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Tumor-Induced Osteomalacia

Tumor-Induced Osteomalacia

Endocrine-Related (2011) 18 R53–R77 REVIEW Tumor-induced

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 , 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 in which patients present with , fractures, and muscle weakness. The cause is high 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 ( 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 , is a rare paraneoplastic (Fig. 1). If the condition develops before growth plate syndrome of abnormal phosphate and vitamin D closure, 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 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 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 , oat cell status, reminiscent of how patients in the past would cancer, hematologic , neurofibromatosis,

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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 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 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 . 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,

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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. 2008, Ogura et al. 2008, Policarpio-Nicolas a small amount available in the extracellular fluid. This freely circulating phosphate is filtered by the et al. 2008, Ratanasuwan et al. 2008, Vollbrecht & Rao glomerulus, and under normal physiologic conditions, 2008, Westerberg et al. 2008, Woznowski et al. 2008, 85–95% of filtered phosphate is reabsorbed. As renal Bahrami et al. 2009, Gore et al. 2009, Harbeck et al. phosphate load increases, phosphate reabsorption 2009, Khadgawat et al. 2009, Mussig et al. 2009, increases until a threshold is reached, at which point Nawrot-Wawrzyniak et al. 2009, Pirola et al. 2009, phosphate is excreted in the urine (Mount & Yu 2008). Radaideh et al. 2009, Rendina et al. 2009, Romualdo- Renal phosphate excretion is the primary mode of Silva et al. 2009, Savage & Zimmer 2009, Sciubba phosphate clearance and regulation of phosphate et al. 2009, Seijas et al. 2009, Szumera-Cieckiewicz balance. The majority of phosphate reabsorption et al. 2009, Uramoto et al. 2009, Woo et al. 2009, takes place in the proximal renal tubule through type Yun et al. 2009, Chouhan et al. 2010, Dehghani et al. 2a and 2c Na-dependent phosphate cotransporters 2010, Haeusler et al. 2010, Ishii et al. 2010, Ito et al. (NaPi-2a and NaPi-2c; Mount & Yu 2008, Bergwitz 2010, Jagtap et al. 2010, Jung et al. 2010, Kobayashi & Juppner 2010). et al. 2010, Kurien et al. 2010, Marshall et al. 2010, For years, it has been recognized that phosphate Mori et al. 2010, Pedrazzoli et al. 2010, Peters et al. concentrations are under the control of parathyroid 2010, Peterson et al. 2010, Xia et al. 2010). The fact hormone (PTH), 1,25-vitamin D, and the so-called that over 200 of these cases have been reported in the ‘phosphatonins’ (Mount & Yu 2008, Bergwitz & last 10 years indicates a growing recognition of this Juppner 2010). While the primary role of PTH is disease. This growing recognition has paralleled the thought to be the maintenance of serum calcium levels, identification of FGF23 as the phosphaturic agent it also plays an important role in phosphate regulation. (ADHR Consortium 2000, White et al. 2001). The In the process of mobilizing calcium from bone, PTH discovery of FGF23 has not only paved the way toward also mobilizes phosphate from bone. To help excrete a better understanding of the pathophysiology and this increased blood phosphate, PTH acts to inhibit treatment of TIO, but has also provided a window renal phosphate reabsorption through endocytosis of into areas of mineral metabolism physiology that for NaPi-2a, thus increasing renal phosphate excretion. years had been unexplained. Hopefully, greater The overall effect is to lower blood phosphate levels recognition of TIO as a distinct disease entity, a better (Renkema et al. 2008). 1,25-vitamin D is thought to understanding of the underlying pathophysiology, play a role in phosphate regulation in both the improved tumor localization strategies, and better gastrointestinal tract and in the kidney, but the medical treatment will make the sort of presentation mechanism is less understood. Increases in 1,25- that is shown in Fig. 1, a historical footnote, as is vitamin D lead to an increase in phosphate absorption

