGF23-independent mechanism regulating phosphate reabsorption. Our data indicate that in the settings of high phosphate-mediated renal resistance of FGF23, phosphate itself may stimulate its urinary secretion via PiT-2-mediated activation of ERK1/2 signalling pathway which results in NaPi-2a downregulation and hyperphosphaturia independent of FGF23.

Abstract #1003217: A Case of X-Linked Hypophosphatemic Rickets with Tertiary Hyperparathyroidism

X-linked hypophosphatemic rickets is a disorder characterized by renal phosphate wasting and subsequent bone demineralization. It is caused by a loss of function mutation of the phosphate regulating endopeptidase gene on the X chromosome leading to an increased production of fibroblast growth factor 23 (FGF23). Increased FGF23 inhibits phosphate reabsorption in the kidney. The resulting hypophosphatemia leads to bone demineralization and rickets. Standard treatment includes phosphate supplementation which lowers ionized calcium concentration eliciting an upregulation of parathyroid hormone (PTH). Progression to tertiary hyperparathyroidism due to development of autonomous hyperfunction of the parathyroid glands has been reported. We present a rare case of X-linked hypophosphatemic rickets with tertiary hyperparathyroidism.

Une fuite rénale de phosphates complexe…

We describe here the case report of a young man of 34-years old suffering from a haemorrhagic rectocolitis and presenting with marked hypophosphatemia secondary to an infusion of ferric-carboxymaltose. The renal phosphate wasting was asserted by a very low renal maximal reabsorption rate of phosphate associated with a high plasma FGF-23 level. Three months later we explored the patient and his father since we learnt that both of them had suffered from kidney stones for years with marked hypercalciuria. Kidney stones were composed of weddellite and carbapatite. We suspected a familial phosphate renal wasting syndrome but however no mutation of the renal phosphate carriers could be identified.

Fix That PHEX Loss

Phosphorous has a critical role in multiple biological functions in the body, such as skeletal mineralization, and an imbalance of this can lead to several musculoskeletal disorders. An important regulator of renal phosphate excretion is fibroblast growth factor 23 (FGF23) which is produced by osteocytes and osteoblasts themselves thus providing a mechanism for the skeletal system to influence its own mineralization needs. PHEX is a gene that regulates FGF23 secretion therefore a loss-of-function mutation in this gene would result in elevated circulating FGF23 and phosphate depletion. This mutation has been identified as a cause for X-linked hypophosphatemia (XLH). Treatment of XLH has been limited and mainly involved phosphorous replacement in combination with 1,25(OH) vitamin D. Antiresorptive osteoporosis treatment can exacerbate the skeletal mineralization process. Here we present a patient with multiple fractures who was on denosumab treatment for presumed osteoporosis before being found to have PHEX mutation. The patient is a 64 year-old female with past medical history of bilateral hip replacement and recurrent femur fractures who was seen in clinic in 2014 due to recurrent fractures and diagnosis of osteoporosis since early 2000s. She had only tried alendronate up until that point. Due to the recurrent fractures she was switched to denosumab therapy while workup was underway for secondary causes. She was found to have low phosphorous levels and elevated FGF23 therefore genetic counseling was pursued and was recommended to check for PHEX mutation. The testing came back positive for loss-of-function mutation in PHEX, and by that point she had received 3 doses of denosumab therapy. She suffered another femoral fracture which was determined to be an atypical fracture, and therefore denosumab treatment was stopped and she was continued on phosphorous replacement as well as 1,25(OH) vitamin D replacement. Most recently her phosphorous levels have been controlled with therapy, and there is current discussion underway to try burosumab, an antibody to FGF23. During evaluation for osteoporosis, it is important to consider phosphorous roles in skeletal mineralization. If recurrent fractures are seen in a patient with low phosphorous levels, especially while they are on conventional antiresorptive osteoporosis medications, genetic testing for PHEX mutations should be considered as well as safely stopping antiresorptive medications.

