Tumor-Induced Osteomalacia

Home , Hyperphosphatemia, Hypophosphatasia, Hypophosphatemia, Oncogenic osteomalacia, Osteomalacia, Short stature

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GRAND ROUNDS CLINICIAN’S CORNER AT THE JOHNS HOPKINS BAYVIEW MEDICAL CENTER

Suzanne M. Jan de Beur, MD Tumor-induced osteomalacia (TIO) is a rare paraneoplastic form of renal phos- CASE PRESENTATION phate wasting that results in severe hypophosphatemia, a defect in vitamin D Ms R, who is 55 years old, developed a metabolism, and osteomalacia. This debilitating disorder is illustrated by the rare disorder nearly 20 years ago that clinical presentation of a 55-year-old woman with progressive fatigue, weak- initially went undiagnosed for more ness, and muscle and bone pain with fractures. After a protracted clinical course than a year despite numerous physi- and extensive laboratory evaluation, tumor-induced osteomalacia was iden- cian visits. Since her initial diagnosis, tified as the basis of her clinical presentation. In this article, the distinctive Ms R receives medical therapy that has clinical characteristics of this syndrome, the advances in diagnosis of TIO, and improved her symptoms; however, definitive therapy has been thwarted be- new insights into the pathophysiology of this disorder are discussed. cause the tumor causing her illness re- JAMA. 2005;294:1260-1267 www.jama.com mains obscure. DR JAN DE BEUR: Back in 1984, nists at 2 different institutions, a psy- care for them and for myself. Now, it is when you had onset of this disorder, chiatrist, and a family practitioner. I was frustrating to know the diagnosis but not what difficulties were you experienc- hospitalized for several days but the be able to definitively treat it. ing at that time? evaluation was unrevealing. DR JAN DE BEUR: Do you have any- MS R: Initially, I experienced pain on DR JAN DE BEUR: What was the ini- one in your immediate or extended fam- the bottom of my right foot that quickly tial finding that suggested your diag- ily with similar symptoms, unex- progressed to pain in both feet. Within nosis? plained broken bones, short stature, a month, the pain had progressed to my MS R: I saw a rheumatologist at an bowed legs, or low blood phosphorus? whole body and had intensified in academic medical center who discov- MS R: No—both my sons are alive severity. ered that I had a low blood phospho- and well and more than 6 feet tall. There DR JAN DE BEUR: What happened rus level. is no one else with low blood phospho- when you began seeking medical at- DR JAN DE BEUR: What were you rus. My sister and brother are alive and tention? treated with and how did you respond well, with normal height and normal MS R: The initial diagnosis was to treatment? blood phosphorus. “fallen arches.” Then I was told that the MS R: Initially, I was treated with At 37 years of age, Ms R presented excruciating muscle weakness and pain phosphorus alone. Despite this treat- with abrupt onset of profound fatigue I was experiencing was stress-related. ment, the fractures I had sustained in accompanied by bone pain that be- When I persisted, some blood work was my ribs and pelvis were not healing, my came progressive and debilitating. She sent but I was told that the blood work blood phosphorus was not improving, sought medical attention but was told was “normal.” At one point, when I be- and my severe pain persisted. Once cal- that her symptoms were psychologi- came so debilitated and weak that I was citriol was added to the phosphorus, my cal, and at one point, was diagnosed as unable to function well in my daily ac- symptoms improved substantially having conversion disorder. Still undi- tivities, I was given the diagnosis of con- within 6 months. agnosed, she experienced rib and pel- version disorder. DR JAN DE BEUR: What has been the vic fractures. Finally, after more than DR JAN DE BEUR: How long did it take most difficult part of living with this rare disorder? Author Affiliation: Department of Medicine, Johns before a diagnosis was made? Hopkins University School of Medicine, and Depart- MS R: Close to a year. I sought medi- MS R: Initially, not knowing what was ment of Endocrinology, Johns Hopkins Bayview Medi- wrong with me and why I was in so cal Center, Baltimore, Md. cal attention from a podiatrist, inter- Corresponding Author: Suzanne M. Jan de Beur, MD, much pain. I wondered if I was losing Johns Hopkins University School of Medicine, Johns my mind. I had the sole responsibility Hopkins Bayview Medical Center, 4940 Eastern Ave, CME available online at for 2 children and I could not function B114, Baltimore, MD 21224 ([email protected]). www.jama.com Grand Rounds Section Editor: David S. Cooper, MD, well. I was worried about being able to Contributing Editor, JAMA.