Downloaded from Bioscientifica.com at 09/30/2021 04:30:57PM via free access www.endocrinology-journals.org R55 W H Chong et al.: Tumor-induced osteomalacia from the gastrointestinal tract. In the kidney, the role source of FGF23 was from the study of patients with is more complex. With chronic administration of FD, wherein it was found that dysplastic osteogenic vitamin D, there is reduction of NaPi-2a and sub- cells are the source of FGF23 (Riminucci et al. 2003). sequent phosphaturia (Friedlaender et al. 2001). With Reasoning that if dysplastic osteogenic cells are the acute administration of vitamin D metabolites, there source of FGF23 in FD, we went on to show that is reduced renal phosphate excretion (Taketani et al. normal bone cells are the physiologic source of FGF23 1998). However, many of the effects of 1,25-vitamin D (Riminucci et al. 2003). Physiologic regulation of on phosphate metabolism were posited before the FGF23 secretion is still being defined, but probably discovery of FGF23. It is now clear that FGF23 and serum phosphorus (Larsson et al. 2003, Ferrari et al. PTH play much more important roles in phosphate 2005, Nishida et al. 2006, Ito et al. 2007) and/or serum homeostasis than 1,25-vitamin D. 1,25-vitamin D (Collins et al. 2005) are important in regulating the levels of FGF23. FGF23 acts by binding to target cells via an FGF Fibroblast growth factor 23 receptor (probably FGFR1), but signaling requires the While Prader was the first to propose the idea of a co-receptor Klotho (Razzaque 2009). When FGFR is circulating factor that could cause phosphate wasting, activated, there is reduction of NaPi-2a transcription the first evidence that a circulating factor was and less NaPi-2a on the basal cell surface of proximal responsible for the hypophosphatemia of phosphaturic tubule cells, which in turn leads to renal phosphate disorders such as TIO was demonstrated in an elegant excretion (Shimada et al. 2004). At this point, it is not set of experiments by Meyer et al. By performing clear how this occurs, as Klotho expression has been parabiosis experiments in hyp mice, the mouse model clearly reported only in distal tubule cells so far (Farrow for X-linked hypophosphatemic rickets, Meyer et al. et al. 2009). There is a secreted form of Klotho, and it (1989) were able to demonstrate that a factor in the hyp is possible that this circulating Klotho may play a role mouse’s circulation could induce hypophosphatemia in in FGF23 signaling (Kurosu et al. 2006). wild-type (WT) mice. A similarly elegant set of There is evidence that the phosphaturic action of experiments by Nesbitt et al. (1992), in which the FGF23 is to some extent PTH-dependent. Subjects transplantation of WT kidneys into hyp mice failed to with hypoparathyroidism, who have very low or correct hypophosphatemia, confirmed the etiology as a undetectable PTH levels, have high serum phosphorus circulating factor and not a primary renal defect. The in the setting of high serum FGF23, which is consis- first evidence to support this concept in humans was the tent with the need for PTH for the full phosphaturic work by Miyauchi et al. (1988), in which a TIO tumor effect of FGF23 (Gupta et al. 2004). This observation resected from a patient and transplanted into nude mice is further supported by the fact that in patients with caused hypophosphatemia and the work that showed TIO and XLH, medically induced hypoparathyroidism that the supernatant from cultured tumor cells could by cinacalcet results in increased renal phosphate also cause hypophosphatemia in mice (Cai et al. 1994). reabsorption and an increase in serum phosphorus This phosphaturic substance was termed ‘phospha- (Geller et al. 2007, Alon et al. 2008). tonin’ by Econs & Drezner (1994) because of its ability In addition to its action on NaPi-2a and NaPi-2c, to lower blood phosphorus level. FGF23 is also a regulatory hormone for 1,25-vitamin D The first identification of FGF23 as the putative (Shimada et al. 2004). Through downregulation of phosphatonin was when mutations in FGF23 were 1a-hydroxylase and up-regulation of 24-hydroxylase, identified by Econs and the autosomal-dominant it leads to a decrease in 1,25-dihydroxy vitamin. hypophosphatemic rickets (ADHR) consortium as the Other compounds such as frizzled related protein-4, cause of ADHR (ADHR Consortium 2000). FGF23 is a matrix extracellular phosphoglycoprotein, and FGF7 have member of the FGF ligand superfamily and functions also been suggested to be phosphatonins (De Beur et al. as an endocrine factor. It has a FGF-like amino 2002, White et al. 2006). However, the preponderance of terminus and a unique carboxy-terminus domain data to date suggests that FGF23 is the primary, if not the (ADHR Consortium 2000). Once identified as the only, clinically relevant phosphatonin. cause of ADHR, elevations in serum FGF23 were soon found in TIO (White et al. 2001), X-linked hypopho- sphatemia (XLH; Jonsson et al. 2003), FD (Riminucci et al. 2003), ADHR (Imel et al. 2007) and autosomal- Tumors associated with TIO have included a wide recessive hypophosphatemic rickets (ARHR; Feng range of histopathological diagnoses, and despite the et al. 2006). The first insight into the physiologic description and classification scheme proposed by

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Weidner (1991) and Folpe et al. (2004),many within a myxoid or myxochondroid matrix with clinicians and pathologists continue to be unaware of ‘grungy’ calcification that can resemble chondroid or these tumors as a distinct entity. The prototypical osteoid. Numerous osteoclast-like giant cells are a phosphaturic mesenchymal tumor (mixed connective frequent finding, and mature fat and even lamellar bone tissue variant) (PMTMCT) contains neoplastic cells may also be seen. A prominent feature of these tumors that are spindled to stellate in shape, normochromatic is an elaborate intrinsic microvasculature with an with small nuclei and indistinct nucleoli. A spectrum of admixture of vessel size and vascular pattern (Folpe histopathological features is shown in Fig. 2A–F. et al. 2004). The most common diagnosis for these The nuclear grade is low, and mitotic activity is usually tumors has been , but it has also absent or very low. The cells are typically embedded included hemangioma, , ossifying fibromas, granulomas, giant cell tumors, and osteoblastomas AB (Weidner 1991, Drezner 2001, Folpe et al. 2004). Weidner (1991) reviewed the literature of w60 cases of TIO that had been described at that time. They were the first to propose a classification system based on the histological findings of their 16 cases of TIO, and designated the tumors as phosphaturic mesenchymal tumors. These were then subdivided into four categories; mixed variant (PMTMCT), -like variant, non-ossifying fibroma-like variant, and ossifying fibroma-like variant. CD The first group, PMTMCT, comprised neoplasias containing primitive stromal cells, prominent vessel, and osteoclast-like giant cells (Fig. 2D and F). Osseous metaplasia and poorly formed -like areas with dystrophic calcification were also present (Fig. 2B and E). They noted that these tumors usually occurred in and were typically benign in behavior. The remaining three groups tended to occur in bone and were also typically benign in behavior. Folpe et al. (2004) reviewed the clinic-pathological features of 32 EF new cases and re-reviewed all of the previously published cases, and made the assertion that virtually all of the cases fell into the category of PMTMCT. Antigen expression was first evaluated in two immunohistochemical studies by Weidner et al. In the first study, the immunostainings were negative for FVIII-related antigen, S-100, and cytokeratin (Weidner et al. 1985). The second study revealed only vimentin immunoreactivity in some cases within the tumor cells. All other antibodies (desmin, S-100 protein, leu-M 1, Figure 2 TIO tumor histopathology. (A) This tumor area shows chromogranin, cytokeratin, neuron-specific enolase, immature mesenchymal cells, with no particular differentiation. There are areas of edema and blood lacunae (arrow). (B) This leukocyte common antigen, and factor VIII-related proliferation is solid, with what seems to be abundant antigen) were negative (Weidner et al.1985). In their intercellular matrix (arrow). The nuclei are typical with some series, Folpe et al. (2004) performed a series of variation in shape and size. (C) Numerous and irregular vascular structures (arrows), as well as areas of solid immunohistochemical stainings, including pan-cyto- proliferation, are seen in this tumor area. (D) This tumor is keratin, desmin, S-100, smooth muscle actin, CD34, composed mostly of irregular vascular structures (arrows) and FGF23. With the exception of smooth muscle actin, embedded in a relatively soft matrix. Variations in size and shapes of the nuclei are evident. (E) Lattice-like areas with which they found reactive in three cases, and FGF23, ossification (arrow). (F) This photomicrograph was taken from a which was positive in about 70% of all the cases lung . The area shows numerous very large studied, all other markers were negative. In terms of osteoclastic-like giant cells (arrows). Note that even though the proliferation is biologically malignant, there are few or no FGF23 staining, it is the proliferating cells within the histological signs of . tumor that usually stain positive for FGF23 (Fig. 3A).