Diagnostic Dilemma of Elevated FGF23 in a Patient With Osteomalacia: A Case Report

Introduction: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome due to FGF23 hypersecretion. It is mostly seen with benign mesenchymal tumors. Establishing the diagnosis could be challenging due to occult nature of the disease. Case: A 54-year-old female presented with right thigh and upper back pain. On presentation, she had hypophosphatemia (1.8 mq/dl), low 25-hydroxyvitamin D (23 ng/ml), normal ionized calcium and normal iPTH (53 pg/mL). CT scan showed healing right 10th rib fracture and right proximal femoral fracture. DEXA scan was remarkable for osteoporosis. 99m-Technetium nuclear bone scan displayed hyperactivity on bilateral femurs and multiple ribs concerning for stress fractures. Patient was thought to have osteomalacia from vitamin D insufficiency and started on ergocalciferol. Two months later, patient was diagnosed with invasive ductal carcinoma. She had unilateral mastectomy and adjuvant chemotherapy. Surveillance studies were negative for recurrence. Patient lost to follow up for 2 years until she returned with right hip and upper back pain. Her labs showed hypophosphatemia (1.2 mg/dL), normocalcemia, elevated iPTH (131 pg/mL), low 25-hydroxyvitamin D (26 ng/ml), low normal 1,25-dihydroxyvitamin D (25 pg/ml, normal: 18 -72) and elevated FGF23 (285 RU/ml, normal level <180). 24-hour urine studies showed phosphate of 330 mg and fractional phosphate excretion (FEPO4) of 12%. Nuclear bone scan reported subacute fractures in left 11th and right 6th ribs and right proximal femur. TIO was entertained as the unifying diagnosis. She was started on calcium, phosphate, ergocalciferol and calcitriol. Localizing studies with a PET scan showed FDG hyperactivity in the right vocal cord. Subsequent MRI showed asymmetric fat tissue between esophagus and left common carotid artery concerning for lipoma. She lost to follow up again during COVID-19 pandemic. Discussion: We present a case of elevated FGF23 with renal phosphate wasting concerning for TIO. This case represents the diagnostic dilemma of elevated FGF23 as well as difficulty in discerning the source in TIO. Although exact tumor source remained unclear in our patient, adipose tissue in the thoracic inlet was a potential culprit. Elevated FGF23 leads to urinary phosphate wasting and inhibition of 1α- hydroxylase. Daily urine phosphate excretion > 100 mg or FEPO4 > 5 % strongly suggest renal phosphate wasting. TIO and iron-induced hypophosphatemia are two most common acquired causes of high FGF23. TIO is mostly caused by benign soft tissue and bone tumors. It can take years to establish the diagnosis due to small size and obscure location of the tumors. Advanced investigation with FDG-PET, 68Ga-DOTATATE scan, octreotide scan and venous sampling of FGF23 can aid in diagnosis. Tumor resection is usually curative. Burosumab (anti-FGF23 monoclonal antibody) can be considered when the tumor is not amenable to resect.

Sternal Phosphaturic Mesenchymal Tumor-Induced Osteomalacia, Diagnosis and Management: A Case Report

