Abstract
Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease, which 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 tumour is often difficult to detect and localize because they are often small, lack localizing symptoms and signs, and dwell in widely variable anatomical locations. Measuring serum/urine phosphate 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. While patients experience severe disability without treatment, complete excision of the tumour is typically curative and results in a dramatic reversal of symptoms. Two additional key current unmet needs in optimizing TIO management are: (1 and 2) 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.
Highlights
Tumor-induced osteomalacia (TIO) or oncogenic osteomalacia is a rare paraneoplastic syndrome caused by phosphate wasting as a result of excess levels of tumour-secreted fibroblast growth factor 23 (FGF23) [1,2,3,4]
FGF23 acts through binding to fibro blast growth factor receptor 1 and co-receptor α-Klotho complex (FGFR1-α-Klotho) to downregulate the activity of sodium-dependent phosphate co-transporter proteins NaPi-IIa and NaPi-IIc, which play a crucial role in reabsorption of phosphate by the renal proximal tubular cells in the kidney [28,29,30]
There is a clear need to improve the time to suspicion, referral, and diagnosis of TIO, as well as to subsequently engage appropriately resourced specialized units or teams, to either take over from referring doctors, or to closely supervise the remainder of the diagnostic pathway and ongoing management of patients
Summary
Tumor-induced osteomalacia (TIO) or oncogenic osteomalacia is a rare paraneoplastic syndrome caused by phosphate wasting as a result of excess levels of tumour-secreted fibroblast growth factor 23 (FGF23) [1,2,3,4]. TIO is difficult to diagnose as the manifestations are non-specific, often leading to a delay in diagnosis of many years, which increases the risk of severe disabilities in affected patients [4,6,7]. To improve timely diagnosis of TIO and specific treatment of affected patients, healthcare providers need to be aware of the options for and challenges of optimal TIO management. It is essential to recognize these challenges and offer solutions to facilitate implementing clear guidelines, raising awareness of TIO and improving patient care. Key challenges associated with the diagnosis, treatment and management of TIO were identified for the purpose of raising awareness of the pathophysiology and enigmatic clinical pre sentation of the disease
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