Tumor-Induced Osteomalacia: A Systematic Clinical Review of 895 Cases

Abstract

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months–90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ − 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences.

Global guidance for the recognition, diagnosis, and management of tumor‐induced osteomalacia

“…(5) direct comparison of the efficacy and safety of conventional therapy versus burosumab; (6) increased understanding of FGF23 levels in TIO and other hypophosphatemic disorders, in order to correctly diagnose TIO patients with inappropriately normal levels of FGF23 [116,117]; (7) more understanding of the FN1-FGFR1 fusion gene effects in the pathogenesis of TIO and how to exploit it as a potential therapeutic target; (8) better understanding of severe myopathy seen in patients with TIO; and (9) increased understanding of the recurrent and malignant transformation of PMT.…”

“…The hallmark biochemical feature of TIO, hypophosphatemia, often goes undetected because serum phosphate is not routinely measured [7] or may be erroneously attributed to another cause (Table 1). Furthermore, the full biochemical evaluations necessary to make the diagnosis of TIO-decreased renal tubular reabsorption of phosphate (TRP), inappropriately normal or low 1,25-dihydroxyvitamin D (1,25[OH] 2 D), and increased (or inappropriately normal) circulating FGF23-are specialized tests that are unfamiliar to many clinicians.…”

“…There are many challenges associated with the diagnosis of TIO. As a rare disease, the clinical presentation is currently poorly recognized, and because serum phosphate is not routinely included in standard chemistry panels [ 1 , 7 ], an increased awareness of the importance of specifically requesting its measurement is required [ 3 , 20 , 21 , 22 ]. There is also often a failure to understand the association between low serum phosphate and presenting clinical symptoms [ 3 , 20 , 21 , 22 ].…”

Osteomalacia in Adults: A Practical Insight for Clinicians

“…Although initially described by the Northern Irish endocrinologist Robert McCance in 1947 in an adult [ 60 ] and by the Swiss pediatrician Andrea Prader in children [ 61 ], its etiology was only identified after the year 2000. Since its initial description, less than 1000 cases have been reported in the medical literature, although its incidence is estimated to be much higher, due to difficulties in its detection [ 62 ], which causes a notable diagnostic delay that exceeds two years in 80% of cases [ 63 ].…”

Mineral Metabolism in Children: Interrelation between Vitamin D and FGF23

“…The measurement of FGF23 levels is most useful in the diagnostic workup of untreated patients with phosphopenic rickets to differentiate between FGF23-mediated and other forms of rickets. FGF23 levels are elevated or inappropriately normal in patients with several inherited hypophosphatemic disorders and tumor-induced osteomalacia (TIO) which normalized after tumor resection [ 119 , 120 ]. The combination of hypophosphatemia in children and adults and intact FGF23 concentrations greater than 30 pg/mL allows for the identification of patients with FGF23-mediated disorders [ 121 ].…”