Background: Tumor induced osteomalacia (TIO) is a rare paraneoplastic disorder in which overproduction of fibroblast growth factor-23 (FGF-23) by mesenchymal tumor results in decreased renal phosphorus reabsorption and low to inappropriately normal 1,25-dihydroxyvitamin D, leading to hypophosphatemia and osteomalacia. Patients often present with bone pain, fractures, muscle weakness, and progressive decline in mobility. Due to the nonspecific nature of presenting symptoms of TIO diagnosis is often delayed. Clinical Case: A 55-year-old male presented with complaints of chest pain, shortness of breath, and generalized weakness following a ground level fall. Patient also reported a 10-year history of osteoarthritis with chronic back pain and 1-year history of generalized weakness, resulting in significant decline in functional status. On work-up, the initial CT scan of chest revealed multiple fractures including ribs, manubrium, scapula, and pubic rami. Subsequent biochemical evaluation was remarkable for hypophosphatemia to low of 1.3 mg/dL (2.4 - 5.0 mg/dL), low of 1,25-dihydroxyvitamin D of 13.1 pg/ml (19.9 - 79.3 pg/mL), reduced tubular phosphate reabsorption rate of 28% (normal > 80%) ratifying for renal phosphate wasting, normal iPTH level, and elevated serum FGF-23 level of 460 (normal < 180). Then, localization imaging for TIO was performed. After PET/CT scan showing increased uptake at the sternal area suggestive of lytic metastasis, subsequent CT angiogram of the chest identified mottled, irregular, mildly expansile appearance of the sternal manubrium. Sternal biopsy revealed phosphaturic mesenchymal tumor with positive FGF 23 mRNA expression. Surgical resection was delayed due to poor functional status and concurrent discovery of an EBV-positive nasopharyngeal carcinoma. Prior to surgery patient was treated with phosphorus and calcitriol supplements. Post-operatively serum phosphorus and FGF-23 levels were normalized. Patient also improved clinically. Patients treatment course was complicated by secondary hyperparathyroidism; however, this improved following surgery. Conclusion: Diagnosis of TIO can be delayed due to its nonspecific symptoms. Thus, in patients with chronic bone pain, muscle weakness, and atraumatic fractures, TIO should be kept on the differential and these patients should undergo thorough biochemical and imaging evaluation. Tumor localization could be challenging. Patients should be managed with supplements of active vitamin D and phosphorus with goal to normalize phosphorus level to prevent further bone demineralization prior to surgery. However, surgical intervention remains the mainstay of management as this is curative of TIO.

A Challenging Case of Phosphaturic Mesenchymal Tumor With Primary Hyperparathyroidism

Background: Localization of tumor-induced osteomalacia (TIO) is often challenging. Primary hyperparathyroidism (HPT) following curative surgery for TIO is rarely reported. Clinical Case: A 49-year-old man presented with fragility rib fractures, generalized bone pain, and muscle weakness worsening over the past 3 years. Rheumatologic workup was negative. Initial tests showed elevated levels of parathyroid hormone (PTH) 114.1 pg/mL (14–72 pg/mL) and alkaline phosphatase (ALP) 283 IU/L (44–174 IU/L), reduced levels of 25(OH)D 16 ng/mL (30–100 ng/mL), 1,25(OH)2D 9 pg/mL (18–72 pg/mL), and phosphorus 1.6 mg/dL (2.5–4.9 mg/dL), calcium levels of 9.2 mg/dL (8.5–10.1 mg/dL), and eGFR 58 mL/min/1.73 m2. A sestamibi scan showed normal parathyroid uptake. The diagnosis was secondary HPT due to chronic kidney disease and vitamin D deficiency. The patient was treated with D3 and phosphate. During a 2-year follow-up, the patient reported improvement of pain and weakness with no additional fractures. Further investigations showed persistent hypophosphatemia with elevated urinary fractional phosphate excretion (44%, ref. <20%), indicating renal phosphate wasting. Fibroblast Growth Factor 23 (FGF23) was high, 291 RU/mL (0–180 RU/mL). DXA results were consistent with osteopenia. TIO was suspected. At a 3-year follow-up, investigations included three whole-body 18F-FDG PET-CT scans revealing several areas suspicious for tumor presence. However, multiple MRIs were inconclusive. Laboratory tests showed persistent hypophosphatemia (despite D3 and phosphate treatment), elevated FGF23 (1330 RU/mL) and PTH (274.4 pg/mL), and normal calcium, 25(OH)D, and 1,25(OH)2D. The patient subsequently underwent 68Ga DOTATATE PET-CT, which revealed a somatostatin receptor-positive lesion involving the left upper lobe of the lung. The mass was resected without complications. Histopathology was compatible with a phosphaturic mesenchymal tumor. At a 6-month postoperative follow-up, the patient reported dramatically improved symptoms with decreased weakness and pain, normal phosphate, calcium, ALP, and FGF23 (160 RU/mL) levels, while DXA results were significantly improved. Phosphorus supplementation was discontinued. At follow-up 3 years post-surgery, the patient had slowly rising PTH (126.3 pg/mL) and calcium (10.1–10.6 mg/dL) levels with normal phosphate, 25(OH)D, and FGF23 (174 RU/mL) levels. A diagnosis of primary HPT was made. Further evaluation was deemed unnecessary since the patient did not meet the criteria for surgical treatment. The development of primary HPT was considered mechanistically related to long-standing hypophosphatemia and hypovitaminosis D stimulating PTH production. Conclusion: This case report highlights the pitfalls contributing to delayed diagnosis of TIO and alerts clinicians to the potential development of primary HPT after curative surgery for TIO.