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In terms of ultrastructural features, Stone et al. 1986, Harvey et al. 1992, Ogose et al. 2001, Uramoto (1992) described features consistent with a neuroendo- et al. 2009). Two of the 19 tumors in our series went on crine tumor in a PMTMCT from a 33-year-old woman. to metastasize (Figs 2F and 3B), a feature that is hard Neurosecretory granules were also found in the case by to predict from the benign histological appearance. Wilkins et al. (1995). However, immunostaining for While metastases are rare, infiltration of surrounding typical markers of neurosecretory tumors, such as connective tissue is typically present, which has S-100, neuron-specific enolase, chromogranin and significant implications for surgical management and synaptophysin, were negative, as was staining for emphasizes the importance for wide surgical margins actin, cytokeratin, epithelial membrane antigen, and to avoid persistence or recurrence – a point that cannot FVIII. The only positive finding was vimentin, be emphasized enough in the management of TIO. confirming what had been already described by It seems to be that PMTMCT constitute a single, Weidner. An additional case communicated by albeit morphologically heterogeneous, histopatho- Shelekhova et al. (2006) also showed similar neuro- logical entity. Regardless of tumor morphology, the secretory granules. hallmark of the diagnosis of a PMTMCT is the While typically benign, malignant presentation and association of the tumor with the clinical syndrome metastases can occur (Wyman et al. 1977, Rico et al. of TIO, which includes an elevation in plasma FGF23 and its disappearance after tumor resection. It is this A heterogeneity that may account for their frequent misdiagnosis (Folpe et al. 2004). To date, the immunohistochemical and electron microscopy findings have not shed light on the cell of origin of these neoplasias, but only served to confirm their mesenchymal origin. It is also quite possible that all of the tumors share a common origin: a primitive mesenchymal cell that itself has the ability to secrete the hormone and which can differentiate into several cell lineages. To summarize, PMTMCT are a group of tumors with a spectrum of histopathologic findings that include a background of spindle/stellate cells with low nuclear and mitotic activity. This is true even in cases of metastatic disease. Prominent vascularity is common and includes vessels of different sizes B and patterns, consistent with the fact that they are most commonly classified as . Lung parenchyma Osteoclast-like giant cells are frequently seen in these tumors and mature fat or lamellar bone can be present as well. FGF23 staining is positive and appears in the cytoplasm of the tumor cells. It is important to note that Metastasis histopathologic diagnosis of malignant disease is difficult, as even in clinically proven metastatic disease the cellular features appear benign.

Clinical evaluation A summary of our approach to the evaluation of these patients can be found in Fig. 4, and a summary of medical treatment recommendations can be found Figure 3 (A) FGF23 of lung metastasis in Box 1. Patients with TIO often present with of a PMTMCT. (B) The tumor shown in this slide was relatively many years of symptoms before they are diagnosed. homogeneous and composed mainly of spindle-shaped cells. The symptoms, which lead to their evaluation, are Note the relatively benign histological appearance of the neoplasia (inset). FGF23 reactivity was present in almost 100% non-specific, and often progressive. Common com- of the tumor cells. plaints are , muscle weakness, and multiple

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Diagnosis and treatment of tumor-induced osteomalacia 1. of tumor-induced osteomalacia

2. Confirm diagnosis • ↓ Pi, ↓ %TRP, ↓ 1,25-D, ↑ FGF23 • Exclude familial forms (if appropriate) Check: PHEX, FGF23, DMP-1, ENPP1

3. Tumor localization

• Functional imaging: FDG-PET/CT + Octreoscan/CT

Unsuccessful • Anatomical imaging: MRI and/or CT Medical treatment

• Venous sampling and/or aspiration (if necessary)

localized Repeat localization (1 year?)

4. Surgical excision (with wide margins)

Figure 4 Summary of the approach to diagnosis and treatment of patients with TIO. Pi, phosphate; %TRP, tubular reabsorption of phosphate; 1,25-D, 1,25-dihydroxyvitamin D. fractures (Jan de Beur 2005). Pediatric patients can Differential diagnosis develop rickets and growth retardation (Jan de Beur The differential diagnosis for hypophosphatemia 2005, Haeusler et al. 2010). These patients are often should first be separated into genetic versus acquired misdiagnosed with a variety of musculoskeletal causes. Genetic causes include XLH, ADHR, and ailments, rheumatologic diseases, and sometimes ARHR, which are essentially biochemical phenocopies even psychiatric disorders (Teasell & Shapiro 2002, of TIO. In all of these genetic forms of hypopho- Lewiecki et al. 2008). Hypophosphatemia caused by sphatemia, the plasma FGF23 is either directly impaired renal phosphate reabsorption is the bio- elevated or inappropriately normal. XLH is almost chemical hallmark of the disease. In many institutions, invariably present in early childhood, while ADHR can phosphate is no longer part of the routine chemistry present in either childhood or adulthood (Econs & panels, thus hypophosphatemia can often go unrecog- McEnery 1997). Therefore, a detailed personal history nized, further delaying diagnosis (Halperin et al. 2007). to identify the age of onset, which can often be aided by

Box 1 Medical treatment of tumor-induced osteomalacia Goal of therapy Low-end of normal for age-appropriate normal range of phosphorus Medication Dosing Phosphorus 15–60 mg/kg per day (w1–3 g/day for adults) Dose should be divided into 4–5 times/day to improve tolerance Calcitriol or alphacalcidiol 15–60 ng/kg per day (w0.75–3 mg/day for adults) Start 1.5 mg/day and titrate. Dose can be divided into BID and TID Monitoring Baseline renal ultrasound for evaluation of nephrolithiasis/nephrocalcinosis. † Repeat if concerning symptoms arise or there is persistent increase in urinary calcium Serum calcium, phosphorus and PTH every 3 months † If phosphorus level is below target, increase phosphorus supplements † If calcium level is below target, add/increase calcium supplements † If PTH elevated, increase calcitriol Urinary calcium (UCa) and creatinine (UCr) every 3 months (2nd AM void) † If UCa/UCr R0.2, check for urinary hemoglobin. Also check 24 h urinary calcium and creatinine with goal of normal range urinary calcium. Decrease calcitriol dose if positive urinary hemoglobin or elevated 24 h urinary calcium † If UCa/UCr %0.2, and serum phosphorus and PTH are at target, continue current regimen

