The Intricacies of Renal Phosphate Reabsorption-An Overview.

To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.

Tumour-Induced Osteomalacia-A Long Way to the Diagnosis Facilitated by [68Ga]Ga-DOTATATE PET/CT.

Background: Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome. Detecting the primary tumour in TIO is challenging using conventional imaging methods. This study assesses the efficacy of [68Ga]Ga-DOTATATE PET/CT in identifying the primary tumour. Methods: Six patients with suspected TIO underwent [68Ga]Ga-DOTATATE PET/CT. The patients' clinical history and biochemical parameters were analysed. Results: [68Ga]Ga-DOTATATE PET/CT successfully identified primary tumours in four patients (femoral bones for two, iliac bone for one, subcutaneous tissue of pubic region for one). Tumour removal led to clinical and laboratory improvement. In one patient, PET/CT showed rib uptake, but the biopsy was negative. One patient showed no tumour lesions on PET/CT despite clinical evidence. Two patients had focal recurrence at the primary tumour site, detected by follow-up PET/CT. Conclusions: [68Ga]Ga-DOTATATE PET/CT is a valuable tool for detecting primary tumours in TIO, aiding in accurate diagnosis and guiding surgery, leading to improved outcomes. Further research is needed to validate these findings and explore [68Ga]Ga-DOTATATE PET/CT in other paraneoplastic syndromes.

Extended curettage for tumour-induced osteomalacia in the bone.

BACKGROUND: extended curettage is generally used to treat infiltrative bone tumours. However, the extent of the curettage performed in previous studies remains unclear. This study aimed to investigate the efficacy of extended curettage for bone tumour-induced osteomalacia. METHODS: we included 12 patients with tumour-induced osteomalacia who underwent extended curettage at our hospital between 2000 and 2022. Extended curettage was applied in cases where tumour resection could cause functional impairment or necessitate complex reconstruction. We investigated patients' clinical and oncological outcomes. RESULTS: patients had a mean age of 55 (24-81) years, and the median follow-up duration after surgery was 3.9 (1.0-14.0) years. The causative tumours were located in the pelvis and lumbar spine. Imaging revealed the tumours to be of the sclerotic, intertrabecular, lytic and mixed types. Intraoperative 3D fluoroscopy was used in 10 patients. Extended curettage with high-speed burring and adjuvant therapy with cauterization using an electric scalpel and ethanol resulted in a remission rate of 83%; no recurrence or metastasis was observed in cases of early postoperative biochemical remission. In cases where the causative tumour was at the lumbar spine and ischium close to the acetabulum, no postoperative biochemical remission was observed, and conservative treatment was continued. Except for one patient with a tumour in the lumbar spine, all patients could walk without a cane. CONCLUSIONS: extended curettage for bone tumour-induced osteomalacia is oncologically and functionally favourable, especially in cases where resection of the causative tumour could cause functional impairment or necessitate complex reconstruction.

Tumor-induced osteomalacia: An overview.

Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin tumors with distinct pathological features, called 'phosphaturic mesenchymal tumors'. FGF23 is the most well-characterized of the phosphaturic factors. Tumors are often small and located anywhere in the body from head to toe, which makes the localisation challenging. Functional imaging by somatostatin receptor-based PET imaging is the first line investigation, which should be followed with CT or MRI based anatomical imaging. Once localised, complete surgical excision is the treatment of choice, which brings dramatic resolution of symptoms. Medical management in the form of phosphate and active vitamin D supplements is given as a bridge to surgical management or in inoperable/non-localised patients. This review provides an overview of the epidemiology, pathophysiology, pathology, clinical features, diagnosis, and treatment of TIO, including the recent advances and directions for future research in this field.

Oncogenic Osteomalacia: Challenges in Diagnosis.

To report a case of osteomalacia induced by a mesenchymal tumour in the head and neck region, in view of its rarity and classical late diagnosis. To review the literature on the usage of fluorodeoxyglucose-positron emission tomography-computed tomography (FDG PET-CT) and octreotide scanning in the localisation of the culprit tumour. An elderly male presented with a 7-year history of chronic muscle pain and weakness, to the extent of functional disability. FDG PET-CT was done which showed uptake in the region of the right anterior ethmoids. Endoscopic excision of the mass was done. However, the patient did not improve significantly. Subsequently, a DOTA-1-NaI3-octreotide (DOTANOC) scan was done which revealed a tumour in the region of the right medial rectus, excision of which was done. This time, the patient improved clinically and biochemically. The histopathology was phosphaturic mesenchymal tumour. A steady but definitive symptomatic improvement was noted in the postoperative period along with reversal of the deranged biochemical parameters, confirming the diagnosis of oncogenic osteomalacia. Octreotide-based PET-CT seems to be the most sensitive imaging modality in localising the tumours that cause oncogenic osteomalacia. However, FDG-based PET-CT still would be a good choice in centres where SSTR-based imaging facilities are not available.