Intravenous Iron Induced Severe Hypophosphatemia

Introduction: Hypophosphatemia is a recently recognized adverse effect of certain intravenous iron formulations. It was previously thought to be asymptomatic and transient, however it can cause severe hypophosphatemia associated with renal phosphate wasting. We present a case of severe hypophosphatemia following intravenous ferric carboxymaltose administration. Clinical Case: A 40-year-old female with history of iron deficiency anemia, Hashimoto’s hypothyroidism and multinodular goiter status post thyroidectomy and obesity status post gastric sleeve presents to the hospital due to dizziness, generalized weakness, bone pain and severe myalgia right after 2nd dose of 750 mg of ferric carboxymaltose administration. She received 1st dose of 750 mg of ferric carboxymaltose a week ago prior to the presentation. She was found to have severe hypophosphatemia with a phosphorus level 1.0 mg/dl (2.4 - 4.8 mg/dl), hypocalcemia with calcium level at 8.7 mg/dl, normal PTH at 40 pg/ml and normal 25-OH Vitamin D level at 59.1 ng/ml. The fractional excretion of filtered phosphate (FEPO4) was 19.5%, supporting renal phosphate wasting. She was hospitalized for 5 days and received intravenous phosphate 45 mmol on hospitalization day 1, 15 mmol on day 2 and 30 mmol on day 3. She was discharged on K-phos Neutral 250 mg TID, Calcium carbonate/Vitamin D3 600 mg/500 IU 2 tablets TID and Calcitriol 0.5 mcg daily. While she was taking K-phos Neutral, Calcitriol and Calcium carbonate/Vitamin D3, her phosphorous level was down to 1.3 mg/dl, which was 4 weeks after 1st dose of ferric carboxymatose administration. She presented to the ED and received intravenous phosphate 15 mmol. She is currently taking K-phos Neutral 250 mg QID, Calcitriol 0.5 mcg daily and Calcium carbonate/Vitamin D3 600 mg/500 IU 2 tablets TID. Her phosphorous levels ranged at 2.5 - 3.0 mg/dl. Her bone pain and myalgia have gradually improved. Conclusion: Clinician should be aware of the side effect of hypophosphatemia following ferric carboxymaltose administration. Recent studies showed that incidence of hypophosphatemia associated with intravenous iron administration was significantly higher in ferric carboxymatose group compared with either iron isomaltoside group or ferumoxytol group. The impact of severe hypophosphatemia should be considered when choosing an intravenous iron medication.

Successful Medical Management of a Non-Localising Case of Tumour-Induced Osteomalacia

