The Changhua Journal of Medicine (2013) 11, 54-58 The Changhua Journal of Medicine journal homepage: http://www2.cch.org.tw/7477 CASE REPORT Tumor-induced osteomalacia mimics osteoporosis: case report Ping-Fang Chiu , Hsin-Hsiung Chang Nephrology Division, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan Received 14 May 2013; accepted 1 July 2013 KEYWORDS Abstract Tumor-induced osteomalacia; Bone demineralization; Osteoporosis Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disorder in which a neoplasm causes systemic bone demineralization. Most cases are benign, but malignant neoplasms have been reported. The prognosis is good if diagnosis is made early and treatment is adequate. We present the case of a previously healthy 40-year-old man who presented with low back pain for the previous year. The initial diagnosis was osteoporosis, but treatment with osteoporosis medications led to no significant improvement. Hypophosphatemia was found incidentally. Positron emission tomography with 18F fluoro-deoxyglucose (FDG-PET) indicated increased FDG uptake over the inner aspect of the right thigh, leading to a diagnosis of TIO. After resection of the tumor, the patient’s pain completely disappeared. Differential diagnosis of bone demineralization disorders, such as osteoporosis and TIO, is important because of the different treatment strategies. Patients with TIO have good prognoses if diagnosis is made early and treatment is adequate. * Corresponding author. Nephrology Division, Department of Internal Medicine, Changhua Christian Hospital 135 Nanhsiao Street, Changhua, 500 Taiwan E-mail address: [email protected] (P.-F. Chiu) Copyright © 2013, Changhua Christian Hospital. P.-F. Chiu et al. Introduction Tumor-induced osteomalacia (TIO) is a rare form of acquired osteomalacia characterized by systemic bone demineralization due to renal phosphate wasting [1]. The biochemical features include hypophosphatemia, high fractional excretion of phosphate (FEPO4), inappropriate low levels of calcitriol, but normal levels of calcium and parathyroid hormone (PTH) [2]. Although most patients with TIO have benign tumors, patients typically suffer from poor quality of life, including bone pain, shortening of stature, fractures, and muscle weakness if adequate treatment is not given. The diagnosis of TIO is often difficult and may take several years [3]. Better recognition of this disorder will allow for earlier diagnosis and more prompt administration of treatment. We describe a patient with a TIO who experienced bone pain for one year. Despite administration of antiinflammatory drugs and recombinant human parathyroid hormone for osteoporosis, his clinical condition worsened and he lost body height. After tumor resection, the patient’s pain had completely resolved. Case Report A previously healthy 40-year-old man presented to our outpatient department because of low back pain for about one year. The patient described the low back pain as dull, progressive, aggravated after sleeping in bed, and associated with bilateral hip soreness. The patient reported a loss of about 13 kg in bodyweight and a loss of about 10 centimeters in height over the past pear. The findings from a clinical examination were normal, except for kyphosis. There was no palpable mass. Initial laboratory studies were unremarkable, with total calcium of 8.8 mg/dL and intact parathyroid hormone (PTH) of 41.2 pg/mL. The serum phosphate level was not determined initially. Plain radiography indicated kyphosis of the thoracolumbar spine and compression fracture. Measurement of bone mineral density by dual-energy X-ray absorptiometry (DEXA) indicated that lumbar spine and femur T scores were less than -2.5 standard deviations, compatible with a diagnosis of severe osteoporosis. Treatment with alendronate and teriparatide was started, but there was no evident improvement in clinical conditions. 