Tumor-Induced Osteomalacia

Tumor-induced osteomalacia (TIO) is a rare, paraneoplastic disease that can be difficult to distinguish from genetic forms of hypophosphatemia and severe osteomalacia. The hallmark of TIO, and its genetic phenocopies, is renal phosphate wasting and abnormal vitamin D metabolism; specifically, lack of compensatory increase in 1, 25-dihydroxyvitamin D (1, 25(OH)2D3) in response to hypophosphatemia. Ultimately, unchecked renal phosphorus excretion and relative 1, 25(OH)3 deficiency leads to osteomalacia, a metabolic bone disease characterized by a failure of mineralization and resultant weak, painful bones. Physical examination often reveals bone pain, especially with palpation of the anterior tibia and sternum. In children, long bone deformity, lower extremity bowing, and chest wall deformity is observed. If TIO is suspected, an extensive examination for masses or nodules is warranted, concentrating on soft tissues adjacent to long bones, distal extremities, the oral cavity and jaw, and the groin. Hypophosphatemia secondary to renal phosphate wasting has a wide differential diagnosis. These disorders can result from primary renal defects, overproduction of the phosphaturic hormone, FGF23, from normal or dysplastic bone and ectopic production of FGF23 or other phosphaturic proteins from tumors. Most tumors responsible for TIO are of mesenchymal origin, and are found in bone or soft tissue. The most common sites are in the long bones and extremities, but nasopharynx, sinuses, and groin are other locations. TIO is only definitively treated by identification and resection of the causative tumor. In addition, recently, the calcium-sensing receptor agonist, cinacalcet, has been shown to be an effective adjuvant in the treatment of TIO.