[Multiple bone fractures caused by severe hypophosphatemia in the course of the mandible tumour].

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The effect of burosumab on intact and C-terminal FGF23 measurements.

OBJECTIVE: To investigate the effect of CRYSVITA® (burosumab-twza) on FGF23 measurements in an intact and a C-terminal immunoassay. METHODS: An intact serum FGF23 (MedFrontier) and a C-terminal plasma FGF23 assay (Immutopics) were used. Serum/plasma pools were spiked to span the burosumab therapeutic range (1.4-11.3 µg/ml) and FGF23 recovery was assessed. Patient serum and plasma samples obtained pre and post-burosumab treatment were evaluated on both assays and compared with corresponding phosphorus measurements RESULTS: Spiking burosumab (1.4-11.3 µg/ml) into sample pools resulted in a dose-dependent negative analytical interference on intact FGF23 measurements and no significant interference for C-terminal FGF23 measurements. However, more than a 500-fold median increase (post- vs. pre-burosumab administration) in in vivo FGF23 concentrations were observed by both assays. CONCLUSIONS: Therapeutic concentrations of burosumab result in a negative analytical interference of the intact, but not the C-terminal FGF23 immunoassay. Despite this in vitro analytical interference in the intact assay, relatively large elevations of both intact FGF23 and C-terminal FGF23 measurements were observed in vivo following burosumab administration. Following burosumab administration, FGF23 measurements must be interpreted within the clinical context of the patient and other relevant biomarker results. SUMMARY: This article describes a negative analytical interference by burosumab in an intact FGF23 immunoassay. The recovery of C-terminal FGF23 is not significantly affected by the presence of burosumab. In vivo, both assays demonstrate extreme FGF23 elevations in the presence of the drug. Furthermore, the measurement of FGF23 blocked by burosumab is not clinically useful regarding hypophosphataemia.

Unusual Presentation and Surgical Treatment of a Phosphaturic Mesenchymal Tumor in a Knee.

A 30-year-old woman presented to our hospital with an 11-year history of gradually enlarging masses around the left knee and 2-year history of progressively worsening bone pain. Tumor-induced osteomalacia (TIO), a rare paraneoplastic syndrome caused by phosphaturic mesenchymal tumors (PMTs) was suspected, but the postoperative pathology of her two operations was both reported as tenosynovial giant cell tumor (TGCT), making its diagnosis confusing. The possibility of hypophosphatemia, insufficient blood supply, innervation of the left lower limbs, as well as the unclear pathology, make it unreasonable to perform tumor-type knee prosthesis replacement directly. Finally, we placed static polymethylmethacrylate (PMMA) spacer at first, then when the concentration of blood phosphorus level rose to the normal range, the pathology was confirmed to be TIO, the blood supply and innervation was satisfying, tumor-type knee prosthesis replacement was performed. She was discharged post operative day 15 after the prothesis implantation without incident. One and a half years after her surgery, the concentration of blood phosphorus was still in the normal range, the symptom of systemic bone pain had improved significantly, the prosthesis was still in a good position and no recurrence was caught.

A literature review to understand the burden of disease in people living with tumour-induced osteomalacia.

This study reviews publications to describe the signs, symptoms and impact of tumour-induced osteomalacia (TIO) on patients' burden of disease. TIO is associated with a spectrum of signs and symptoms imposing a significant clinical burden, but the psychosocial impact of this rare disease has been poorly researched so far. INTRODUCTION: To describe the signs, symptoms and impacts of tumour-induced osteomalacia (TIO) and summarise the state of research on the burden of disease of this ultra-rare condition. METHODS: A targeted literature review was conducted in PubMed using pre-defined search terms. Relevant articles published between 1980 and 2021 were screened for inclusion. Seventy records were selected for analysis. Data were extracted and grouped into categories and sub-categories to identify recurrent signs, symptoms and impacts of TIO and describe the burden on patients. Chord diagrams were created to analyse the relationships between different TIO outcomes and characterise the presentation of TIO. RESULTS: Although the number of articles on TIO published have been increasing over the past 20 years, most studies were case reports and case series (n = 65/70) and only few were studies with higher quality of evidence (n = 5/70). Most articles were based on data reported by clinicians (n = 67/70). Patients with TIO experienced a combination of outcomes including chronic pain, weakness, skeletal-related manifestations and limitations in mobility. Only a few studies (n = 2/70) analysed the burden of TIO on the emotional wellbeing and on the work life of the patient. CONCLUSION: Patients with TIO present with a spectrum of signs and symptoms that impose a significant burden. The impact on the psychosocial wellbeing of patients should be further investigated, as this has been poorly researched so far. Studies with high quality of evidence should be designed to further the understanding of the burden of disease of TIO from the patient's perspective.