TUMOR-INDUCED OSTEOMALACIA a year, an astute physician recognized 1.1 mg/dL (97 µmol/L), a low phos- mia stimulates calcitriol synthesis via the connection between her low se- phorus level of 1.2 mg/dL (0.36 mmol/ 25-hydroxyvitamin D–1␣-hydroxy- rum phosphorus levels and her pro- L)(normal range, 2.5-4.5 mg/dL [0.81- lase in the kidney, leading to in- found fatigue, weakness, bone pain, and 1.45 mmol/L]), an elevated alkaline creased calcium and phosphorus ab- fractures, and she was diagnosed as hav- phosphatase level of 137 U/L (normal sorption in the intestine and enhanced ing osteomalacia. Medical therapy was range, 30-120 U/L), and an inappro- mobilization of calcium and phospho- initiated with oral phosphorus alone, priately low 1,25-dihydroxyvitamin D rus from bone (FIGURE 1). The result- with little improvement, then cal- level of less than 5 pg/mL (normal ant increased serum calcium and in- citriol was added and significant im- range, 9-52 pg/mL). Her tubular reab- creased calcitriol inhibit PTH secretion, provement in her symptoms followed. sorption of phosphate was very low at with a subsequent increase in urinary It was upon transferring her care when 10% (normal range, 78%-98%), indi- calcium excretion and increased tubu- she moved to Baltimore, Md (more than cating renal phosphate wasting. Her 25- lar reabsorption of phosphorus. Thus, 10 years after her original diagnosis) hydroxyvitamin D level was normal. normal serum calcium levels are main- that the diagnosis was refined from os- Her intact parathyroid hormone (PTH) tained and serum phosphorus levels teomalacia to tumor-induced osteoma- level, which was reportedly normal be- are returned to normal. In addition, hy- lacia (TIO). The distinguishing clini- fore initiation of therapy, was elevated pophosphatemia is a potent stimula- cal features that suggested TIO were the at 124 pg/mL (normal range, 10-65 pg/ tor of renal tubular reabsorption of presence of renal phosphate wasting mL) when she was evaluated in Balti- phosphate. and an inappropriately low 1,25- more, after she had been treated for sev- The kidney is the principal organ that dihydroxyvitamin D level before treat- eral years. Fibroblast growth factor 23 regulates phosphate homeostasis. Se- ment with calcitriol. In an effort to lo- (FGF-23) levels measured during treat- rum inorganic phosphorus is filtered by cate and remove the causative tumor, ment were markedly elevated at 3768 the glomerulus and 80% of the filtered Ms R has endured a series of disap- relative units/mL (normal range, 0-150 load is reabsorbed predominantly along pointing tumor localization proce- relative units/mL). Of note, Ms R had the proximal nephron. Regulation of dures and has had complications of the previously documented normal se- proximal renal tubular reabsorption of medical therapy for TIO. Extensive im- rum phosphorus levels. phosphate is achieved through changes aging, including octreotide scanning, in the activity, number, and intracel- has been unrevealing in locating the DISCUSSION lular location of the brush border mem- causative tumor. In pursuit of the tu- Ms R’s case is instructive for 2 rea- brane type IIa sodium-phosphate co- mor, she has undergone 2 surger- sons: first, it shows that an internist transporter (NaPiIIa). ies—1 to remove a suspected sinus tu- should consider TIO in any patient with Parathyroid hormone is the best- mor and 1 to remove a suspected tumor persistent, enigmatic bone pain accom- characterized physiological regulator of near her thyroid. Neither surgery panied by low serum phosphorus lev- phosphorus reabsorption, but its prin- yielded the causative tumor or led to els. Second, basic investigation of TIO cipal function is to maintain calcium the remission of the biochemical mani- is providing exciting breakthroughs in homeostasis. Parathyroid hormone in- festations of TIO. Ms R has experi- understanding of the pathogenesis of creases urinary phosphate excretion via enced complications of long-term treat- TIO and other metabolic disorders of cyclic adenosine monophosphate– ment with phosphorus and calcitriol; phosphate homeostasis. dependent inhibition of NaPiIIa expres- she has developed both nephrolithia- sion. This effect is rapid and is achieved Phosphate Homeostasis: sis and tertiary hyperparathyroidism. by internalization of NaPiIIa transport- Currently, the location of Ms R’s tu- Current Understanding ers from the brush border membrane mor is unknown. Phosphorus is a critical element in skel- and enhanced lysosomal degradation. On physical examination, her vital etal development, bone mineralization, However, this classic PTH–vitamin D signs are normal; her height is 66 in. Her membrane composition (phospholip- axis does not account for all the com- physical examination results are normal. ids), nucleotide structure (adenosine tri- plexities of phosphate homeostasis, and In particular, she has no bowed legs or phosphate, which provides energy and the study of renal phosphate-wasting sequelae of rickets. She has no palpable serves as components of DNA and RNA), syndromes has revealed several novel masses with special attention to the ex- and cellular signaling (phosphorylated regulators. tremity examination and oral cavity ex- intermediates). amination. The serum phosphorus level is main- Tumor-Induced Osteomalacia Ms R’s laboratory evaluation before tained within the normal range through Tumor-induced osteomalacia, or on- treatment included a normal calcium a complex interplay among intestinal cogenic osteomalacia, is a paraneo- level of 8.4 mg/dL (2.1 mmol/L) (nor- absorption, exchange with intracellu- plastic syndrome of renal phosphate mal range, 8.4-10.5 mg/dL [2.1-2.6 lar and bone storage pools, and renal wasting (FIGURE 2). Since the initial ob- mmol/L]), a normal creatinine level of tubular reabsorption. Hypophosphate- servation by McCrance,1 clinical and ex-