Downloaded from Bioscientifica.com at 09/30/2021 04:30:57PM via free access www.endocrinology-journals.org R59 W H Chong et al.: Tumor-induced osteomalacia review of the growth chart in the case of young aminoaciduria, low molecular weight proteinuria, patients, and a detailed family history, looking for bicarbonaturia, calciuria, and others. However, the family members with short stature and bowed legs, is most important fact that distinguishes these genetic especially important in children and young adults. syndromes of hypophosphatemia from TIO is that Some genetic forms, especially XLH, are associated plasma FGF23 is high in TIO, but low in HHRH and with dental findings, including enamel hypoplasia, Fanconi syndrome. FGF23 levels in XLRH have not dental abscesses, and caries; thus, a detailed dental been reported, but should be low as well. The genes history is important (Baroncelli et al. 2006). Generally, for the genetic forms of hypophosphatemia, as well as the younger the patient is at presentation, the more various features, are detailed in Table 1. likely is a genetic cause. Additional genetic disorders In addition to the genetic causes of non-TIO hypo- that can present with hypophosphatemia and should phosphatemia, there are acquired causes. Most of the be considered in the hypophosphatemic patient are acquired forms of hypophosphatemia are the result of hereditary hypophosphatemic rickets with hypercal- direct renal tubular damage by a drug or a toxin. Tubular ciuria (HHRH; Bergwitz et al.2006), X-linked damage usually results in a generalized tubulopathy, recessive hypophosphatemia (XLRH)/Dent’s disease similar to what is seen in the genetic Fanconi-type (Scheinman 1998), and the inherited renal Fanconi tubulopathies mentioned above (Bonnardeaux & Bichet syndromes, Fanconi-Bickel syndrome (MIM ID 2008). This type of tubulopathy can be seen as a result 227810) (Santer et al. 1997) and Fanconi renal tubular of burns (Nordstrom et al.1977), heavy metal exposure syndrome (MIM ID 134600) (Lichter-Konecki et al. (cadmium, lead and arsenic) (Omdahl & DeLuca 2001). HHRH and XLRH differ from the other genetic 1971, Aranami et al.2010), aminoglycoside antibiotics, causes of hypophosphatemia in that hypercalciuria due certain chemotherapeutic agents, especially cisplatin, to increased 1,25-vitamin D accompanied by nephro- and the anti-retroviral drug, tenfovir, which is used in calcinosis and/or nephrolithiasis is a feature. Patients the treatment of HIV and hepatitis B (Davis et al.1980, with XLRH also have proteinuria. Patients with the Izzedine et al.2003, Earle et al.2004). It can also occur genetic Fanconi syndromes have a more generalized in association with and other dyspro- renal tubulopathy. This can include any combination of teinemias (Dash et al.1997). 1,25-vitamin D levels are

Table 1 Differential diagnosis of hypophosphatemia

Disease Gene FGF23 Other findings References

Genetic causes XLH PHEX Elevated Childhood onset, rickets and dental caries The HYP Consortium (1995) ADHR FGF23 Elevated Variable age of onset, may spontaneously White et al. (2000) remit and recur ARHR DMP-1, Elevated May have consanguinity in parents Feng et al. (2006) ENPP1 Lorenz-Depiereux et al. (2006a) Levy-Litan et al. (2010) Lorenz-Depiereux et al. (2010) HHRH SLC34A3 Low Increased 1,25-vitamin D, increased urinary Bergwitz et al. (2006) calcium, low PTH, and nephrocalcinosis Ichikawa et al. (2006) Lorenz-Depiereux et al. (2006b) XLRH/Dent’s CLCN5 Unknown Male predominance, hypercalciuria, Pook et al. (1993) nephrocalcinosis, kidney stones, and Lloyd et al. (1996) renal failure Oudet et al. (1997) Inherited Fanconi Various Low Glucosuria, aminoaciduria, calciuria, and Chadha & Alon (2009) proximal renal tubular acidosis Acquired causes TIO NA Elevated Variable age of onset, low 1,25-D, low Drezner (2001) TmP/GFR Jan de Beur (2005) Acquired Fanconi NA Low Glucosuria, aminoaciduria, proximal renal Izzedine et al. (2003) tubular acidosis, history of exposure to heavy metals, chemotherapeutic agents, etc. (see text)

XLH, X-linked hypophosphatemic rickets; ADHR, autosomal-dominant hypophosphatemic rickets; ARHR, autosomal-recessive hypophosphatemic rickets; XLRH, X-linked recessive hypophosphatemic rickets; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; XLRH, X-linked recessive hypophosphatemic rickets; TIO, tumor-induced osteomalacia.

