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Tumour-induced osteomalacia


Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.

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Figure 1: Phosphate homeostasis.
Figure 2: The histological features of phosphaturic mesenchymal tumours.
Figure 3: Fibronectin–fibroblast growth factor receptor 1 signalling and translocations.
Figure 4: Phosphate transport in bone.
Figure 5: A diagnostic algorithm.
Figure 6: Histology and imaging of tumour-induced osteomalacia.
Figure 7: An algorithm to locate and treat the tumour associated with tumour-induced osteomalacia.


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The authors thank J. Berglund (NIH, Bethesda, Maryland, USA) for the image used in Figure 3b.

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Introduction (S.M.); Epidemiology (S.M.); Mechanisms/pathophysiology (M.P. and S.F.); Diagnosis, screening and prevention (S.M., J.P., S.H.T. and M.T.C.); Management (S.M. and C.C.); Quality of life (S.F.); Outlook (all); Overview of Primer (S.M.).

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Correspondence to Salvatore Minisola.

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Competing interests

S.M. has served as speaker for Abiogen, Amgen, Diasorin, Eli Lilly, Italfarmaco, Fujii, Merck Sharp & Dohme and Takeda. He has also served on the advisory boards of Amgen and Eli Lilly. All other authors declare no competing interests.

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Minisola, S., Peacock, M., Fukumoto, S. et al. Tumour-induced osteomalacia. Nat Rev Dis Primers 3, 17044 (2017).

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