TUMOR-INDUCED OSTEOMALACIA perimental studies implicate the hu- Clinical and Biochemical Features ceeds 2.5 years.2 Once the syndrome is moral factor(s) propagated by tumors As Ms R illustrates, most patients with recognized, inability to locate the un- in the profound biochemical and skel- TIO are adults who report long- derlying tumor3 further delays defini- etal alterations observed in TIO. Tumor- standing, progressive muscle and bone tive treatment by an average of 5 years. induced osteomalacia is a rare disor- pain, weakness, and fatigue that often In Ms R’s case, the tumor remains elu- der, with approximately 120 cases predate the recurrent fractures that com- sive to date, 19 years after the diagno- reported in the literature (undoubt- plicate TIO. When manifested in child- sis. Until the causative tumor is identi- edly, there are many more cases that hood, rachitic features including gait dis- fied, the diagnosis of TIO is presumptive have not been reported),2 yet progress turbances, growth retardation, and and other renal phosphate-wasting syn- in understanding its pathogenesis is skeletal deformities are observed. The oc- dromes must be considered. Therefore, contributing to understanding of hy- cult nature of TIO delays its recogni- it is important to note that in patients pophosphatemic disorders and nor- tion, and the average time from onset of with TIO, a family history of hypophos- mal phosphate homeostasis. symptoms to a correct diagnosis often ex- phatemia and bone disorders is absent

Figure 1. Phosphate Homeostasis

Hypophosphatemia activates homeostatic mechanisms in the kidney, intestinal tract, In the parathyroid gland, increased 2+ and bone to maintain serum phosphate (Pi) levels in the normal range. 1,25-(OH)2 vitamin D and serum Ca levels decrease parathyroid hormone Low serum Pi levels stimulate the final step of the conversion of (PTH) synthesis via inhibition of PTH gene vitamin D to its active form, 1,25-dihydroxyvitamin D (1,25- transcription. Increased serum Ca2+ levels [OH]2 vitamin D) via the enzyme renal 1α-hydroxylase. also inhibit the release of PTH-containing secretory granules.

25-OH Vitamin D Increased 1,25-(OH)2 Vitamin D

Increased 1,25-(OH)2 vitamin D 1α-Hydroxylase levels increase intestinal absorption of calcium (Ca2+) and PARATHYROID KIDNEY 2+ 2+ GLAND 1 Pi and mobilize Ca and Pi from Ca bone.

Pi 2 Increased 1,25-(OH)2 Vitamin D Serum Ca2+ (Calcitriol) Ca2+

INTESTINAL TRACT 3 Decreased PTH Secretion BONE

In the proximal renal tubule, low serum Pi levels and decreased PTH levels Homeostatic Response to Hypophosphatemia increase the expression and activity of apical sodium-phosphate cotransporters (NaP IIa), increasing P reabsorption. i i Low Serum Pi

4 1 Increased Synthesis Increased of 1,25-(OH)2 Vitamin D Pi Reabsorption LUMEN 2 Increased 2+ Serum Ca ?

Decreased PTH levels and 2+ 3 Decreased PTH NaP IIa increased serum Ca levels i Ca2+ 2+ Secretion Cotransporter inhibit renal Ca reabsorption.

Decreased Renal 4 Increased Renal 2+ Reabsorption of Ca 5 Reabsorption of Pi Increased Ca2+ 5 Excretion

2+ Normal Serum Pi and Ca Levels PROXIMAL TUBULE

TUMOR-INDUCED OSTEOMALACIA and onset and severity of symptoms are secondary to reduced proximal renal tu- Diagnostic Evaluation more acute than in some other hypo- bular phosphorus reabsorption, and Laboratory Studies. The evaluation of phosphatemic syndromes, such as X- frankly low or inappropriate normal suspected TIO consists of a battery of se- linked hypophosphatemia (XLH). Iden- levels of serum calcitriol (1,25- rum and urine measurements, includ- tification of previously normal serum dihydroxyvitamin D) that should be el- ing fasting serum phosphorus; a chem- phosphorus levels in an adult patient evated in the face of hypophosphate- istry panel with serum calcium, alkaline supports the diagnosis of TIO, al- mia. The degree of hypophosphatemia phosphatase, and creatinine; intact PTH; though in rare instances patients with au- is usually profound and can range from serum 1,25-dihydroxyvitamin D (cal- tosomal dominant hypophosphatemic 0.7 to 2.4 mg/dL.2 Serum calcium and citriol); and fasting 2-hour urine phos- rickets (ADHR) may present in adult- 25-hydroxyvitamin D levels are nor- phorus, creatinine, calcium, amino ac- hood. In cases in whom inherited hypo- mal and serum concentrations of in- ids, and glucose. The best way to assess phosphatemic rickets must be ex- tact PTH are only occasionally el- phosphate homeostasis is by calculat- cluded, genetic testing for mutations of evated. Serum alkaline phosphatase is ing the maximum tubular resorption of the PHEX gene (phosphate-regulating typically elevated and is primarily de- phosphorus factored for glomerular fil- gene with homologies to endopepti- rived from bone. In TIO, a more global tration rate (TmP/GFR). This represents dases on the X chromosome; defective proximal tubular defect (known as Fan- the concentration above which most in XLH) and the FGF-23 gene (defec- coni syndrome) that results in glucos- phosphate is excreted and below which tive in ADHR) is useful. In the manage- uria and amino aciduria occasionally most is absorbed. To calculate TmP/ ment of presumptive TIO, clinical dili- accompanies phosphaturia. Bone his- GFR, the tubular reabsorption of phos- gence, serial physical examination, and tomorphometry demonstrates osteo- phate is calculated first: 1−urine appropriate imaging are required to suc- malacia, with clear evidence of a min- phosphorusϫserum creatinine/urine cessfully detect the causal tumor. eralization defect with increased creatinineϫserum phosphorus (all mea- One of the major obstacles to diag- mineralization lag time and excessive sured in milligrams per deciliter). With nosing TIO is that serum phosphorus osteoid (unmineralized bone matrix) the tubular reabsorption of phosphate measurements are no longer included (Figure 2). The dual defect of renal calculated and the serum phosphate mea- in the standard comprehensive meta- phosphate wasting in concert with im- sured, a nomogram is used to estimate 5 bolic panel. Therefore, hypophospha- paired calcitriol synthesis results in poor TmP/GFR. When serum phosphorus is temia is often not identified unless a bone mineralization and, ultimately, low, the TmP/GFR should be relatively physician orders a serum phosphorus fractures.2,4 If untreated, severe osteo- high. In renal phosphate wasting, the measurement specifically. As demon- malacia may lead to fractures of the long TmP/GFR is lower than expected for a strated by Ms R, the biochemical hall- bones as well as the vertebra and ribs, given serum phosphorus concentration. marks of TIO are low serum concen- with resultant chest wall deformity and In some instances, when confirma- trations of phosphorus, phosphaturia respiratory compromise. tion of the diagnosis is warranted, a

