Elevated Fibroblast Growth Factor 23 in a Patient With Metastatic Prostate Cancer and Hypophosphatemia

Abstract

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by severe hypophosphatemia, renal phosphate wasting, and osteomalacia.1Jan de Beur S.M. Tumor-induced osteomalacia.JAMA. 2005; 294: 1260-1267Crossref PubMed Scopus (181) Google Scholar Fibroblast growth factor 23 (FGF-23), a known phosphatonin, is implicated in the pathogenesis of this syndrome. Although increased FGF-23 levels were documented in patients with TIO secondary to various tumors, an association with prostate cancer has not been described to date. We present a case of TIO secondary to metastatic prostate cancer in the setting of an increased FGF-23 level. An 83-year-old man presented with persistent hypophosphatemia detected during workup of generalized weakness. Two years before presentation, high-grade prostate adenocarcinoma was diagnosed. He underwent radical prostatectomy at that time, with a decrease in prostate-specific antigen (PSA) level from 10 to 5 ng/mL. Antiandrogenic therapy was started with goserelin (a synthetic decapeptide analogue of luteinizing hormone–releasing hormone), and PSA subsequently was undetectable for 22 months. At this time, apparent hormone refractoriness developed, manifested by a 10-fold increase in PSA and alkaline phosphatase levels to greater than 1,000 IU/L. Bone scintigraphy showed widely metastatic disease, and 2 years after prostatectomy, chemotherapy was started with docetaxel (75 mg/m2) every 3 weeks, as well as monthly intravenous zoledronic acid (4 mg). Concurrent with the administration of docetaxel and zoledronic acid, the patient’s serum phosphorus level decreased from 3.3 mg/dL (1.07 mmol/L; normal, 2.5 to 4.5 mg/dL [0.81 to 1.45 mmol/L]) to a nadir of 0.8 mg/dL (0.26 mmol/L) over approximately 2 months. Concomitant symptoms included severe fatigue, myalgias, and weakness. The patient was seen at an outside facility, where intact parathyroid hormone (PTH) level was 270 pg/mL (270 ng/L), 25-hydroxyvitamin D level was normal, and 24-hour urine phosphorus excretion was 1.5 g in the setting of a serum phosphorus level of 1.6 mg/dL (0.52 mmol/L) and normal serum calcium level. A presumptive diagnosis of primary hyperparathyroidism was made, docetaxel and zoledronic acid therapy were withheld, and the patient was treated with up to 8 packets of potassium phosphate (2 g of elemental phosphorus) per day in divided doses. He did not tolerate the supplement well secondary to the development of significant diarrhea. For the next 4 months, serum phosphorus levels ranged from 1.4 mg/dL (0.45 mmol/L) to 1.7 mg/dL (0.55 mmol/L), and fatigue and weakness persisted. On the patient’s initial evaluation at our institution 10 months after the start of chemotherapy, serum creatinine level was 0.8 mg/dL (71 μmol/L), serum phosphorus level was 1.4 mg/dL (0.45 mmol/L), and a random urine phosphorus excretion was 44.4 mg/dL (14.34 mmol/L). Fractional excretion of phosphorus was 21%, and renal phosphate threshold (tubular maximum for phosphate corrected for glomerular filtration rate [TmP/GFR]) was low at 1.25 mg/100 mL. Serum calcium and 25-hydroxyvitamin D levels were normal at 8.7 mg/dL (2.17 mmol/L) and 32 ng/mL (2.496 nmol/L), respectively. The 1,25 dihydroxyvitamin D level was low at 20 pg/mL (52 pmol/L), with normal values ranging from 22 to 67 pg/mL (57 to 174 pmol/L). Intact PTH level was 96 pg/mL (96 ng/L; normal, 12 to 75 pg/mL). There was no evidence of glucosuria, amino aciduria, hypouricemia, monoclonal gammopathy, or increased PTH-related peptide. He did not have diarrhea. FGF-23 level was increased at 326 reference units (RU)/mL (normal, 0 to 180 RU/mL). A presumptive diagnosis of TIO was made. Given the important role of phosphorus in cell membrane structure, bone mineralization, adenosine triphosphate generation, urinary buffering, and phosphorylation of cellular signaling enzymes, serum phosphorus level is maintained in the 2.5- to 4.5-mg/dL (0.8- to 1.45-mmol/L) range.1Jan de Beur S.M. Tumor-induced osteomalacia.JAMA. 2005; 294: 1260-1267Crossref PubMed Scopus (181) Google Scholar, 2Amanzadeh J. Reilly R.F. Hypophosphatemia: An evidence-based approach to its clinical consequences and management.Nat Clin Pract Nephrol. 