55 Several months later, hypophosphatemia was found incidentally (serum phosphate, 1.1 mg/dL; normal range, 2.4-4.1 mg/dL). Laboratory studies indicated alkaline phosphatase of 239 IU/L, urine phosphate fractional excretion (FEPi ) of 20%, and urine calcium fractional excretion of 0.2%. These findings led us to suspect hypophosphatemic osteomalacia. Further questioning indicated no family history of the heritable forms of renal phosphate wasting or osteomalacia. Initial imaging examinations (radiotracer bone scan and magnetic resonance imaging) of the spine were unremarkable. However, positron emission tomography with 18F fluorodeoxyglucose (18F-FDG) indicated increased FDG uptake over the inner aspect of the right thigh (Fig. 1). Complete tumor resection indicated a phosphaturic mesenchymal tumor with a focal hemangiopericytoma-like pattern, calcification, and focal chondroid differentiation (Fig. 2). The patient’s clinical symptoms had completely resolved two months after surgery. Discussion Osteoporosis has a high world-wide incidence [4]. DEXA is a simple, non-invasive, and widely-used method for the diagnosis of osteoporosis, but is less effective and specific than histological histomorphometry [5]. Misdiagnosis can occur if the common causes of secondary osteoporosis are not excluded. A previous report recommended a basic laboratory evaluation for the diagnosis of osteoporosis [6], but serum phosphate, which is essential for bone mineralization, is often ignored. In the differential diagnosis of osteoporosis, evaluation of serum phosphate is important because hypophosphatemia disorders, such as osteomalacia, are associated with symptoms similar to those of osteoporosis. Additionally, the pharmacologic therapy of osteoporosis (bisphosphonates and intermittent administration of recombinant human parathyroid hormone) will exacerbate hypophosphatemia if there is a misdiagnosis. Most patients with hypophosphatemia are asymptomatic, but bone pain and fractures can be present. The clinical diagnosis of hypophosphatemia is based on measurement of FEPi from a random urine specimen [7]. Renal phosphate wasting is diagnosed if the FEPi is more than 10-15% [8]. The common causes of severe hypophosphatemia with hyperphosphaturia are listed in table 1. 56 Tumor-induced osteomalacia mimics osteoporosis Figure 1. 18F-FDG PET image showing increased FDG uptake over the inner aspect of the right thigh (arrow). Figure 2. Haematoxylin-eosin staining of the tumor, indicating a phosphaturic mesenchymal tissue with a focal hemangiopericytoma-like pattern, calcification, and focal chondroid differentiation (× 200 magnification). Table 1. The common causes of severe hypophosphatemia with hyperphosphaturia Hypercalcemia (increased serum PTH or PTHrP) Increased urine Ca2+ excretion Primary or post-renal transplant hyperparathyroidism Paraneoplastic syndrome with elevated PTHrP Reduced urine Ca2+ excretion (CaSR loss of function) Familial hypocalciuric hypercalcemia Neonatal severe hyperparathyroidism Normocalcemia (isolated renal phosphate wasting) Increased serum FGF23 level XLHR (PHEX mutation) ADHR (FGF23 mutation), ARHR (DMP-1 mutation) Tumor-induced osteomalacia (acquired) Decreased serum FGF23 level HHRH (NaPi IIa or IIc mutation) Hypocalcemia (tubulopathy) Fanconi syndrome Renal tubular acidosis Bartter’s-like syndrome P.-F. Chiu et al. Abbreviations: ADHR, autosomal dominant hypophosphatemic rickets; ARHR, autosomal recessive hypophosphatemic rickets; CaSR, calcium-sensing receptor; DMP-1, dentin matrix protein 1; FGF, fibroblast growth factor; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; PHEX, phosphate regulating gene with homologies to endopeptidase on the X chromosome; PTHrP, parathyroid hormone related peptide; XLHR, X-linked hypophosphatemic rickets [10]. TIO is a rare, but curable, paraneoplastic syndrome characterized by renal phosphate wasting [9]. The clinical manifestations are proximal muscle weakness, bone pain, non-traumatic fracture, and progressive functional disability [10]. The symptoms are nonspecific and similar to those of other rheumatological, neurological, and orthopedic disorders [11]. Diagnosis of TIO is challenging, and the time needed for a correct diagnosis may exceed 2.5 years [3]. The biochemical markers of TIO include hypophosphatemia, hyperphosphaturia (high FEPi), normocalcemia, increased serum alkaline phosphatase, inappropriately low serum calcitriol, and increased phosphatonin [3,12]. Elevated serum alkaline phosphatase and hypophosphatemia are the most common laboratory abnormalities [13]. Various methods can be used to localize the tumor, including physical examination, radiography, ultrasonography, computerized tomography, magnetic resonance imaging, octreotide scintigraphy, and 18F-FDG PET [3,12]. We used 18FFDG PET and identified the tumor due to the presence of highly vascularized hemangiogenic tissue [12]. The definitive treatment of TIO is complete removal of the underlying tumor, and tumor resection led to complete recovery eventually. In conclusion, TIO does not lead to death in most patients, but it does cause prolonged disabilityt and poor quality of life if incorrect diagnosis made. 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