Figure 2. Radiographic and Histologic Features of Tumor-Induced Osteomalacia

A B C

A, Octreotide scan demonstrating small mesenchymal tumor in the head of the humerus (arrowhead). B, Hemangiopericytoma with numerous pericytes and vascular channels (hematoxylin and eosin stain). Original magnification ϫ100. C, Bone biopsy with Goldner stain. Excessive osteoid or unmineralized bone matrix composed mainly of collagen stains pink. Mineralized bone stains blue. Normal bone usually has a very thin, barely visible layer of osteoid. The presence of excessive osteoid is indicative of osteomalacia. This bone biopsy demonstrates severe osteomalacia. Original magnification ϫ20.

TUMOR-INDUCED OSTEOMALACIA tetracycline-labeled iliac crest bone bi- ful tumor localization has been reported induced osteomalacia is a disorder of opsy is obtained for bone histomorpho- in a few patients with other imaging tech- impaired renal phosphorus reabsorp- metric studies. Bone biopsy reveals niques, such as whole-body magnetic tion; therefore, the discussion of the dif- prominent features of osteomalacia with resonance imaging8 and positron emis- ferential diagnosis will be focused on increased unmineralized bone or oste- sion tomography.9 In 1 instance, venous other renal phosphate-wasting disor- oid surface and an increased mineral- sampling for FGF-23 was used to con- ders and differentiating them from TIO. ization lag time, as indicated by a firm that a groin mass was the source of In contrast with more common forms reduced distance between the 2 tetra- FGF-23 and, thus, the causative tumor of osteomalacia that share clinical fea- cycline labels in the bone. in a patient with TIO.10 Unfortunately, tures with TIO, patients with TIO have Imaging. Patients with TIO display ra- inMsR,octreotidescanning,whole-body normal serum calcium, normal serum diographic features of osteomalacia in- magnetic resonance imaging, and com- 25-hydroxyvitamin D, normal intact cluding generalized osteopenia, pseudo- puted tomography have been unsuccess- PTH, low 1,25-dihydroxyvitamin D, and fractures, and coarsened trabeculae. ful in locating a tumor. inappropriately elevated urinary phos- Technecium Tc 99 bone scintigraphy phorus (reduced tubular reabsorption of demonstrates diffuse skeletal uptake, re- Tumors phosphorus) levels. With the appropri- ferred to as a “superscan,” and focal up- The mesenchymal tumors that are as- ate battery of biochemical tests, TIO is take at sites of fractures. In general, plain sociated with TIO are characteristi- readily distinguishable from the most films demonstrate features of osteoma- cally slow-growing, complex, polymor- common forms of osteomalacia; how- lacia; however, it is impossible to distin- phous neoplasms, which have been ever, TIO is biochemically indistinguish- guish the underlying etiology of the os- subdivided into 4 groups based on their able from several inherited forms of hy- teomalacia with these modes. histological features: (1) phosphatu- pophosphatemic rickets, XLH and Complete surgical resection cures TIO ric mesenchymal tumor, mixed con- ADHR.13 X-linked hypophosphatemia and, thus, underscores the importance nective tissue type (PMTMCT); (2) os- and ADHR typically present in child- of early detection and localization of the teoblastoma-like tumors; (3) ossifying hood, although ADHR can exhibit a vari- culprit tumor. Localization is often ac- fibrous-like tumors; and (4) nonossi- able and delayed age of onset. This un- complished through serial physical ex- fying fibrous-like tumors.11 The derscores the importance of eliciting a amination with attention to palpable PMTMCT subtype, which includes careful family history in patients with hy- masses (especially in the extremities and hemangiopericytomas, is the most com- pophosphatemia. In contrast with XLH, the oral cavity) and appropriate imag- mon and comprises approximately 70% patients with TIO exhibit symptoms of ing. The barrier to localization with con- to 80% of the mesenchymal tumors as- weakness, pain, and fractures that are ventional imaging techniques is that the sociated with TIO.11,12 Characterized by more severe, with rapid progression to tumors are often small, slow-growing, an admixture of spindle cells, osteo- disability. However, patients with adult- and frequently situated in unusual ana- clast-like giant cells, prominent blood onset ADHR may present with severe tomicalsites.TumorsassociatedwithTIO vessels, cartilage-like matrix, and meta- pain and weakness. Stress and insuffi- are more commonly found in craniofa- plastic bone, these tumors occur equally ciency fractures are a more prominent cial locations and in the extremities; in soft tissue and bone. Although typi- feature of TIO and lower-extremity de- therefore, special attention to these areas cally benign, malignant variants of formity and short stature are characteris indicated when conventional imaging PMTMCT have been described. istic of XLH and ADHR. When a defini- such as magnetic resonance imaging or tive diagnosis is imperative, genetic computed tomography is used. In vitro Differential Diagnosis testing of the PHEX and FGF-23 genes, studies demonstrate that some mesen- Osteomalacia in adults and rickets in which are defective in XLH and ADHR, chymal tumors express somatostatin re- children may arise from a variety of con- respectively, is commercially available. ceptors (SSTRs)6 and, therefore, can be ditions, including abnormal vitamin D The definitive diagnosis of TIO is estab- detected with a scanning technique that metabolism (which, in itself, has a long lished by identification of the causative uses a radiolabeled somatostatin analog, differential diagnosis), abnormal bone tumor and remission of the syndrome indium In 111–pentetreotide scintigra- matrix, enzyme deficiencies (such as after complete tumor resection. The fea- phy (octreotide scan).3,7 The mesenchy- hypophosphatasia), inhibitors of min- tures that support the diagnosis of TIO mal tumors that express SSTRs are not eralization (such as aluminum, fluo- in Ms R are an adult onset with previ- limited to those associated with TIO; ride, bisphosphonates), calcium or ously documented normal serum phos- thus, careful biochemical confirmation phosphorus deficiency, and renal phosphorus; prominent and progressive of the syndrome is necessary before em- phate wasting (such as cadmium, TIO, symptoms of pain, weakness, and frac- barking on exhaustive imaging.6 Some inherited hypophosphatemic rickets). tures; absent family history of bone and tumors associated with TIO do not ex- Impaired renal phosphorus reabsorp- mineral disorders; and the characteris- press SSTRs and, therefore, are not lo- tion is one common mechanism that tic biochemical derangements (hypo- calized by octreotide scanning. Success- leads to hypophosphatemia. Tumor- phosphatemia, hyperphosphaturia, low