A mysterious case of recurrent fracture: Tumour-induced osteomalacia.

We report a case of tumour-induced osteomalacia in a 59-year-old man who presented with a long-standing history of myalgia, bone pain and pathological fracture of the bilateral femur at different intervals in the past 4 years. A biochemical evaluation revealed hypophosphatemia secondary to phosphaturia. Localization study by Ga-68 DOTANOC PET-CT for adult-onset hypophosphatemic osteomalacia revealed a tumour in the right femoral head. Resection of the tumour resulted in clinical improvement as well as normalization of biochemical parameters.

Extended Whole-body Ga-68 DOTATATE PET-CT in evaluating Tumour-Induced Osteomalacia: Case report and review of literature.

Tumour-induced osteomalacia is a rare paraneoplastic syndrome that manifests as chronic hypophosphataemia, non-specific bone pain and muscle weakness. It is generally caused by phosphaturic mesenchymal tumour (PMT), which is uncommonly associated with synchronous tumours. However, diagnosis is often delayed for several years due to the rarity, indolent growing nature and non-specific symptoms of the disease, often resulting in an overlook by clinicians during assessments. The patient initially presented with hypophosphataemia and generalised skeletal pain with multiple atraumatic fractures. Blood tests revealed serum calcium levels at the upper limit and extremely low inorganic phosphate levels. Herein, we report a case where two synchronous PMTs from two different sites were detected by 'extended' whole-body Ga-68 DOTATATE PET-CT, leading to remission of the disease after complete surgical removal. Early detection and diagnosis of PMT neoplasm is crucial, as complete surgical resection of this tumour is the only definitive treatment currently known. Upon excision, this curable disease will result in complete resolution of symptoms and blood parameters, leading to remission of the disease which significantly improves the patient's quality of life. PMT often over-expresses somatostatin receptors (SSTR), predominantly subtype 2A, and Ga-68 DOTATATE PET-CT is a selective SSTR imaging that targets this characteristic over-expression in these tumours. The high diagnostic accuracy of Ga-68 DOTATATE PET-CT should be the primary imaging modality for full evaluation of this disease.

Osteomalacia oncogénica secundaria a tumor mesenquimal fosfatúrico del pie / Oncogenic osteomalacia secondary to phosphaturic mesenchymal tumour of the foot

RESUMEN La osteomalacia oncogénica es un síndrome metabólico paraneoplásico caracterizado por hipofosfatemia debida a la pérdida renal de fosfato, con nivel bajo de vitamina D. Este trastorno está asociado con la liberación de factores fosfatúricos por células tumorales, especialmente el factor de crecimiento fibrolástico 23 (FGF23). Las neoplasias relacionadas con la osteomalacia oncogénica suelen ser tumores pequeños de linaje mesenquimatoso y pueden ser difíciles de localizar en algunos casos debido a su tamaño y ubicación poco accesible al examen físico. Presentamos a un paciente que desarrolló fracturas vertebrales y de cadera debido a osteomalacia oncogénica asociada con un tumor mesenquimatoso fosfatúrico del tejido graso profundo de la planta del pie, que finalmente se diagnosticó después de 3 años del inicio de los síntomas, cuando el tumor pudo ser localizado por el rastreo gammagráfico óseo con pentatreótido marcado con indio-111 y por las imágenes de resonancia magnética nuclear.

ABSTRACT 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.

Left maxillary sinus tumour-induced hypophosphataemic osteomalacia and combined with thyroid papillary carcinoma: a case report and literature review.