Downloaded from Bioscientifica.com at 09/30/2021 04:30:57PM via free access R60 www.endocrinology-journals.org Endocrine-Related Cancer (2011) 18 R53–R77 variable, and can be low, as seen in TIO. Unlike TIO, In using these algorithms, it is important that units Fanconi-type syndromes tend to be associated with more for urine creatinine, urine phosphate, serum creatinine, severe proximal renal tubular defects and metabolic and serum phosphate are consistent. acidosis. Again, the key factor in discriminating these The normal reference ranges for TmP/GFR are age- sorts of disorders from TIO is the plasma FGF23 level, and gender-dependent, but have not been well defined which is low in cases of tubular damage, and high in TIO. in large patient populations. Reasonable age- and Other disorders which can be associated with hypopho- gender-dependent values are listed in Table 2, and are sphatemia are hematologic malignancies, total parenteral derived from data compiled by Stark et al. (1986), nutrition, organ transplant, refeeding syndrome, correc- Alon & Hellerstein (1994) and Payne (1998). tion of diabetic ketoacidosis, and dietary deficiency. TmP/GFR should be calculated from testing done in the fasting state, typically from second morning-void urine and blood samples taken at the same time. In the Approach to the diagnosis of TIO non-disease state, the values for TRP and TmP/GFR Diagnosis confirmation will be high when there is hypophosphatemia. In TIO, these values are abnormally low. It is important to note TIO should be suspected in patients who present with that the calculations of %TRP and TmP/GFR in consistent symptoms and with hypophosphatemia. patients with suspected TIO need to be done off of If hypophosphatemia is present, the presence of renal phosphate wasting should be confirmed. phosphate supplementation. Phosphate supple- Two ways to evaluate urinary phosphate wasting are mentation will elevate urinary phosphate in both the calculation of percent tubular reabsorption of subjects with and without TIO and can lead to falsely phosphate (%TRP) and tubular maximum for phos- low determinations of %TRP and TmP/GFR in patients phate corrected for glomerular filtration rate (GFR) without the disease. (TmP/GFR). Open access programs that calculate After confirming renal phosphate wasting as the %TRP and/or TmP/GFR can be found on the Internet etiology for hypophosphatemia, additional lab tests (by searching under these terms), but caution should be can be helpful in making the diagnosis of TIO. 1,25- exercised to enter the proper units (traditional versus vitamin D can be low or inappropriately normal. SI), as indicated by the site. TmP/GFR can be Calcium and PTH are usually normal, but PTH can calculated only in the fasting state, but %TRP can be be high reflecting secondary hyperparathyroidism, calculated at any time using the following formula: which is the normal response to low 1,25-vitamin D caused by elevated FGF23. Measurement of blood 100!ð1Kððurine phosphate=urine creatinineÞ FGF23 is now commercially available and is essential for the diagnosis. Currently, only the less-sensitive !ðserum creatinine=serum phosphateÞÞÞ: C-terminus assay is widely available for commercial When phosphate is normal, the normal range is testing (Imel et al. 2006). It is important to note that between 85 and 95%. this is only valid for plasma, not serum, samples. The The TmP/GFR is another measure of renal phos- most sensitive and specific assay for use in the phate handling and is independent of plasma phosphate diagnosis of TIO is the intact assay manufactured by and renal function. TmP/GFR can be determined using Kainos (Imel et al. 2006), which at present is typically a nomogram or algorithm (Kenny & Glen 1973, only used in research laboratories. Walton & Bijvoet 1975). Use of the algorithm is less Once the diagnosis of an FGF23-dependent, phos- cumbersome and there is no clinically significant phate wasting disorder is made, a thorough history can difference between the values obtained, making it the aid in excluding the genetic causes, such as XLH, preferred method (Barth et al. 2000). The formula used ADHR, and ARHR. Genetic testing can also be done. to calculate TmP/GFR is dependent on the value of Having narrowed the diagnosis to TIO, a careful TRP and can be calculated using the formulas below: physical examination should be performed, as the If TRP is %0:86 ð86%Þ; then TmP=GFR tumors that cause TIO can sometimes be found in the subcutaneous tissue (Fig. 5; Colt et al. 2005, Dewitt Z ! : TRP phosphate et al. 2007, Ogura et al. 2008). It is also prudent to ask If TRP is O0:86 ð86%Þ; then TmP=GFR the patient if she/he has noticed any new ‘lumps’ or ‘bumps’ as well as to examine the oral cavity, as Z : ! = K : ! ! : 0 3 TRP ð1 0 8 TRPÞ phosphate tumors have been reports in the jaws (Yun et al. 2009).

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Table 2 Normal ranges for tubular maximum for phosphate that are not tumors. This is especially true in patients with corrected for GFRa many areas of active fracture healing (Fig. 6). Another important functional imaging modality is Age Male mg/dl (mmol/l) Female mg/dl (mmol/l) 111Indium octreotide scintigraphy, ideally combined with Newborn 5.7–8.1 (1.27–2.59) 5.7–8.1 (1.27–2.59) single photon emission CT and CT (SPECT/CT). 1 month–2 years 3.6–5.4 (1.15–1.73) 3.6–5.4 (1.15–1.73) Somatostatin receptors have been found to be present 2–12 years 3.8–5.0 (1.22–1.60) 3.8–5.0 (1.22–1.60) on many TIO tumors (Duet et al. 2008)and111Indium- 12–16 years 3.4–4.6 (1.09–1.47) 3.4–4.6 (1.09–1.47) 16–25 years 3.33–5.9 (1.07–1.89) 3.18–6.41 (1.02–2.05) octreotide has a high affinity for the somatostatin receptor, 25–45 years 3.09–4.18 (0.99–1.34) 2.97–4.45 (0.95–1.42) especially subtype 2 and to a lesser extent subtype 5. As 45–65 years 2.78–4.18 (0.89–1.34) 2.72–4.39 (0.87–1.40) with FDG PET/CT, emphasis should be placed on making 65–75 years 2.47–4.18 (0.79–1.34) 2.47–4.18 (0.79–1.34) sure these imaging tests cover the entire body, from aReferences (Stark et al. 1986, Alon & Hellerstein 1994, head to toe, including the hands and feet. Standard Payne 1998). PET/CT and octreotide often exclude portions of the extremities and may exclude portions of the head. Localizing studies: functional imaging Addition of co-registered CT to both FDG-PET and octreotide significantly increases the ability to localize As tumors can arise in bone or soft tissue, occur from tumors, and whenever possible it should be performed. head to toe, and are typically very small in size, locating More recently, 68Ga-DOTANOC PET/CT has been these tumors is often quite challenging. We have seen explored as a means of finding TIO tumors (Hesse et al. in our cohort of patients that tumors are found more 2007a, von Falck et al. 2008). This scan combines the commonly in bone than in soft tissue. specificity of octreotide scanning with the sensitivity of We advocate a stepwise approach, first performing PET/CT. It utilizes a modified octreotide molecule functional tests. In our hands, F-18 fluorodeoxyglucose (DOTANOC) that has increased affinity for both positron emission tomography, with computed tomo- somatostatin receptor 2 and 5 (Wild et al. 2003, graphy (FDG-PET/CT), has proven to be most sensitive 2005). Labeling this compound with the positron for localizing TIO tumors (Dupond et al. 2005b, emitter 68Ga results in a PET compound that may be Andreopoulou et al.2010a, Jagtap et al.2010). However, more specific than FDG. However, studies comparing while FDG-PET/CT may be very sensitive, it is also 68Ga-DOTANOC PET/CT with standard octreotide non-specific and identifies areas of metabolic activity SPECT/CT in the diagnosis of TIO have not been done.