TUMOR-INDUCED OSTEOMALACIA calcitriol levels, and normal calcium and factor (or factors) produced by mesen- Circulating FGF-23 is detectable in PTH levels). chymal tumors, termed phosphatonin. human serum.34,35 In most patients with Hereditary hypophosphatemic rick- Tumorextracts can inhibit phosphorus TIO, serum levels of FGF-23 are el- ets with hypercalciuria, another inher- transport in vitro,16-19 produce phospha- evated. In a few instances when both ited renal phosphate-wasting syn- turia and hypophosphatemia in vivo,20 presurgical and postsurgical samples drome, is clinically similar to TIO, with and inhibit renal 25-hydroxyvitamin have been available, FGF-23 levels have bone pain, osteomalacia, and muscle D–1␣-hydroxylase activity in cultured plummeted after complete tumor re- weakness as prominent features, yet the kidney cells.21 Further evidence that the section. However, some individuals distinction is easily made with bio- tumor is the source of the humoral fac- with TIO have normal levels or only chemical testing. Both syndromes are tor(s) that leads to the biochemical de- mildly elevated levels, underscoring the characterized by hypophosphatemia rangements is that complete surgical re- heterogeneous composition of phos- secondary to impaired renal phospho- section of tumor tissue results in phatonin. Elevated serum FGF-23 lev- rus reabsorption; however, patients normalization of serum phosphorus and els are also observed in XLH, albeit to with hereditary hypophosphatemic calcitriol, reversal of renal phosphorus a more modest degree.34,35 rickets with hypercalciuria exhibit el- loss, and eventual remineralization of FGF-23 is also central in the patho- evated levels of calcitriol and hypercal- bone.2,4 genesis of an inherited renal phosphate ciuria, which distinguish it from TIO, FGF-23: Phosphatonin Front-Runner. wasting syndrome, ADHR. Missense mu- XLH, and ADHR.13,14 Initially,identifying phosphatonin was tations in 1 of 2 arginine residues at po- Recently, a new hypophosphatemic hampered by the slow growth of cul- sitions 176 or 179 have been identified disorder was described in 2 individu- tured tumor cells and the frequent loss in affected members of ADHR fami- als with mutations in the sodium- of phosphate-inhibitory activity by tu- lies.36 These mutated arginine residues phosphate cotransporter gene (NPT2), mor cells in culture. By adopting a new prevent the degradation of FGF-23, re- which is the major sodium-phosphate strategy of examining gene expression sulting in prolonged and/or enhanced cotransporter in the renal proximal tu- profiles of these tumors to identify FGF-23 action.26,29,37-39 bule and is responsible for reabsorp- highly and differentially expressed Additional evidence suggests that tion of up to 85% of filtered phospho- genes, I and other investigators22-25 have FGF-23 may also be key in the patho- rus. The clinical consequences of these identified several candidate genes for genesis of XLH. X-linked hypophospha- mutations are renal phosphate wast- the phosphaturic substance produced temiaiscausedbymutationsinthe PHEX ing, hypophosphatemia, and osteope- by these tumors. Included among these gene,40 which encodes an endopeptidase. nia or nephrolithiasis. The presence of genes is FGF-23, a member of the fi- Speculation about how loss of endopep- hypercalciuria and elevated calcitriol broblast growth factor family. tidase activity results in phosphate wast- make these patients easily distinguish- The FGF-23 gene is expressed at very ing has led to the hypothesis that FGF-23 able from patients with TIO.15 low levels in normal tissue but highly is a substrate for PHEX and that failure There are other disorders in which expressed in TIO tumors.25-27 The to cleave FGF-23 prolongs or enhances hypophosphatemia and renal phos- FGF-23 protein can inhibit phospho- its activity. Although there is disagree- phate wasting are part of a more global rus transport in cultured renal proxi- ment in the literature, PHEX is thought renal proximal tubular defect known as mal tubular epithelium26,28 and re- toeitherdirectly26,41 orindirectly42,43 regu- Fanconi syndrome. Global proximal tu- duces serum phosphorus and increases late FGF-23. bular dysfunction is a manifestation of fractional excretion of phosphorus25,29 FGF-23 plays a central role in 4 dis- multiple myeloma, Wilson disease, and when injected into mice. Mice chroni- tinct disorders of renal phosphate wast- cystinosis. cally exposed to FGF-23 become hypo- ing (FIGURE 3). In TIO, tumors produce phosphatemic with increased renal phos- FGF-23, which then exerts its activity Pathophysiology phorus clearance, demonstrate reduced at the proximal renal tubule to inhibit Dual Defect: Renal Phosphate Wast- bone mineralization, and have reduced tubular reabsorption of phosphorus ing and Abnormal Vitamin D Metabo- expression of renal 25-hydroxyvitamin and down-regulate 25-hydroxyvitamin lism. The basic pathophysiology of TIO D–1␣-hydroxylase with decreased cir- D–1␣-hydroxlase,resultinginhypophos- is hypophosphatemia secondary to in- culating levels of calcitriol.25 The bio- phatemia and osteomalacia. In ADHR, hibition of renal phosphorus reabsorp- chemical and skeletal abnormalities of FGF-23 bears mutations that enhance tion, which leads to hypophosphate- transgenic mice that overexpress FGF-23 its biological activity and render it resis- mia compounded by a vitamin D mimic human TIO.30,31 Conversely, tant to proteolytic cleavage and, again, synthetic defect that blocks the com- FGF-23–deficient mice exhibit growth the result is hypophosphatemia, phos- pensatory rise in calcitriol stimulated retardation and early death with bio- phaturia, bone deformity,and rickets. In by the hypophosphatemia. Phosphate chemical abnormalities that include XLH,mutatedPHEXdirectlyorindirectly wasting and the defect in vitamin D syn- hyperphosphatemia, elevated calcitriol leads to the accumulation of FGF-23 in thesis in TIO are caused by a humoral- levels, and hypercalcemia.32,33 the circulation and exerts its phospha-