Introduction: TIO is a rare paraneoplastic syndrome characterised by renal phosphate wasting due to fibroblast growth factor-23 (FGF23) over-secretion from a phosphaturic mesenchymal tumour (PMT). While surgery is potentially curative, localisation is often challenging. Clinical Case: A 53 year old lady presented with recurrent fragility fractures in the spine (T10-L1, L4, S1-2), right femoral neck fracture and pelvic fractures at the bilateral superior and inferior pubic rami, associated with a 2 year onset of lower limb pain and proximal myopathy. Power was 2/5 proximally, rendering her progressively chairbound. She had no family history of fragility fractures. Biochemistry revealed hypophosphatemia of 0.48 mmol/l (NR 0.86–1.45 mmol/l), normal adjusted calcium of 2.32 mmol/l (NR 2.15–2.55 mmol/l), hyperphosphaturia (TmP/GFR 0.39 mmol/l, NR 0.88–1.42 mmol/l), mildly insufficient 25(OH)D level of 25 μg/l, inappropriately suppressed 1,25(OH)2D at 13 pg/ml (NR 18–78 pg/ml) and raised FGF23 at 484 RU/ml (NR<180 RU/ml). Localisation of the PMT was unsuccessful, despite multiple investigations including 68-Gallium-DOTANOC PET-CT, bilateral lower limb MRI for non-specific inguinal lymph nodes and various ultrasonographic evaluation of soft tissue lesions including biopsy of a benign breast tumour. Surgical removal of the breast papilloma did not affect FGF23 levels. In the absence of any suspicious lesion, selective venous sampling was not performed due to uncertain utility. She was treated medically, requiring 16mmol oral phosphate, 1000 IU cholecalciferol and 0.5mcg calcitriol daily, with a view to perform interval DOTA-peptide scan. Despite an increase in FGF23 to 760 RU/ml over 29 months, phosphate level was maintained in the low-normal range and alkaline phosphatase, as a marker of disease activity, normalised from 370 U/l to 92 U/l (NR 40-130U/l). Development of secondary hyperparathyroidism improved with uptitration of calcitriol. There was no hypercalciuria on monitoring of urinary calcium. Symptoms of generalised body pain resolved, and her bone mineral density (BMD) improved over 47 months of medical therapy. Power improved to 4/5, and she was able to ambulate with assistance. BMD at the femoral neck, total hip and lumbar spine increased by 68.2%, 44.6% and 65.2% respectively. Conclusion: This is a challenging case of TIO which has failed to localise despite best efforts. One must consider FGF23-independent and dependent causes of osteomalacia when patients present with severe frailty and hypophosphatemia as substantial morbidity results from delayed diagnosis and treatment. TIO-related PMTs can be difficult to localise, even with a combination of functional and anatomical imaging. With medical therapy, bone mineralisation and symptoms can improve significantly. Patients need to be monitored for complications of long-term phosphate and calcitriol replacement.

Tumor Induced Osteomalacia - Long Term Medical Treatment When Surgery Is Risky

Introduction: Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by bone pain, muscle weakness and fractures caused by production of a phosphaturic factor by rare mesenchymal bone or soft tissue tumors that causes isolated renal phosphate loss and osteomalacia. Low phosphate (iP), high bone alkaline phosphatase (BAP), and normal or low 125 dihydroxy D, are salient biochemical findings. Fibroblast derived growth factor (FGF 23) may be high or inappropriately normal. Gallium-68 Dotatate (DoT) imaging has become the imaging method of choice. Long term medical management may be required when removal of the tumor is risky or not feasable. Case Report: 65 yr old woman with carcinoid tumor of the right lung and a bony lesion in the T3 vertebral body diagnosed with TIO. She was initially screened for osteoporosis after traumatic rib fractures. Bone scan and SPECT-CT revealed numerous foci of increased uptake. She had elevated alkaline phosphatase 186 IU/L (0–140) and PTH 83 pg/ml (15–65) with a low phosphate 1.5 mg/dl (2.5–4.5), along with normal FGF23 level 102 RU/ml Ref Range < + 180 RU/ml. DoT and PET CT imaging for TIO evaluation showed a foci of increased uptake right lower lobe of her lung, and “osseous metastatic disease” in the right scapula, vertebral body, iliac, and pubic ramus. Sclerosis of T3 vertebral body was noted in the area of intense Gallium Dotatate uptake. Transbronchial excision of the lesion showed a well differentiated neuroendocrine carcinoma. Chromogranin A and 24 hour urine for 5HIAA were normal. She responded well to medical therapy with oral phosphate, calcium and calcitriol. Follow up, DoT and FDG PET showed persistent intense uptake in the sclerotic lesion on T3 vertebral body, while the rest of the hot spots resolved. Sclerotic T3 lesion is likely the primary lesion that is responsible for the TIO. Neuroendocrine tumor of the lung may be a mere association. Biopsy of the T3 lesion was not feasible and excision was considered risky to the patient. Discussion: Our case illustrates that awareness is the key to early diagnosis of TIO. FGF 23 in some TIO cases may be inappropriately normal in commercial assays and even in research labs. Measurement of fibronectin 1 (FN1) and FGF receptor 1 fusion gene which is noted in up to 60% of tumors are not commercially available. While DoT and PET CT are imaging modality of choice, CT and MRI may be useful to define the anatomy of the lesion. Long term medical management may be necessary when removal of primary lesion is not possible or risky. Most tumors are benign while some may prove to be malignant.

