Consensus on Clinical Management of Tumor-Induced Osteomalacia
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor, often of mesenchymal origin. This condition leads to hypophosphatemia, resulting in clinical symptoms such as muscle weakness, bone pain, impaired mobility, and fractures. Due to its rarity, the diagnosis and management of TIO remain challenging, often leading to delays in appropriate treatment. This consensus aims to provide up-to-date guidance on the assessment and treatment of TIO, based on expert opinions and limited available evidence.
Diagnosis of TIO
The diagnosis of TIO is based on a combination of clinical manifestations, biochemical findings, and the identification of the causative tumor. Patients presenting with symptoms such as bone pain, weakness, and radiological signs of osteomalacia, including obscure bone structure, concave changes of vertebrae, inward bending of the pelvic sidewall, and pseudofractures (Looser zones), should be suspected of having TIO. Laboratory findings typically include decreased serum phosphate, reduced tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR), low or inappropriately normal levels of 1,25-dihydroxyvitamin D (1,25(OH)2D), elevated alkaline phosphatase (ALP), and increased FGF23. It is crucial to exclude inherited disorders or other acquired causes of hypophosphatemic rickets/osteomalacia at the initial stage of diagnosis.
A stepwise approach is recommended to locate the causative tumor, as these tumors are often small, slow-growing, and can be found in unexpected locations throughout the body. The first step involves a thorough inquiry and physical examination, followed by functional imaging. Somatostatin receptor imaging, such as 68Ga-DOTA-conjugated-somatostatin-receptor-targeting-peptides positron emission tomography/computed tomography (PET/CT) and octreoscan with single-photon emission computed tomography/CT (SPECT/CT), is recommended as the first-line imaging investigation. Once a suspected lesion is identified, anatomical imaging techniques, including radiography, magnetic resonance imaging (MRI), CT, or ultrasound, should be used to confirm the lesion. In cases with multiple suspicious regions, selective venous sampling may be useful to confirm the causative tumor. For patients in whom the tumor cannot be located, medical therapy should be initiated, and imaging studies should be repeated within 1 to 2 years.
Pathology of TIO
The majority of TIO-associated tumors are of mesenchymal origin. These tumors are morphologically and genetically distinct neoplasms known as phosphaturic mesenchymal tumors (PMTs). PMTs typically present as non-specific soft tissue or bone masses and produce a characteristic “smudgy” matrix that calcifies in a peculiar “grungy” or flocculent fashion.
Management and Treatment of TIO
Surgical Treatment
Surgical removal of the causative tumor is the first-line therapy for TIO when feasible. Complete excision of the tumor can correct biochemical abnormalities and accelerate bone remineralization. However, if even a small amount of tumor tissue remains, symptoms may persist or relapse. Non-remission and recurrent patients should undergo repeat diagnostic work-up to exclude other diseases and re-locate the causative tumor, followed by reoperation if possible.
Medical Treatment
For inoperable patients, medical therapy should be initiated to alleviate symptoms. Biochemical tests should be monitored every 3 to 6 months. The first-line medical treatments include burosumab or phosphate supplementation with active vitamin D. The therapeutic goal of conventional medical treatment is to alleviate clinical symptoms, increase serum phosphate levels, normalize ALP, and maintain parathyroid hormone (PTH) within the normal range. Complete normalization of serum phosphate usually indicates an overdose. The recommended dosage of elemental phosphate is 20 to 40 mg/kg daily (1–3 g/d for adults), and calcitriol is recommended at 20 to 30 ng/kg daily (0.5–1.5 mg/d for adults). The equivalent dosage of alfacalcidol is 1.5 to 2 times that of calcitriol. Phosphate supplements should be divided into 4 to 6 doses per day and titrated to the target dose over several days to weeks. Renal function, serum calcium, phosphate, ALP, PTH, and 24-hour urinary calcium should be monitored every 3 to 6 months to adjust the dosage and prevent complications such as secondary or tertiary hyperparathyroidism, nephrolithiasis, and reduced renal function.
Burosumab, a fully human monoclonal antibody against FGF23, is a promising treatment for TIO. The recommended initial dosage is 0.5 mg/kg once every 4 weeks, rounded to the nearest 10 mg, with a maximum dosage of 2 mg/kg (not exceeding 180 mg) every 2 weeks. Dosage adjustment should be based on fasting serum phosphate levels, measured 2 weeks post-dose, for the first 3 months of treatment and as clinically necessary thereafter.
Radiofrequency ablation and cryoablation can be considered for patients who are unwilling or unable to undergo complete excision surgeries. The effectiveness of other treatments, such as FGF receptor inhibitors or cinacalcet, remains uncertain due to insufficient evidence.
Monitoring of TIO
After complete tumor removal, serum phosphate levels typically normalize within 5 days (2–10 days). Serum 1,25(OH)2D levels rise synchronously with the decrease in FGF23. For patients with complete tumor removal, biochemical parameters, especially serum phosphate, should be measured every 6 months initially, then at yearly intervals, with dual-energy X-ray absorptiometry (DXA) examinations. For patients on long-term medical therapy, biochemical parameters should be monitored every 3 to 6 months to adjust drug doses and prevent side effects.
Future Prospects
In terms of diagnosis, specific and easily obtained criteria are needed to facilitate quick suspicion of TIO in primary healthcare institutions. Further research is required to understand the mechanisms of tumorigenesis and FGF23 overproduction, develop detailed models and risk markers for stratifying severity, and identify refractory cases of TIO. Prospective evidence on the effectiveness of novel drugs, including burosumab and FGFR1 inhibitors, will greatly expand treatment options for TIO in the future.
Conclusion
The consensus on the clinical management of TIO provides comprehensive guidance on the diagnosis, pathology, treatment, and monitoring of this rare condition. Surgical removal of the causative tumor remains the first-line therapy, with medical treatment options available for inoperable patients. Regular monitoring of biochemical parameters is essential to ensure effective management and prevent complications. Future research is needed to improve diagnostic criteria and explore new treatment options for TIO.
doi.org/10.1097/CM9.0000000000001448
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