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Tumor-Induced Osteomalacia Endocrine-Related Cancer (2011) 18 R53–R77 REVIEW Tumor-induced osteomalacia William H Chong1, Alfredo A Molinolo2, Clara C Chen3 and Michael T Collins1 1Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, 2Oral Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research and 3Nuclear Medicine, Radiology and Imaging Sciences, Hatfield Clinical Research Center, National Institutes of Health, Bethesda, Maryland 20892, USA (Correspondence should be addressed to M T Collins; Email: [email protected]) Abstract Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1a-hydroxylation of 25-hydroxyvitamin D, leading to hypophos- phatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed. Endocrine-Related Cancer (2011) 18 R53–R77 Introduction Tumor-induced osteomalacia (TIO), also known as present with advanced primary hyperparathyroidism oncogenic osteomalacia, is a rare paraneoplastic (Fig. 1). If the condition develops before growth plate syndrome of abnormal phosphate and vitamin D closure, rickets is also present. There is also a group metabolism caused by typically small endocrine of patients with a TIO-like syndrome in which a tumor tumors that secrete the phosphaturic hormone, fibro- is never found. Whether or not this is due to the blast growth factor 23 (FGF23; Drezner 2001, Folpe inability to find the tumor or this represents a separate et al. 2004, Jan de Beur 2005). Biochemical hallmarks syndrome is not known. In our series of 31 patients of the disorder are hypophosphatemia due to renal with TIO syndrome in which genetic causes of phosphate wasting, inappropriately normal or low hypophosphatemia have been excluded, we have 1,25-dihydroxy vitamin D, and elevated or inappropri- been able to find the tumor in 19 (61%) of them. ately normal plasma FGF23. TIO is counted among the Given that most of the patients referred to our center ranks of endocrine neoplasms that have a striking have already failed tumor localization at the referring presentation and, when resected, a dramatic and institution at least once, the percent of patients in satisfying resolution. Due to a lack of knowledge of whom we have not been able to find the tumor is the existence of the disease, the length of time from probably higher than is seen in patients being evaluated onset of symptoms until diagnosis is often long. As a for the first time. result, patients frequently present with multiple A TIO-like syndrome can also be seen in association fractures, height loss, and generalized debilitated with other diseases such as prostate cancer, oat cell status, reminiscent of how patients in the past would cancer, hematologic malignancies, neurofibromatosis, Endocrine-Related Cancer (2011) 18 R53–R77 Downloaded from Bioscientifica.comDOI: 10.1530/ERC-11-0006 at 09/30/2021 04:30:57PM 1351–0088/11/018–R53 q 2011 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.orgvia free access W H Chong et al.: Tumor-induced osteomalacia A B CD Figure 1 Clinical effects of advanced tumor-induced osteomalacia (TIO). The patient in the gown in panel A is depicted standing next to his father. The patient was previously taller than his father, but this is no longer the case. Panel B demonstrates kyphosis and pectus carinatum, which resulted from multiple compression fractures due to osteomalacia. While these findings are the result of advanced osteomalacia, they are strikingly similar to those seen in advanced hyperparathyroidism, as demonstrated by the famous patient reported by Fuller Albright, Captain Martell, shown in panels C and D, who suffered from years of untreated hyperparathyroidism. (Photo of patient and father are reproduced with their permission. Material is reproduced with permission from Albright & Reifenstein (1948)). epidermal nevus syndrome, and polyostotic fibrous The first person to clearly recognize that the disease dysplasia of bone (FD; Saville et al. 1955, Dent & was the result of a ‘rachitogenic’ substance was Andrea 1 Gertner 1976, Taylor et al. 1984, Carey et al. 1986, Prader. In 1959, he described an 11 ⁄2 -year-old girl Rao et al. 1987, Konishi et al. 1991, Nakahama et al. who developed severe rickets over the course of a year 1995, Ivker et al. 1997, Reese & Rosen 1997, Collins (Prader et al. 1959). Evaluation