Hypophosphatémie et fer injectable : à propos d’un cas et revue de la littérature

Iron deficiency and iron-deficiency anemia are common medical conditions. Management of the etiology and iron supplementation are both necessary to treat this condition. Use of intravenous iron preparations is increasing due to its advantages over oral iron. Indeed, the total dose required can be provided in a single infusion, and it is more effective and increases hemoglobin levels more quickly than oral iron. Hypophosphatemia, sometimes severe, following intravenous iron administration, has been described in literature these past years, in particular with ferric carboxymaltose. We report here a case of severe hypophosphatemia with ferric carboxymaltose and carry out a literature review to determine the incidence of hypophosphatemia and to precise its clinical presentation, its pathophysiological mechanisms and its treatment. We found that hypophosphatemia is frequent with ferric carboxymaltose. Most of the time, there are no clinical manifestations, but cases of symptomatic osteomalacia have been described. Duration of hypophosphatemia is variable, from a few weeks to several months in case of prolonged administration. Hypophosphatemia owing to renal phosphate wasting is caused by an increase in intact fibroblast growth factor 23 (FGF-23) levels. However, the mechanism of ferric carboxymaltose- induced increase in intact FGF-23 is still unknown.

Switching from conventional therapy to burosumab injection has the potential to prevent nephrocalcinosis in patients with X-linked hypophosphatemic rickets.

X-linked hypophosphatemic rickets (XLH) is a congenital fibroblast growth factor (FGF)23-related metabolic bone disease that is treated with active vitamin D and phosphate as conventional therapies. Complications of these therapies include nephrocalcinosis (NC) caused by excessive urine calcium and phosphate concentrations. Recently, an anti-FGF23 antibody, burosumab, was developed and reported to be effective in poorly-controlled or severe XLH patients. This study aimed to reveal the impact of switching treatments in relatively well-controlled XLH children with the Rickets Severity Scale less than 2.0. The effects of the two treatments in eight relatively well-controlled XLH children with a mean age of 10.4 ± 1.9 years were compared retrospectively for the same treatment duration (31 ± 11 months) before and after the baseline. Actual doses of alfacalcidol and phosphate as conventional therapy were 150.9 ± 43.9 ng/kg and 27.5 ± 6.3 mg/kg per day, respectively. Renal echography revealed spotty NC in 8/8 patients, but no aggravation of NC was detected by switching treatments. Switching treatments increased TmP/GFR (p=0.002) and %TRP (p<0.001), and improved the high urine calcium/creatinine ratio to the normal range (p<0.001) although both treatments controlled disease markers equally. Additionally, low intact parathyroid hormone during conventional therapy was increased within the normal range by switching treatments. Our results suggest that a high dose of alfacalcidol was needed to control the disease, but it caused hypercalciuria and NC. We concluded that switching treatments in relatively well-controlled XLH children improved renal phosphate reabsorption and decreased urine calcium extraction, and may have the potential to prevent NC.