Tumor-induced Osteomalacia: A Systematic Review and Individual Patient’s Data Analysis

Rendina, Domenico; Abate, Veronica; Cacace, Gianluigi; Elia, L.; Filippo, Gianpaolo De; Vecchio, Silvana Del; Galletti, Ferruccio; Cuocolo, Alberto; Strazzullo, Pasquale

doi:10.1210/clinem/dgac253

Cited by 21 publications

(21 citation statements)

References 40 publications

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“…A systematic review of 895 TIO cases reported that, of the 858 cases with information on sex, 58.3% were male and 41.7% were female [ 7 ]. Similar results were reported in another recent systematic review [ 40 ]. Bone pain in the distal extremities is the most common initial symptom in adults [ 37 ], with ankles and feet being the most often affected.…”

Section: Recognizing Clinical Signs and Symptoms That Raise Suspicion...supporting

confidence: 92%

“…Cases have been reported in individuals as young as 9 months old [ 38 ], with a median age of onset of 46 years and a range of 9 months–90 years [ 7 , 39 ]. Previous accounts indicated that equal proportions of men and women are affected by TIO [ 35 ]; however, more recent evidence from systematic reviews suggests that more men than women are diagnosed [ 7 , 40 ]. A systematic review of 895 TIO cases reported that, of the 858 cases with information on sex, 58.3% were male and 41.7% were female [ 7 ].…”

Section: Recognizing Clinical Signs and Symptoms That Raise Suspicion...mentioning

confidence: 99%

“…2 ). In a systematic review of over 1725 cases of TIO, the TIO‐causing tumors were identified in 1493 patients, and surgery was successful in >90% of these patients [ 40 ]. However, the difficulty of early recognition and diagnosis of TIO has been demonstrated by a review of 252 patients with TIO, for whom the average time from onset of symptoms to surgical removal of tumor was 5.4 (standard deviation 4.2) years [ 30 ].…”

Section: Management Of Tiomentioning

confidence: 99%

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Global guidance for the recognition, diagnosis, and management of tumor‐induced osteomalacia

et al. 2022

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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.

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Section: Recognizing Clinical Signs and Symptoms That Raise Suspicion...supporting

confidence: 92%

Section: Recognizing Clinical Signs and Symptoms That Raise Suspicion...mentioning

confidence: 99%

Section: Management Of Tiomentioning

confidence: 99%

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Global guidance for the recognition, diagnosis, and management of tumor‐induced osteomalacia

et al. 2022

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“…Systematic reviews estimate this delay to be approximately 4 years, with a wide range spanning from 0.2 to 25 years. 6,12 The initial symptomatology predominantly comprises musculoskeletal discomfort, including diffuse muscle pain and progressive weakness, often leading to substantial impairment in the patient's mobility and quality of life. As the disease advances, it progressively impacts the skeletal system, resulting in debilitating bone pain.…”

Section: Discussionmentioning

confidence: 99%

Transformation of a long‐standing phosphaturic tumor‐inducing osteomalacia into malignancy

Malagon‐Rangel,

Solis,

Zavala‐Jonguitud

et al. 2023

Clinical Case Reports

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Key Clinical MessageTumor‐induced osteomalacia is a paraneoplastic syndrome characterized by renal phosphate wasting and deranged bone turnover. Clinicians should consider tumor‐induced osteomalacia in unexplained hypophosphatemia and investigate for underlying tumors.AbstractTumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by renal phosphate wasting, which leads to deranged bone turnover. TIO is usually associated with benign mesenchymal tumors, although it has also been reported in malignant tumors. We present the case of a 56‐year‐old individual who experienced a protracted 6‐year clinical course characterized by hypophosphatemia, weakness, and kyphosis, alongside the presence of a foot tumor. Subsequently, this lesion displayed malignant behavior and was ultimately diagnosed as a high‐grade sarcoma. To date, this case is among the 10 reported cases in the literature of a mesenchymal tumor associated with TIO undergoing malignant transformation. This report underscores the importance of a comprehensive evaluation of patients with unexplained hypophosphatemia and highlights the need for diligent follow‐up to detect possible malignant transformation of the underlying tumor. Clinicians should consider TIO in the differential diagnosis of hypophosphatemia and promptly investigate for the presence of an underlying tumor, as early detection may improve the patient's prognosis.

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“…The curative treatment for TIO is localization and resection of the tumor. However, the tumors are small and could take years to locate; in the meantime, the administration of phosphate and calcitriol is essential ( 11 , 12 ).…”

Section: Tumor-induced Osteomalacia and X‐linked Hypophosphatemic Ric...mentioning

confidence: 99%

New treatments for rare bone diseases: hypophosphatemic rickets/osteomalacia

Marques¹,

Moreira²,

Borba³

2022

Archives of Endocrinology and Metabolism

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Phosphorus is one of the most abundant minerals in the human body; it is required to maintain bone integrity and mineralization, in addition to other biological processes. Phosphorus is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], and fibroblast growth factor 23 (FGF-23) in a complex set of processes that occur in the gut, skeleton, and kidneys. Different molecular mechanisms -overproduction of FGF-23 by tumors responsible for oncogenic osteomalacia, generation of an FGF-23 mutant that is resistant to cleavage by enzymes, and impaired FGF-23 degradation due to a reduction in or loss of the PHEX gene -can lead to FGF-23-stimulating activity and the consequent waste of urinary phosphate and low levels of 1,25(OH) 2 D 3 . Conventional treatment consists of multiple daily doses of oral phosphate salts and vitamin D analogs, which may improve radiographic rickets but do not normalize growth. Complications of the conventional longterm treatment consist of hypercalcemia, hypercalciuria, nephrolithiasis, nephrocalcinosis, impaired renal function, and potentially chronic kidney disease. Recently, burosumab, an antibody against FGF-23, was approved as a novel therapy for children and adults with X-linked hypophosphatemia and patients with tumor-induced osteomalacia. Burosumab showed good performance in different trials in children and adults. It increased and sustained the serum phosphorus levels, decreased the rickets severity and pain scores, and improved mineralization. It offers a new perspective on the treatment of chronic and disabling diseases.

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Tumor-induced Osteomalacia: A Systematic Review and Individual Patient’s Data Analysis

Cited by 21 publications

References 40 publications

Global guidance for the recognition, diagnosis, and management of tumor‐induced osteomalacia

Global guidance for the recognition, diagnosis, and management of tumor‐induced osteomalacia

Transformation of a long‐standing phosphaturic tumor‐inducing osteomalacia into malignancy

New treatments for rare bone diseases: hypophosphatemic rickets/osteomalacia

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