Tumour-induced osteomalacia (TIO) is a rare disease characterised by hypophosphataemia and clinical symptoms of osteomalacia. Herein we report the case of a 29-year-old man who was admitted to hospital with progressive bone pain and was diagnosed with TIO caused by maxillary sinus tumours. In the preoperative evaluation, it was found that the patient had thyroid malignant tumours at the same time. Two operations were performed separately on the left maxillary sinus tumour and thyroid tumour after complete examination. After tumour resections, the symptoms of bone pain were relieved and the level of blood phosphorus was restored, long-term replacement therapy was needed for thyroid. When a patient is diagnosed with TIO, it is necessary to screen for the presence of other malignant tumours and explore the treatment options in order to benefit patients preferably.

Lessons learnt from delayed diagnosis of FGF-23-producing tumour-induced osteomalacia and post-operative hungry bone syndrome.

Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by a fibroblast growth-factor-23 (FGF-23)-secreting phosphaturic mesenchymal tumour (PMT) and is characterised by hypophosphataemic osteomalacia. We present a 36-year-old man initially presenting with diffuse bone and joint pain who was inappropriately treated for presumed ankylosing spondylitis for 2 years. Whole-body bone scan suggested metabolic bone disease, prompting referral to our endocrine institution. He was subsequently diagnosed with persistent hypophosphataemia, inappropriately high renal tubular phosphate excretion, 1,25-dihydroxyvitamin D3 suppression, severe osteoporosis and severe osteomalacia. FGF-23 concentrations (140 ng/L) were raised 3-fold above the upper limit of normal. Initial Gallium-68 (68Ga) DOTATATE positron emission tomography (PET)/CT scan missed an active lesion in the left fibular head as the field only included the mid-brain to the proximal femora. Histopathology results from tumour resection confirmed a PMT over-expressing FGF-23. Serum phosphate and FGF-23 normalised immediately post-operatively. He developed severe hypocalcaemia 3-weeks post-operatively (1.77 mmol/L) which normalised after 1 month of high-dose caltrate and calcitriol therapy. Osteomalacia, osteoporosis and associated symptoms resolved during medium-term follow-up with >100% improvement in his bone mineral density. This case report and discussion highlights the pitfalls contributing to delayed diagnosis of TIO and alerts clinicians to the potential complication of hungry bone syndrome post-tumour resection.

Mutational landscape and genetic signatures of cell-free DNA in tumour-induced osteomalacia.

Tumour-induced osteomalacia (TIO) is a very rare paraneoplastic syndrome with bone pain, fractures and muscle weakness, which is mostly caused by phosphaturic mesenchymal tumours (PMTs). Cell-free DNA (cfDNA) has been regarded as a non-invasive liquid biopsy for many malignant tumours. However, it has not been studied in benign tumours, which prompted us to adopt the targeted next-generation sequencing approach to compare cfDNAs of 4 TIO patients, four patients with bone metastasis (BM) and 10 healthy controls. The mutational landscapes of cfDNA in TIO and BM groups were similar in the spectrum of allele frequencies and mutation types. Markedly, deleterious missense mutations in FGFR1 and loss-of-function mutations in MED12 were found in 3/4 TIO patients but none of BM patients. The gene ontology analysis strongly supported that these mutated genes found in TIOs would play a potential role in PMTs' process. The genetic signatures and corresponding change in expression of FGFR1 and FGF23 were further validated in PMT tissues from a test cohort of another three TIO patients. In summary, we reported the first study of the mutational landscape and genetic signatures of cfDNA in TIO/PMTs.

Worsening of unrecognized tumour-induced osteomalacia with inadvertent use of recombinant human parathyroid hormone.

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Oncogenic osteomalacia and metastatic breast cancer: a case report and review of the literature.

OBJECTIVES: Oncogenic osteomalacia is a rare paraneoplastic metabolic syndrome that is characterised by severe hypophosphataemia, hyperphosphaturia and osteomalacia secondary to renal loss of phosphate. It is commonly caused by overproduction of fibroblast growth factor-23 (FGF23) from benign tumours of mesenchymal origin. Currently, there is no clear evidence on the management of oncogenic osteomalacia in patients with metastatic solid tumours. METHODS: We report a case of breast cancer-induced oncogenic osteomalacia and discuss its diagnosis and management. RESULTS: A 71-year-old woman with advanced breast cancer developed symptomatic oncogenic osteomalacia with raised FGF23, severe hypophosphataemia and hypocalcaemia. The electrolytic disturbances were exacerbated after the administration of bisphosphonates in the context of her oncological treatment. Systemic chemotherapy and maintenance endocrine treatment along with phosphate and calcium supplementation reduced the activity of oncogenic osteomalacia and resolved the electrolytic imbalances. CONCLUSIONS: To our knowledge, this is the first reported case of oncogenic osteomalacia in a patient with breast cancer. Oncogenic osteomalacia constitutes a diagnostic and therapeutic challenge. Pre-clinical and clinical evidence suggest that a possible underlying mechanism is the presence of molecular alterations in the FGF/FGFR signalling pathway leading to overexpression of FGF23. In metastatic setting, anticancer treatment can potentially lead to the normalisation of the electrolytic disturbances and reduction of the activity of oncogenic osteomalacia. The use of antiresorptive therapy in patients with bone metastases can potentially trigger FGF23 overexpression. Its use should be guided by the patients' risk of skeletal-related events and electrolytic disturbances as well as the degree of activity of oncogenic osteomalacia.

