Hypophosphatemia and FGF23 tumor-induced osteomalacia in two cases of metastatic breast cancer

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by factor-induced dysregulation of phosphate and vitamin D metabolism resulting in alterations in bone formation, leading to bone pain and fractures. While the true incidence is likely underestimated, less than 500 cases of TIO have been reported since initial description in 1947. TIO cases have classically been associated with mesenchymal tumors of bone and soft tissue, but have also rarely been linked to malignant tumors, with scant reports implicating non-mesenchymal tumors. TIO is mediated through inappropriate tumor overproduction of fibroblast growth factor 23 (FGF23). Increased FGF23 secretion leads to hypophosphatemia by (1) reduced phosphate reabsorption via activation of the proximal renal tubular epithelial cells to internalize sodium phosphate cotransporters and (2) reduced activation of vitamin D3 via inhibition of the renal enzyme 1-alpha hydroxylase. Low circulating levels of active vitamin D lead to reduced intestinal phosphate absorption and impaired mineralization of osteoid matrix. TIO in breast cancer poses a distinct diagnostic challenge due to the common adjunct oncologic management with bone protection therapy such as denosumab or bisphosphonates. These agents can be culprits of hypophosphatemia and hypocalcemia, rendering timely diagnosis of TIO difficult. Delay of diagnosis of TIO can result in worsening functional status, and early morbidity and mortality. To date, there has been one prior case report of TIO in breast cancer, and herein we describe two additional cases of TIO in this setting.