ABD

C

E

Figure 5 Subcutaneous TIO tumor detectable on physical examination. Physical examination of a patient with TIO (the same patient shown in Fig. 1) revealed a subcutaneous (A). This nodule was implicated as the culprit tumor by the fact that it was detected on functional imaging, FDG-PET (B). The was visualized on CT scan, which also suggested intralesional calcification (C, arrow). On the low-power view, it can be seen that the tumor was completely contained in the subcutaneous tissue (D), and on a high-power view, it was revealed that the calcification in the lesion was actually ossification and contained areas of lamellar bone (E). TIO resolved after excision.

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ABD

C E

Figure 6 Multiple imaging modalities may be needed to localize TIO tumors. In this patient, FDG PET/CT revealed multiple areas of increased uptake (A). Octreotide scan only demonstrated a single lesion (B–D). MRI revealed a tumor in the area identified on functional imaging (E). TIO resolved after excision of the lesion.

201Thallium and 99Technetium MIBI scintigraphy resonance imaging (MRI) scans. Some investigators have been used in TIO (Kimizuka et al. 2004, Hodgson advocate total body MRI as an initial imaging study. et al. 2006), but we have not found them to add However, we have not found this approach to be anything to FDG-PET or octreotide scanning. fruitful. It should also be noted that there are ‘blind’ 99Tc-MDP (bone scans) has not spots on both FDG-PET and octreoscan; brain uptake proven to be a useful study in localization of TIO on FDG-PET may obscure intracranial tumors, and tumors (Lee et al. 1995, Garcia & Spencer 2002). It liver and spleen uptake of octreotide may obscure often reveals multiple foci of uptake at areas of fracture potential in these regions. Therefore, ana- and may actually misdirect the effort to localize the tomical imaging of these areas may be indicated if a tumor. Of interest, though, is that 99Tc-MDP bone tumor has not been identified. scans often show uptake at the costochondral junctions (a sort of adult rachitic rosary) and areas of the bone in Venous sampling skeletally mature adults where the growth plates were previously located (Fig. 7). This finding should suggest Usually, the combination of functional and anatomical the diagnosis of TIO, and may represent a sort of imaging is successful in localizing the FGF23- ‘pseudo-reactivation’ of growth plates in the adult secreting tumor. However, there are certain circum- skeleton. The pathophysiology underlying this inter- stances in which more certainty and testing are esting and frequently observed phenomenon is unclear indicated. Often, more than one lesion is found on at this time. Importantly, this finding should not be functional imaging, particularly FGD-PET, each with a misinterpreted as evidence of metastatic tumor, as it reasonable degree of suspicion or the suspicious lesion sometimes is. is located in an area where the indicated operation is associated with a high level of potential morbidity. In these cases, additional certainty and testing are Localizing studies: anatomical imaging indicated. Of particular utility is selective venous Once suspicious lesions have been identified with sampling with measurement of FGF23 (Andreopoulou functional imaging, one should proceed to anatomical et al. 2010b). Examples of the utility of venous imaging to confirm the location of the tumor. Anatomic sampling in distinguishing between multiple sites and imaging studies include X-rays, CT, and/or magnetic difficult sites are shown in Fig. 8.

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A C is diagnostic of a culprit lesion. Inspection of cells in the aspirate may reveal cellular morphology consistent with that of a phosphaturic mesenchymal tumor, further supporting that the aspirated lesion represents the culprit lesion (Sciubba et al. 2009). Despite all of the advances in imaging that are available today, tumor localization may not be successful. If this is the case, imaging studies should be repeated in hopes that a tumor may be more evident with time. This can be done every 1–2 years. B

Treatment Surgical resection The treatment of choice for TIO is resection of the tumor with a wide margin to insure complete resection. Resection with a wide surgical margin is of utmost importance, as recurrences of these tumors have been reported (Clunie et al. 2000, Ogose et al. 2001, Figure 7 ‘Pseudo-reactivation’ of growth plate. X-ray (A) and Uramoto et al. 2009). Tumor resection is almost bone scan (B) of a patient with TIO showing areas of intense always curative, and following complete resection of tracer uptake and evidence of ‘growth plates’ in a 54-year-old the tumor, there is relatively rapid improvement. man who had senesced his growth plates decades before. A bone scan of another adult patient with TIO (C) revealed intense FGF23 has a halflife of w45 min and disappears tracer uptake at multiple costochondral junctions, creating the rapidly from the circulation (Khosravi et al.2007). The equivalent of an adult rachitic rosary. majority of patients demonstrate surgical cure, as evidenced by the return of serum phosphate to normal, Venous sampling has been attempted in localizing by post-operative day 5. Some patients may take as tumors in the absence of any suspicious lesions long as 10 days and, in children, we have seen identified on either functional or anatomical imaging, phosphate return to normal in as few as 2 days. In fact, the so called ‘blind sampling’. In a trial designed to test it is return of serum phosphorus to normal after tumor this, we were unable to localize tumors by venous resection that confirms the diagnosis of TIO. Most sampling without a ‘target’ lesion suggested by patients feel better within days to weeks of tumor anatomical or functional imaging, and concluded this removal. Bone healing starts immediately, but depend- was not a useful approach (Andreopoulou et al. ing on the severity of the disease, it may take up to a 2010b). Van Boekel et al. (2008) advocated a two- year or more for significant clinical improvement. step approach to venous sampling. They suggested that Late recurrence due to metastatic disease is rare but if a suspected tumor cannot be localized by imaging, possible. This probably occurs in !5% of the patients whole body venous sampling can be performed with with TIO (Ogose et al. 2001, Folpe et al. 2004). Lung is assessment of the average values for samples from a common site for metastasis (Fig. 3), and as such different anatomical regions. If the average values in should be closely evaluated when there is a late samples from a region appear to be higher, more recurrence without evidence of local disease. The detailed sampling is performed in the smaller branches lesions can be quite small and difficult to visualize. of the veins in that region. In the one patient studied by Therefore, high-resolution CT is recommended as the this approach, it appeared to suggest a particular imaging modality of choice. More advanced disease region. However, in retrospect, the tumor was evident may present with a miliary pattern. The course after on an MRI that had been performed prior to venous metastasis is quite variable, and survival of up to 30 sampling, so the utility of this approach is not clear. years has been reported (Harvey et al. 1992). In our An additional approach that can be used for series of 31 cases of TIO, we have seen two cases of confirmation that a suspicious lesion identified on recurrence due to tumor metastasis in the lung (Fig. 3). functional or anatomical imaging is the culprit tumor is There is no chemotherapeutic regimen with any aspiration of the lesion. Elevated FGF23 in the aspirate demonstrated efficacy in treating metastatic TIO.