TUMOR-INDUCED OSTEOMALACIA turic activity at the renal proximal tu- phosphorus supplementation serves to siently lowers serum calcium, leading to bule. In some patients with polyostotic replace ongoing renal phosphorus loss intermittent stimulation of the parathy- fibrous dysplasia who exhibit renal phos- and the calcitriol supplements in- roid glands. Prolonged stimulation of the phate wasting, serum FGF-23 is elevated sufficient renal production of 1,25- parathyroid glands with unopposed and correlates with the severity fibrous dihydroxyvitamin D and enhances renal phosphorus supplementation may ulti- dysplastic skeletal involvement.44 FGF- and gastrointestinal phosphorus reab- mately lead to parathyroid autonomy and 23 is not the only factor secreted by tu- sorption. Generally, patients are treated tertiary hyperparathyroidism. As in Ms mors in TIO that affects renal phosphate with phosphorus, 1 to 4 g/d, in divided R’s case, appropriate treatment results handling and bone mineralization.45-48 doses and calcitriol, 1 to 3 µg/d.2 In some in reduced muscle and bone pain and Other compelling phosphatonin candi- cases, administration of calcitriol alone healing of the osteomalacia within sev- dates have been identified and are the may improve the biochemical abnor- eral months. subject of ongoing research. malities seen in TIO and heal the osteo- Monitoring for therapeutic compli- malacia.50 Therapy and dosing should be cations of high doses of calcitriol and Treatment tailored to improve symptoms, main- phosphorus is important to prevent un- The definitive treatment for TIO is com- tain fasting phosphorus in the low nor- intended hypercalcemia, nephrocalci- plete tumor resection. This results in mal range, normalize alkaline phospha- nosis, and nephrolithiasis. To assess rapid correction of the biochemical de- tase, and maintain PTH in the normal safety and efficacy of therapy, moni- rangements and remineralization of range without inducing hypercalcemia toring of serum calcium and phospho- bone.49 As in the present patient, often or hypercalciuria. Phosphorus supple- rus, urine calcium, renal function, se- the tumor remains obscure or incom- mentation should be accompanied by rum alkaline phosphatase, and PTH is pletely resected and medical manage- calcitriol treatment to avoid the devel- recommended at least every 3 months. ment becomes necessary. opment of secondary hyperparathyroid- Unfortunately, Ms R has experi- As demonstrated by Ms R, TIO is ism. Although the mechanism is not well enced a number of complications re- treated with phosphorus supplementa- understood, it is thought that multiple lated to long-term therapy for TIO. She tion in combination with calcitriol. The doses of oral phosphate binds and tran- developed hypercalcemia and nephrolithiasis with transiently impaired renal function in the setting of escalat- Figure 3. Mechanisms of FGF-23 Excess in Renal Phosphate-Wasting Syndromes ing doses of calcitriol therapy. As a result of previous unopposed phospho- Autosomal Dominant X-Linked Tumor-Induced Normal Tissues Hypophosphatemic Hypophosphatemic rus supplementation, Ms R developed Osteomalacia Rickets Rickets tertiary hyperparathyroidism that re-

