Tumor-induced osteomalacia

Abstract

Tumor-induced osteomalacia is a rare paraneoplastic syndrome with approximately 500 cases reported. It presents with a variety of nonspecific symptoms including weakness, muscle and bone pain, and fracture. Characteristic laboratory findings are hypophosphatemia, an elevated alkaline phosphatase, normal parathyroid hormone, normal serum calcium concentration, and an inappropriately low 1,25(OH)2-vitamin D3 concentration. Initially, tumor-induced osteomalacia is misdiagnosed in over 95% of cases. Hypophosphatemia results from renal phosphate wasting occurring as a consequence of FGF-23 production by the tumor. FGF-23 reduces expression and stimulates endocytosis of two sodium-phosphate cotransporters found in the luminal membrane of the proximal tubule resulting in renal phosphate wasting. FGF-23 also inhibits the formation and stimulates the degradation of 1,25(OH)2 vitamin D3. The most common tumor causing tumor-induced osteomalacia is a mixed connective tissue tumor known as a “phosphaturic mesenchymal tumor.” Due to its rarity, it is often misdiagnosed. Molecular studies have shed light on the mechanisms of tumorigenesis with the identification of a fibronectin and fibroblast growth factor receptor 1 fusion protein expressed in about half of cases and a fibronectin and fibroblast growth factor 1 fusion protein in a small subset of tumors. Often small and slow growing, the tumors may be found in unusual locations, such as the extremities and nasal sinuses and are difficult to localize. Definitive treatment involves identification and removal of the tumor. Absent tumor removal, therapeutic goals include improvement of symptoms, raising the serum phosphorus concentration to the lower limit of normal, and maintenance or achievement of normal parathyroid hormone and alkaline phosphatase concentration. Two recent drugs that target pathways involved in the molecular pathogenesis of tumor-induced osteomalacia have recently been developed and are in early-phase clinical trials: the humanized anti-FGF-23 monoclonal antibody burosumab (KRN23) and the FGFR-1,2,3 inhibitor NVP-BGJ398.