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

Abstract

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.

Imaging glucose metabolism to reveal tumor progression

“…Monitoring aerobic glycolysis in tumor tissue might lead to improved methods for diagnosing and treating cancer ( Ma et al, 2022 ; Raskov et al, 2022 ). Molecular imaging is an emerging interdisciplinary subject in imaging, medicine, and molecular biology ( Jan De Beur et al, 2022 ). Early detection, tailored treatment, and real-time tumor monitoring will benefit from non-invasive molecular imaging of glucose metabolism in cancer.…”

Tumor‐induced Osteomalacia: A Case Report and Etiological Analysis with Literature Review

“…In cases where the tumor cannot be localized or completely resected, image guided ablation combined with cryoablation or radiofrequency ablation can be used as an alternative treatment 9,13 . Small molecule targeted drugs can significantly improve symptoms and inhibit disease progression in unresectable, relatively concealed, or unidentified PMTs, but there is still a lack of evidence regarding their long‐term efficacy and safety 14,15 . The anti‐FGF23 monoclonal antibody (burosumab) has been proven to be safe and effective in improving objective indicators and symptoms of TIO 15 .…”

“…9,13 Small molecule targeted drugs can significantly improve symptoms and inhibit disease progression in unresectable, relatively concealed, or unidentified PMTs, but there is still a lack of evidence regarding their long-term efficacy and safety. 14,15 The anti-FGF23 monoclonal antibody (burosumab) has been proven to be safe and effective in improving objective indicators and symptoms of TIO. 15 The pan FGFR tyrosine Other Tumors Caution should still be exercised before diagnosing osteomalacia caused by other tumors, unless it is confirmed that they produces FGF23 separately without the coexistence of phosphate mesenchymal tumors.…”

“…14,15 The anti-FGF23 monoclonal antibody (burosumab) has been proven to be safe and effective in improving objective indicators and symptoms of TIO. 15 The pan FGFR tyrosine Other Tumors Caution should still be exercised before diagnosing osteomalacia caused by other tumors, unless it is confirmed that they produces FGF23 separately without the coexistence of phosphate mesenchymal tumors. In addition, complete recovery of TIO after surgical resection will contribute to the clinical diagnosis of osteomalacia caused by other types of tumors.…”

Osteomalacia in Adults: A Practical Insight for Clinicians

“…If the above alternatives fail and the neuroendocrine origin of the phosphaturic tumor has been confirmed, radioactive treatment with products such as lutetium-dotatate, which combines a somatostin analogue (octreotate) with Lu177, a beta emitter with tumor-cytolytic potential, can be chosen [ 73 ]. Very recently, the Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended that burosumab be approved for the treatment of FGF23-related hypophosphatemia in TIO associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in children and adolescents aged 1 to 17 years and in adults [ 74 , 75 , 76 ]. Lastly, other drugs are in the experimental phase, such as infigratinib (inhibitor of tyrosine kinases involved in the signal of FGFR1, FGFR2, and FGFR3), a drug approved for the treatment of advanced cholangiocarcinoma [ 77 , 78 , 79 ].…”