FGF-23 Mesenchymal Mutation in Mutation in quired subtotal parathyroidectomy. Tumor FGF-23 Gene PHEX Gene Octreotide in vitro and in vivo has PHEX been shown to inhibit secretion of hor- Overproduction FGF-23 FGF-23 mones by many neuroendocrine tu- Regulation of of FGF-23 Resistance to Impaired PHEX FGF-23 Levels and Other mors. Some mesenchymal tumors ex- Enzymatic Enzymatic Through Enzymatic Phosphatonins Cleavage Cleavage press SSTRs that bind octreotide; this Cleavage has provided the rationale for a thera- FGF-23 FGF-23 FGF-23 FGF-23 peutic trial of octreotide in several patients with TIO and residual tumor. In Normal Circulating Increased Circulating 1 case, treatment with subcutaneous oc- FGF-23 Levels FGF-23 Levels treotide, 50 to 100 µg 3 times a day, re- Decreased Expression of Down-Regulation of sulted in correction of hypophospha- α NaPiIIa Cotransporters Renal 1 -Hydroxylase temia, improvement in phosphaturia, Inhibition of Tubular and reduction of alkaline phospha- Reabsorption of P Low to Normal 7 Pi Homeostasis i tase. However, in 2 other patients, de- 1, 25-(OH)2 Vitamin D (No Compensatory Increase) spite 8 weeks of treatment with subcu- Phosphaturia taneous octreotide, up to 200 µg 3 times Normal Pi Level Hypophosphatemia daily, serum levels of phosphorus and calcitriol failed to increase serum phos- In tumor-induced osteomalacia, fibroblast growth factor 23 (FGF-23) and other phosphatonins ectopically pro- phorus, and tubular reabsorption of duced by a mesenchymal tumor lead to excess circulating FGF-23 levels. In autosomal dominant hypophos- phosphate remained depressed.3 Given phatemic rickets, FGF-23 excess results from mutations in the FGF-23 gene that render the protein resistant to cleavage and inactivation. In X-linked hypophosphatemia, the mechanism of FGF-23 excess is more specula- the limited and mixed experience with tive; mutations in the PHEX endopeptidase (presumably located on osteoblasts or osteocytes), are thought to octreotide treatment in TIO, this either directly or indirectly result in FGF-23 excess by interfering with processing and inactivation of FGF-23. therapy should be reserved for the most

