Endocrine Abstracts

Tumor-induced osteomalacia (TIO) or ‘oncogenic osteomalacia’ is a rare paraneoplastic disorder, usually resulting from Fibroblast Growth Factor 23 (FGF23) oversecretion by a benign small ‘phosphaturic mesenchymal tumor’, causing hypophosphatemia and reduced 1,25-dihydroxyvitamin D synthesis. Calcium and parathyroid hormone (PTH) levels are usually normal, but secondary/tertiary hyperparathyroidism has been reported in up to 5% of the cases, mainly due to 1,25-dihydroxyvitamin D deficiency and long-term phosphate supplementation. Non-specific clinical manifestations (muscle weakness, osteomalacia, bone pain) and difficult localization of the tumor often delay diagnosis for years. Surgical removal represents the first-line treatment. We report a case of a patient with TIO, supplemented for years with phosphate salts, who developed hyperparathyroidism after tumor removal.

Case report: In 1987, after femur stress fracture, a 27-year-old man was diagnosed with ‘phosphate diabetes’ and then treated until 2010 with phosphate, calcium and vitamin D supplementation. The late onset of disease with no family history of hypophosphatemia nor skeletal deformities did not suggest hereditary conditions. Medical history included only beta-thalassemia trait. No further evaluation was made until 2010, when a small phosphaturic mesenchymal tumor was identified during investigations of non-healing tibial fracture. Histological specimens confirmed a FGF23-expressing neoplasia. Before surgery hypophosphatemic hyperphosphaturia with normal PTH, calcium and creatinine levels and borderline 25-hydroxyvitamin D were observed. Immediately post-surgery phosphatemia normalized. However, calcemia and PTH levels slowly increased and few months later the patient was diagnosed with primary hyperparathyroidism (PTH 110 pg/ml normal range 5-39, calcemia 11.1 mg/dl, mild hypophosphatemia, increased 1,25-dihydroxyvitamin D and reduced 25-hydroxyvitamin D levels). Neck ultrasonography and parathyroid MIBI-scintigraphy did not reveal adenomas. Exploratory cervicotomy was proposed, but the patient was lost at follow-up. In 2019 hypercalcemic hyperparathyroidism with hypophosphatemia and nephrolithiasis was observed (calcemia 10.5 mg/dl, phosphatemia 1.8 mg/dl, PTH 78 pg/ml, normal creatinine and 25-hydroxyvitamin D levels). FGF23 levels were normal. After negative imaging, exploratory cervicotomy with subtotal parathyroidectomy was performed; histology confirmed parathyroid hyperplasia. Post-surgery PTH fell to undetectable levels while phosphatemia normalized; treatment with calcium salts, calcitriol and Cholecalciferol was introduced.

Conclusions: TIO diagnosis should always be excluded when treating persistent hypophosphatemia, as tumor removal is usually curative. Long-term treatment with phosphate salts may induce secondary/tertiary hyperparathyroidism. Thus, phosphocalcic metabolism should be periodically evaluated during follow-up of surgically untreated TIO, but also after tumor removal, due to the possible hyperparathyroidism development.

References: Brandi et al. Challenges in the management of tumor-induced osteomalacia (TIO). Bone. 2021 Nov;152:116064. doi: 10.1016/j.bone.2021.116064. PMID: 34147708.