2006; 2: 136-148Crossref PubMed Scopus (257) Google Scholar The majority (85%) of the body’s 700 g of phosphorus is contained in the bones and teeth, with the remainder found in soft tissues and extracellular fluid.2Amanzadeh J. Reilly R.F. Hypophosphatemia: An evidence-based approach to its clinical consequences and management.Nat Clin Pract Nephrol. 2006; 2: 136-148Crossref PubMed Scopus (257) Google Scholar Under the influence of PTH and 1,25 dihydroxyvitamin D, the kidney and small intestine are the main sites of phosphorus reabsorption and excretion. Under normal conditions, approximately 80% of the filtered phosphorus load is reabsorbed in the proximal tubule.1Jan de Beur S.M. Tumor-induced osteomalacia.JAMA. 2005; 294: 1260-1267Crossref PubMed Scopus (181) Google Scholar However, under conditions of decreased phosphorus intake, fractional excretion of phosphorus can decrease to less than 1%. Hypophosphatemia leads to increased renal 25-hydroxyvitamin D-1α-hydroxylase activity, with a subsequent increase in 1,25 dihydroxyvitamin D levels. Thereafter, calcium and phosphorus reabsorption increases, bone mineral stores are mobilized, and PTH is inhibited.1Jan de Beur S.M. Tumor-induced osteomalacia.JAMA. 2005; 294: 1260-1267Crossref PubMed Scopus (181) Google Scholar An approach to hypophosphatemia is shown in Fig 1.1Jan de Beur S.M. Tumor-induced osteomalacia.JAMA. 2005; 294: 1260-1267Crossref PubMed Scopus (181) Google Scholar, 2Amanzadeh J. Reilly R.F. Hypophosphatemia: An evidence-based approach to its clinical consequences and management.Nat Clin Pract Nephrol. 2006; 2: 136-148Crossref PubMed Scopus (257) Google Scholar, 3Walton R.J. Bijvoet O.L.M. Nomogram for derivation of renal threshold phosphate concentration.Lancet. 1975; 16: 309-310Abstract Scopus (659) Google Scholar A renal leak of phosphorous is established by examining urinary excretion of phosphorous. Although intuitively appealing, checking the fractional excretion of phosphorous (ie, percentage of filtered phosphorous excreted) does not take into account the influence of increased filtered load or increase in GFR. Thus, calculating a parameter that accounts for both tubular reabsorption and GFR is preferred, as described in the calculation of the renal phosphate threshold (TmP/GFR) by using a nomogram.1Jan de Beur S.M. Tumor-induced osteomalacia.JAMA. 2005; 294: 1260-1267Crossref PubMed Scopus (181) Google Scholar, 3Walton R.J. Bijvoet O.L.M. Nomogram for derivation of renal threshold phosphate concentration.Lancet. 1975; 16: 309-310Abstract Scopus (659) Google Scholar The patient was treated with 2 μg/d of calcitriol, along with 2 g of elemental phosphorus (as potassium phosphate powder). Chemotherapy with docetaxel was reinstituted, and at clinic follow-up 5 months after initial evaluation at our institution, his symptoms had improved, alkaline phosphatase level had decreased from greater than 1,000 IU/L to 250 IU/L, and PSA level decreased to less than 2 ng/mL. However, he still had a serum phosphorus level of 1.6 mg/dL (0.52 mmol/L), and a repeated FGF-23 level was 2,140 RU/mL. Three months later, at his most recent evaluation, his symptoms had essentially resolved, and laboratory investigation showed the following values: serum phosphorus, 2.2 mg/dL (0.71 mmol/L); alkaline phosphatase, 528 IU/L; PSA, 2.1 ng/mL; 1,25 dihydroxyvitamin D, 42 pg/mL (109 pmol/L; normal, 22 to 67 pg/mL [57 to 174 pmol/L]), and FGF-23, 2,160 RU/mL. TIO is a disorder characterized by renal phosphate wasting, hypophosphatemia, inappropriately