TUMOR-INDUCED OSTEOMALACIA severe cases that are refractory to cur- 10. Takeuchi Y, Suzuki H, Ogura S, et al. Venous sam- 30. Larsson T, Marsell R, Schipani E, et al. Transgenic pling for fibroblast growth factor-23 confirms preop- mice expressing fibroblast growth factor 23 under the rent medical therapy. erative diagnosis of tumor-induced osteomalacia. J Clin control of the alpha1(I) collagen promoter exhibit growth Endocrinol Metab. 2004;89:3979-3982. retardation, osteomalacia, and disturbed phosphate CONCLUSION 11. Weidner N, Santa CD. Phosphaturic mesenchy- homeostasis. Endocrinology. 2004;145:3087-3094. mal tumors. Cancer. 1987;59:1442-1454. 31. Shimada T, Urakawa I, Yamazaki Y, et al. FGF-23 In conclusion, TIO is a rare disorder that 12. Folpe AL, Fanburg-Smith JC, Billings SD, et al. Most transgenic mice demonstrate hypophosphatemic rick- presents with muscle weakness, bone osteomalacia associated mesenchymal tumors are a single ets with reduced expression of sodium phosphate co- histopathological entity. Am J Surg Pathol. 2004;28:1- transporter type IIa. Biochem Biophys Res Commun. pain, and osteomalacia (and ultimately, 30. 2004;314:409-414. if left untreated, fractures). Because the 13. Jan de Beur SM, Levine MA. Molecular pathogen- 32. Shimada T, Kakitani M, Yamazaki Y, et al. Tar- esis of hypophosphatemic rickets. J Clin Endocrinol geted ablation of Fgf23 demonstrates an essential physi- symptoms are often nonspecific and be- Metab. 2002;87:2467-2473. ological role of FGF23 in phosphate and vitamin D cause phosphorus measurement is no 14. Tieder M, Modai D, Samuel R. Hereditary hypo- metabolism. J Clin Invest. 2004;113:561-568. phosphatemic rickets with hypercalciuria. N Engl J Med. 33. Sitara D, Razzaque M, Hesse M, et al. Homozy- longer on routine chemistry panels, as- 1985;312:611-617. gous ablation of fibroblast growth factor-23 results in tute physicians must consider measur- 15. Prie D, Huart V, Bakouh N, et al. Nephrolithiasis and hyperphosphatemia and impaired skeletogenesis, and osteoporosis associated with hypophosphatemia caused reverses hypophosphatemia in PHEX-deficient mice. Ma- ing serum phosphorus in patients with by mutations in the type 2a sodium-phosphate trix Biol. 2004;23:421-432. enigmatic bone pain, muscle weakness, cotransporter. N Engl J Med. 2002;347:983-991. 34. Yamazaki Y, Okazaki R, Shibata M, et al. Increased 16. Cai Q, Hodgson SF, Kao PC, et al. Brief report: in- circulatory level of biologically active full-length FGF-23 and fractures. Tumor-induced osteoma- hibition of renal phosphate transport by a tumor prod- in patients with hypophosphatemic rickets/osteomalacia. lacia is usually caused by benign mes- uct in a patient with oncogenic osteomalacia. J Clin Endocrinol Metab. 2002;87:4957-4960. enchymal tumors and cure can be N Engl J Med. 1994;330:1645-1649. 35. Jonsson KB, Zahradnik R, Larsson T, et al. Fibro- 17. Wilkins GE, Granleese S, Hegele RG, Holden J, blast growth factor 23 in oncogenic osteomalacia and achieved by complete resection of these Anderson DW, Bondy GP. Oncogenic osteomalacia: evi- X-linked hypophosphatemia. N Engl J Med. 2003;348: tumors; therefore, localizing the tumor dence for a humoral phosphaturic factor. J Clin Endo- 1656-1663. crinol Metab. 1995;80:1628-1634. 36. ADHR Consortium. Autosomal dominant hypo- is of paramount importance. 18. Nelson AE, Namkung HJ, Patava J, et al. Charac- phosphataemic rickets is associated with mutations in Financial Disclosures: None reported. teristics of tumor cell bioactivity in oncogenic FGF 23. Nat Genet. 2000;26:345-348. Funding/Support: This work was sponsored by Na- osteomalacia. Mol Cell Endocrinol. 1996;124:17-23. 37. White KE, Carn G, Lorenz-Depiereux B, et al. Au- tional Institutes of Health grants R03DK0602944 and 19. Rowe PS, Ong AC, Cockerill FJ, Goulding JN, Hewi- tosomal dominant hypophosphatemic rickets muta- K08DK02652. son M. Candidate 56 and 58 kDa protein(s) respon- tions stabilize FGF-23. Kidney Int. 2001;60:2079-2086. Role of the Sponsor: The sponsor did not contribute sible for mediating the renal defects in oncogenic hy- 38. Bai XY, Miao D, Goltzman D, Karaplis AC. The au- pophosphatemic osteomalacia. Bone. 1996;18: tosomal dominant hypophosphatemic rickets R176Q to the design, collection, management, analysis, or in- 159-169. mutation in fibroblast growth factor 23 resists proteo- terpretation of the data or preparation, review, or ap- 20. Jonsson K, Mannstadt M, Miyauchi A, et al. Ex- lytic cleavage and enhances in vivo biological potency. proval of the manuscript. tracts from tumors causing oncogenic osteomalacia in- J Biol Chem. 2003;278:9843-9849. Acknowledgment: I thank my patient for sharing her hibit phosphate uptake in opossum kidney cells. 39. Saito H, Kusano K, Kinosaki M, et al. Human fibro- story and reviewing the manuscript. I am grateful to J Endocrinol. 2001;169:613-620. blast growth factor-23 mutants suppress Naϩ- David Hellmann, MD, Johns Hopkins University School 21. Popovtzer MM. Tumor-induced hypophospha- dependent phosphate co-transport activity and 1␣,25- of Medicine, for helpful suggestions for improving the temic osteomalacia (TIO): evidence for a phosphaturic dihydroxyvitamin D3 production. J Biol Chem. 2003;278: manuscript. cyclic AMP-independent action of tumor extract. Clin 2206-2211. Res. 1981;29:418A. 40. The HYP Consortium. A gene (PEX) with homolo- REFERENCES 22. Miyauchi A, Fukase M, Tsutsumi M, Fujita T. gies to endopeptidases is mutated in patients with X- Hemangiopericytoma-induced osteomalacia: tumor linked hypophosphatemic rickets. Nat Genet. 1995;11: 1. McCrance RA. 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