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A C 700

600 L acetabular lesion

500

400 R patellar lesion

300 FGF23 (pg/ml) 200 B 100

0

r hepatic r sfv high r sfv lower R popI vertebral low I sfv prox r internal iliac I int iliac low I int iliac mid r deepr commonfem low iliac r pop very high I commonI common iliac fem r pop above knee I circumflex prox r pop above patella r lower pop very low I sfv very low distalI int iliac ischI internal border iliac small

I internal iliacI internal large branch... iliac large branch.. I internal iliac large branch low

D E F

G H 100 90 80 Catheter tip 70 60 50 40 Catheter 30 Venous sampling FGF23 (pg/ml) 20 10 0

Peripheral Right sinus Right petrosal Right jugular (low) Right anterior facial

Superior sagittal sinus (mid) Superior sagittal sinus (mid) Superior sagittal sinus (anterior) Superior sagittal sinus (posterior)

Figure 8 Utility of selective venous sampling in TIO. Selective venous sampling is useful in distinguishing between multiple suspect lesions, as in this patient who had uptake at both the region of the acetabulum (A) and patella (B). Elevated FGF23 in the veins draining the acetabular region (C) identified the lesion in this region as the causative lesion. Selective venous sampling is also useful in identifying lesions in places difficult to image or to approach surgically. The brain shows generalized increased uptake on FDG PET/CT (D) making identification of a lesion in this area difficult. A lesion was seen on octreotide scan (E) and MRI (F). It was felt that this could be a TIO tumor or a meningioma, which are also octreotide positive. Venous sampling (G) demonstrated elevated FGF23 (H), confirming that the lesion was the FGF23-secreting tumor. This material is reproduced from Andreopoulou et al. 2010b with permission of John Wiley & Sons, Inc. r, right; l, left; pop, popliteal; sfv, superficial femoral vein; fem, femoral; prox, proximal; comm, common; int, internal; isch, ischial; mid, middle. (RFA) has also been treatment. The patient showed complete biochemical reported as a possible treatment modality (Hesse et al. and symptomatic recovery within weeks, and had 2007b). Hesse et al. reported use of RFA in a 40-year-old unremarkable follow-up at 1 year. While this is woman with TIO, in whom the tumor was located in promising, long-term follow-up and effectiveness in the femoral head. In order to preserve the hip joint, other cases remains to be seen. Again, the need for a wide CT-guided RFA was performed in two rounds of margin is advocated to avoid recurrence or metastasis.

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Medical treatment low urinary calcium, or hypocalcemia. As bone healing When the tumor cannot be localized or is not surgically progresses, the regimen needs to be modified. Calcium resectable, medical therapy with phosphate supple- supplementation and/or active vitamin D treatment usually need to be decreased. One consequence of mentation and calcitriol or alfacalcidiol is used. The over-treatment with active vitamin D is the develop- treatment regimen that follows is essentially the same ment of hypercalciuria and the risk for nephrocalci- as that used in non-TIO causes of hypophosphatemia. nosis/nephrolithiasis. While on chronic treatment, When initiating treatment, it is prudent to check periodic measurement of urine calcium should be weekly labs to guide titration of medications until performed. Prolonged phosphorus supplementation can treatment targets are reached. lead to the development of tertiary hyperparathy- Phosphorus supplementation is the mainstay of roidism. This may require partial parathyroidectomy, treatment. However, since phosphorus is rapidly or treatment with the calcium-sensing receptor absorbed and cleared, multiple doses throughout the agonist, cinacalcet. day are necessary (at least 3–4 times per day) in an The treatment regimen is to give 15–60 mg/kg per attempt to try and get the serum phosphorus to the day of elemental phosphorus (typically 1–3 g/day) lower end of the age-appropriate normal range. divided into 4–6 doses. Various formulations with Treatment to the lower end of the age-appropriate varying amounts of phosphorus are available (Table 3). range has been shown by bone to improve bone Calcitriol or alfacalcidiol is given at 15–60 ng/kg disease. Whether treatment to targets below the normal per day, with a typical starting dose of 1.5 mg/day in range is effective remains unclear. GI upset and an adult. diarrhea may develop as a result of phosphate A new treatment approach that holds promise, but supplementation. GI side effects can sometimes be needs additional study for confirmation of efficacy and alleviated with divided dosing and administration with establishment of safety, is cinacalcet, an agonist of the food; however, they should not be provided with calcium-sensing receptor that lowers blood PTH levels calcium-rich foods. GI side effects can also sometimes (Geller et al. 2007). The use of cinacalcet was be avoided by using concentrated oral preparations that advocated on the basis of evidence that FGF23 action were developed for treatment of constipation or for was PTH-dependent. Gupta et al. (2004) found that bowel preparation prior to endoscopy. Various both FGF23 and serum phosphorus were high in the phosphorus supplement preparations are listed in blood of patients with hypoparathyroidism, indicating Table 3. Secondary hyperparathyroidism can be seen that in the absence of PTH, FGF23 was unable to on presentation, due to suppression of 1,25-vitamin D adequately lower blood phosphorus level. This led to by FGF23, or it can develop as a result of phosphorus the notion that medically induced hypoparathyroidism supplementation. Active vitamin D (calcitriol or may be a potential treatment for TIO (Geller et al. alfacalcidiol) is used to prevent or treat secondary 2007). In this paper, we were able to show that hyperparathyroidism. The dose is titrated to keep the cinacalcet increased %TRP and serum phosphorus, PTH in the normal range. In the early phases of the allowed for a decrease in phosphate supplementation, treatment of severe , additional calcium and led to bone healing, as assessed by iliac crest bone supplementation may be necessary to provide mineral biopsy. However, hypercalciuria developed, necessi- ion substrate to heal the bone. Addition of calcium tating the addition of a thiazide diuretic to lower supplements or increases in calcitriol and/or alfacalci- urinary calcium. Similarly, cinacalcet has shown diol are indicated for difficult to suppress PTH, very promise in treating patients with XLH, which is also a disorder of excess FGF23 (Alon et al. 2008, Table 3 Phosphorus supplements Yavropoulou et al.2010). In patients with TIO Phosphorus source Amount of elemental phosphorus treated with cinacalcet, urinary calcium must be monitored carefully to avoid nephrocalcinosis and/or Neutra-Phos 8 mmol (248 mg) per capsule/packet nephrolithiasis. Neutro-Phos K 8 mmol (248 mg) per capsule/packet A previously advocated treatment for TIO was the K-Phos Neutral 8 mmol (248 mg) per tablet K Phos Original 3.68 mmol (114 mg) per tablet somatostatin analog, octreotide (Seufert et al. 2001). Fleet’s Phospho Soda 4.15 mmol (128.65 mg) per ml This appeared to be a logical treatment, given the Joulies Solution Varies depending on compounding presence of somatostatin receptors on the cell surface of TIO tumors and the ability to detect the tumors with Adapted from http://www.globalrph.com/phosphate_supplements. radiolabeled octreotide. However, most clinicians have htm; http://www.newbornnetworks.org.uk/staffs/Nutrition.pdf. not been able to reproduce the success that Seufert