Phosphaturic mesenchymal tumors among elderly patients: a case report and review of literature.

Phosphaturic mesenchymal tumor (PMT) represents a rare cause of osteomalacia. The clinical signs and symptoms are vague and these lead to diagnosis delay. In the presence of hypophosphatemia and relatively high urine phosphate excretion, this entity should be taken into consideration in the deferential diagnosis of osteomalacia. In the present article, we report 81-year-old man presented to our clinic for evaluation due to osteopenia. His laboratory results disclosed hypophosphatemia, relatively increased urine phosphate excretion and increased level of intact fibroblast growth factor 23 (FGF23). A 68Gallium DOTATATE PET/CT revealed pathological uptake in the upper aspect of the left shoulder adjacent to the coracoid process. For suspected PMT a wide resection of the tumor was performed and pathological findings were consistent for PMT. Laboratory tests were normalized postoperatively. Reviewing the literature, we had identified 33 reported cases of PMTs among elderly patients age ≥70 years. Unlike previously reported data, where tumors predominantly localized in the lower extremities and pelvis, our search disclosed a high rate of tumor localization (10 cases - 33.3%) in the head with equal number of tumors (14 cases - 42.4%) localized in the head and upper extremity as well as in pelvis and lower extremity. The present case describes unique tumor localization in an elderly patient and our literature search demonstrated for the first time a high rate of tumor localization in the head among this group of patients. Learning points: PMTs represent a rare entity that should be considered in the differential diagnosis of elderly patients presented with persistent hypophosphatemia. Unlike previously reported data, head and neck tumor localization is frequent among elderly patients. 68Gallium-conjugated somatostatin peptide analogs, such as 68Ga-DOTATATE PET/CT demonstrated the greatest sensitivity and specificity for tumor localization in patients with phosphaturic mesenchymal tumors (PMTs). Wide tumor resection using intraoperative ultrasound is of major importance in order to ensure long-term cure.

Occult phosphaturic mesenchymal tumour of femur cortex causing oncogenic osteomalacia - diagnostic challenges and clinical outcomes.

BACKGROUND: Tumor induced osteomalacia (TIO) are extremely rare paraneoplastic syndrome with less than 300 reported cases. This report highlights the pitfalls and challenges in diagnosing and localizing TIO in patients with refractory and resistant osteomalacia. PATIENT AND METHODS: 41- year gentleman with 4-year history of musculoskeletal weakness and pathologic fractures presented in wheelchair bound incapacitated state of 1-year duration. Investigations were significant for severe hypophosphatemia, severe phosphaturia, normal serum calcium, reduced 1,25-dihydroxy vitamin-D, elevated ALP, elevated intact parathyroid hormone (iPTH), and pseudo-fractures involving pelvis and bilateral femur. Whole body MRI and 99mTc methylene diphosphonate bone-scan were also normal. Whole body FDG-PET scan involving all 4 limbs revealed a small FDG avid lesion at lateral border of lower end of left femur (SUV max 3.9), which was well characterized on 3-dimensional CT reconstruction. Plasma C-terminal fibroblast growth factor (FGF)-23 was 698 RU/ mL (normal < 150 RU/ml). Wide surgical excision of the tumor was done. Histopathology confirmed mesenchymal tumor of mixed connective tissue variant. Serum phosphorous normalized post-surgery day-1. High dose oral calcium and vitamin-D was continued. FGF-23 normalized post surgery (73RU/ml). Physical strength improved significantly and now he is able to walk independently. CONCLUSION: TIO is frequently confused with normocalcemic hyperparathyroidism and vitamin-D resistant rickets/osteomalacia, which increases patient morbidity. Imaging for tumor localization should involve whole body from head to tip of digits, cause these tumors are notoriously small and frequently involve digits of hands and legs. Complete surgical removal of the localized tumor is key to good clinical outcomes.