Downloaded from www.jama.com at Johns Hopkins University, on November 23, 2005 GRAND ROUNDS CLINICIAN’S CORNER AT THE JOHNS HOPKINS BAYVIEW MEDICAL CENTER Tumor-Induced Osteomalacia 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, de- finitive 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. 1260 JAMA, September 14, 2005—Vol 294, No. 10 (Reprinted) ©2005 American Medical Association. All rights reserved. Downloaded from www.jama.com at Johns Hopkins University, on November 23, 2005 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.