Downloaded from Bioscientifica.com at 09/30/2021 04:30:57PM via free access R66 www.endocrinology-journals.org Endocrine-Related Cancer (2011) 18 R53–R77 et al. had in the single patient they reported. Paglia given to localization of the tumor. We were unable to et al. (2002) reported their lack of success in a single replicate these findings in a single patient in whom we patient, and we saw no effect in five patients and have attempted this treatment (unpublished data). Whether abandoned further attempts (unpublished data). calcitonin is truly an effective treatment awaits further Few reports are available on the role of external investigation. beam radiation or in the treatment of Future treatment will likely be guided by a better these patients. In the few reports that mention radiation understanding of the biology of FGF23 and the nature therapy, there does not appear to be any clear benefit of these tumors. Recent investigations have led to a (Fuentealba et al.2003, Uramoto et al.2009). rudimentary understanding of FGF23 synthesis, post- Chemotherapy regimens that have been reported translational modification, and signaling. While eluci- include the combination of cisplatin, doxorubicin, dation of the transcriptional and translational and methotrexate (Terek & Nielsen 2001) as well as regulation of FGF23 is still lacking, it has become the use of dasatinib (Peters et al. 2010). In the first case, evident that posttranslational glycosylation by UDP-N- chemotherapy was pursued as the first option as the acetyl-alpha-D-galactosamine:polypeptide N-acetylga- patient was felt to have an . Following lactosaminyltransferase 3 (GalNAc-T3) is essential for treatment, the patient’s phosphate normalized (Terek the secretion of biologically active FGF23 (Topaz et al. & Nielsen 2001). In the second case, the patient had 2004, Benet-Pages et al. 2005, Frishberg et al. 2005, recurrent disease that could not be completely resected. Dumitrescu et al. 2009). The fact that patients null for Due to strongly positive immunohistochemical stain- GalNAc-T3 have a phenotype that is completely ing of platelet-derived growth factor receptor, the confined to abnormalities in mineral metabolism patient was started on dasatinib and has been stable on suggests that GalNAc-T3 may eventually be a this therapy (Peters et al. 2010). Given the limited therapeutic target for diseases of FGF23 excess, such evidence for either radiation or chemotherapy, their as TIO. A promising therapeutic currently in clinical roles in treating these patients are not known at this trials are monoclonal antibodies that target the FGF23– time. Given the slowly proliferating nature of these FGFR1interaction(Aono et al.2009, 2010). A tumors, we would expect that these treatments would monoclonal antibody that disrupts the interaction of have little efficacy. FGF23 with the FGFR appears to be the mechanism of action with this approach. Medical treatment: monitoring A baseline ultrasound should be obtained, and blood Conclusion and urine studies should be monitored approximately TIO is a fascinating paraneoplastic syndrome caused every 3 months. For urine tests, checking the second by unregulated over-secretion of the recently identified morning void for calcium and creatinine is suggested to phosphate and vitamin D regulating hormone, FGF23. assess for hypercalciuria. If the calcium/creatinine is It is a debilitating disease that is cured with excision of R0.2, urinalysis should be done to check for the the tumors. The benign-appearing histopathology presence of blood in the urine. If this is present, typically seen in these tumors can be misleading, as calcitriol should be decreased and a 24 h urine for even clinically proven metastatic disease can have calcium and creatinine should be checked with a goal benign cellular features. While the tumors can be of obtaining normal urinary calcium/creatinine ratio. If difficult to locate, a step-wise approach that involves this remains elevated, calcitriol should be decreased functional imaging, followed by anatomical imaging, further. If calcium/creatinine is !0.2 and the serum and, if necessary, selective venous sampling or phosphorus and PTH are within targets, the current aspiration for confirmation is usually successful. regimen can be maintained. A summary of medical Excision with wide margins is important to avoid late therapy and monitoring is provided in Box 1. recurrence. When tumors cannot be identified, medical treatment can be successful though periodic surveil- Future directions lance is necessary. Treatment with calcitonin has also been explored as a method to suppress FGF23 (van Boekel et al. 2008). A Declaration of interest single s.c. injection of calcitonin was able to suppress The authors declare that there is no conflict of interest that FGF23 levels by 44.6% at 9 h post-injection. Long- could be perceived as prejudicing the impartiality of the term treatment, however, was not pursued as focus was research reported.

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