low serum 1, 25-dihydroxyvitamin D levels, normal 25-hydroxyvitamin D level, and normal or slightly increased serum PTH values.1Jan de Beur S.M. Tumor-induced osteomalacia.JAMA. 2005; 294: 1260-1267Crossref PubMed Scopus (181) Google Scholar A definitive diagnosis of TIO requires remission of the syndrome after tumor resection. In cases of metastatic disease in which resection of a discrete tumor is not possible, as in our patient, one may see improvement of the syndrome with treatment of the underlying cancer. The disorder is rare and likely underrecognized, with approximately 120 cases reported in the literature. Typically, TIO is associated with a slow-growing mesenchymal tumor, mixed connective tissue type,4Weidner N. Santa C.D. Phosphaturic mesenchymal tumors.Cancer. 1987; 59: 1442-1454Crossref PubMed Scopus (271) Google Scholar the most common of which is the hemangiopericytoma. An association between osteomalacia and metastatic prostate cancer was known since the first reported cases in 1975.5Hosking D.J. Chamberlain M.J. Shortland-Webb W.R. Osteomalacia and carcinoma of the prostate with major redistribution of skeletal calcium.Br J Radiol. 1975; 48: 451-456Crossref PubMed Scopus (29) Google Scholar, 6Delbarre F. Ghozlan R. Amor B. Metastases osseuse avec osteomalacie au cours du cancer de la prostate.Nouv Presse Med. 1975; 4: 1277-1278PubMed Google Scholar A single-center retrospective review in 2005 of 128 patients with hormone-refractory metastatic prostate adenocarcinoma during a 10-year period from 1989 to 1999 showed that 5.7% of these patients had a serum phosphorus level less than the normal laboratory reference range of 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L).7Pelger R.M. Lycklama A. Nijeholt G.B. Papapoulos S.E. Hamdy N.T. Severe hypophosphatemic osteomalacia in hormone-refractory prostate cancer metastatic to the skeleton: Natural history and pitfalls in management.Bone. 2005; 36: 1-5Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar However, a paucity of reported cases of TIO associated with metastatic prostate cancer exist,7Pelger R.M. Lycklama A. Nijeholt G.B. Papapoulos S.E. Hamdy N.T. 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Uno H. et al.Prostate cancer-induced oncogenic hypophosphatemic osteomalacia.Urol Int. 1993; 55: 38-40Crossref Scopus (36) Google Scholar, 17Reese D.M. Rosen P.J. Oncogenic osteomalacia associated with prostate cancer.J Urol. 1997; 158: 887Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar and to our knowledge, this is the first report of a patient with metastatic prostate adenocarcinoma, clinical characteristics consistent with TIO, and an increased FGF-23 level. Recently, advances were made regarding the pathogenesis of TIO. Three phosphatonins secreted by tumor cells, FGF-23, secreted frizzled related protein 4 (sFRP4), and matrix extracellular phosphoglycoprotein (MEPE), were implicated in the renal phosphate wasting that characterizes TIO.18Berndt T. Craig T.A. Bowe A.E. et al.Frizzled related protein 4 is a potent phosphaturic agent.J Clin Invest. 1997; 112: 785-794Google Scholar, 19Rowe P.S. Kumagai Y. 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Vassiliadis J. et al.Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism.J Bone Miner Res. 2002; 17: 1102-1110Crossref PubMed Scopus (190) Google Scholar, 23White K.E. Jonsson K.B. Carn G. et al.The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting.J Clin Endocrinol Metab. 2001; 86: 497-500Crossref PubMed Scopus (253) Google Scholar, 24Shimada T. Mizutani S. Muto T. et al.Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia.Proc Natl Acad Sci U S A. 2001; 98: 6500-6655Crossref PubMed Scopus (1223) Google Scholar and FGF-23 led to urinary phosphate wasting in vivo and inhibition of renal phosphate transport in vitro.25Shimada T. Yoneya T. Hino R. Takeuchi Y. Fukumoto S. Yamashita T. Transgenic mice expressing fibroblast growth factor 23 (FGF23) demonstrate hypophosphatemia with low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] and rickets/osteomalacia.J Bone Miner Res. 2001; 16 (abstr): S151Google Scholar, 26Bowe A. Finnegan R. Jan de Beur Sm et al.FGF-23 inhibits phosphate transport in vitro and is a substrate for the PHEX endopeptidase.Biochem Biophys Res Commun. 2001; 284: 977-981Crossref PubMed Scopus (298) Google Scholar, 27Yamashita T. Konishi M. Miyake A. Inui K. Itoh N. Fibroblast growth factor (FGF)-23 inhibits renal phosphate reabsorption by activation of the mitogen-activated protein kinase pathway.J Biol Chem. 2002; 277: 28265-28270Crossref PubMed Scopus (192) Google Scholar Furthermore, FGF-23 decreased 25-hydroxyvitamin D-1α-hydroxylase production, thus resulting in decreased production of 1,25-dihyroxyvitamin D.28Popovtzer M.M. Tumor-induced hypophosphatemic osteomalacia (TIO): Evidence for a phosphaturic cyclic AMP-independent action of tumor extract.Clin Res. 1981; 29 (abstr): 418AGoogle Scholar Because the ability to accurately measure serum FGF-23 has improved,21Jonsson K.B. Zahradnik R. Larsson T. et al.Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.N Engl J Med. 2003; 348: 1656-1663Crossref PubMed Scopus (769) Google Scholar we may see an increase in its measurement to assist clinicians in diagnosing TIO. A recent case report described the use of an enzyme-linked immunosorbent assay for FGF-23 determination combined with positron emission tomography/computed tomography.29Dupond J.L. Mahammedi H. Prie D. et al.Oncogenic osteomalacia: Diagnostic importance of fibroblast growth factor 23 and F-18 fluorodeoxyglucose PET/CT scan for the diagnosis and follow-up in one case.Bone. 2005; 36: 375-378Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Although an increased FGF-23 level can support the diagnosis of TIO in the appropriate clinical setting, as seen with our case, a negative FGF-23 level does not rule out the diagnosis of TIO given the role of such alternative phosphatonins as sFRP4 and MEPE and those not yet characterized. Additionally, as evidenced by our case, it is not clear that serum FGF-23 level correlates with the treatment of metastatic prostate cancer or the extent of the underlying cancer and degree of phosphate wasting. When approaching the treatment of patients with TIO, a multifaceted approach is required. First, resection of the responsible tumor or chemotherapy for metastatic lesions should be undertaken to eliminate the source of the responsible phosphatonin.1Jan de Beur S.M. Tumor-induced osteomalacia.JAMA. 2005; 294: 1260-1267Crossref PubMed Scopus (181) Google Scholar, 7Pelger R.M. Lycklama A. Nijeholt G.B. Papapoulos S.E. Hamdy N.T. Severe hypophosphatemic osteomalacia in hormone-refractory prostate cancer metastatic to the skeleton: Natural history and pitfalls in management.Bone. 2005; 36: 1-5Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar To improve phosphorus reabsorption and avoid tertiary hyperparathyroidism, 1 to 3 μg/d of calcitriol is required, along with 1 to 4 g/d of elemental phosphorus.30Jan de Beur S.M. Tumor-induced osteomalacia.in: Favus M.J. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. ed 5. Lippincott Williams & Wilkins, Philadelphia, PA2003: 418-422Google Scholar Normalization of serum phosphorus level may not occur if the neoplastic process is not adequately treated. However, treatment should be titrated to normal alkaline phosphatase and PTH levels, as well as a serum phosphorus level that results in a minimization of symptoms,1Jan de Beur S.M. Tumor-induced osteomalacia.JAMA. 2005; 294: 1260-1267Crossref PubMed Scopus (181) Google Scholar eg, at least 2 mg/dL, if possible. Regular monitoring of serum phosphorus, calcium, creatinine, alkaline phosphatase; urine calcium; and PTH levels is recommended. Support: None. Financial Disclosure: None.