showed decreased et al. 2001, Riminucci et al. 2003). In these cases, the tubular phosphate reabsorption but otherwise normal primary disease is usually obvious, and as such it may studies of kidney function. A tumor, classified as a be useful to refer to this as secondary TIO. In cases of giant cell granuloma, was identified in a rib and secondary TIO, the goal is treatment of the underlying resected with resultant healing of her rickets. Prader disease. However, when the underlying disease is not highlighted the association between the resection of the amenable to cure or adequate treatment, as is the case tumor and the cure of the rickets and posited that the in FD, the medical treatment of the hypophosphatemic granuloma was secreting a rachitogenic substance. syndrome is the same as in cases of primary TIO. Since this association was first made, w337 cases of Robert McCance is often credited with the first what may be referred to as primary TIO have been reported case of TIO. McCance (1947) reported a reported in the literature (English) (Sharkis et al. 1997, patient with manifestations of what was clearly TIO. Yang et al. 1997, Malabanan et al. 1998, Baronofsky The patient had pain, weakness, gait abnormalities, and et al. 1999, Drezner 1999, Fukumoto et al. 1999, low phosphorus levels. She was treated with high doses Gascon et al. 1999, Hasegawa et al. 1999, Heylen et al. of vitamin D, but her symptoms did not completely 1999, Lamont et al. 1999, Nguyen & Wang 1999, resolve until a tumor in her femur was resected. Ohashi et al. 1999, Zura et al.1999, Clunie et al. 2000, Her cure, however, was attributed to the high-dose Nelson et al. 2001, 2003, Ogose et al. 2001, Park et al. vitamin D therapy. She was diagnosed with resistance 2001, Rhee et al. 2001, Sakamoto et al. 2001, Sato to vitamin D. During that period, vitamin D resistance et al. 2001, Seufert et al. 2001, Furco et al. 2002, was believed to be the mechanism of what would Garcia & Spencer 2002, Jan de Beur et al. 2002, Lui eventually come to be understood as FGF23-mediated et al. 2002, Moran & Paul 2002, Paglia et al. 2002, phosphate wasting disorders (Albright et al. 1937). Reis-Filho et al.2002, 2004, Teasell & Shapiro 2002, Downloaded from Bioscientifica.com at 09/30/2021 04:30:57PM via free access R54 www.endocrinology-journals.org Endocrine-Related Cancer (2011) 18 R53–R77 Yamazaki et al. 2002, Casari et al. 2003, Dissanayake now the case with the primary hyperparathyroidism et al. 2003, Fuentealba et al. 2003, Kimizuka et al. (Albright & Reifenstein 1948). 2004, Nayak et al. 2004, Takeuchi et al. 2004, This review aims to provide insight into the Toyosawa et al. 2004, Ungari et al. 2004, Ward et al. pathophysiology and mechanism of TIO as well as 2004, Auethavekiat et al.2005, Colt et al. 2005, guidance in evaluating and diagnosing this rare Dupond et al. 2005a, Narvaez et al. 2005, Zimering disease. Clinical presentation, diagnostic testing and et al. 2005, Cheung et al. 2006, Dowman & Khattak therapeutic options are discussed with an emphasis on 2006, Hodgson et al. 2006, Imel et al. 2006, recent advances. Future areas of interest for research Inokuchi et al. 2006, Kaylie et al. 2006, Koriyama are also discussed. et al. 2006, Ladha et al. 2006, Nguyen 2006, Sahnoune et al. 2006, Tartaglia et al.2006, Vandergheynst et al. 2006, Yoshioka et al. 2006, Ahn et al. 2007, Beech Physiology and pathophysiology et al. 2007, Elston et al. 2007, Geller et al. 2007, Phosphate homeostasis Gershinsky et al. 2007, Halperin et al. 2007, Hesse et al. 2007a,b, Jacob et al. 2007, Kaul et al. 2007, Phosphate is vital to normal physiologic functioning; it Khosravi et al. 2007, Oka et al. 2007, Roarke & plays a role in intracellular signaling, membrane Nguyen 2007, Umphrey et al. 2007, Williams et al. function, energy metabolism, and bone mineralization 2007, van Boekel et al. 2008, Duet et al. 2008, Endo (Sommer et al. 2007, Renkema et al. 2008). et al. 2008, von Falck et al. 2008, Habra et al. 2008, Approximately, 65% of dietary phosphate is absorbed Hannan et al. 2008, Harish et al. 2008, Kenealy et al. in the duodenum and jejunum (Mount & Yu 2008). 2008, Lewiecki et al. 2008, Mannstadt et al. 2008, Phosphate is predominantly stored in the skeleton with Nasu et al.
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