Improvement of severe bone pain and activities of daily living in a patient with tumor-induced osteomalacia following the resection of a FGF23-producing- tumor in the oral cavity

Kousuke IBA, Koichi SASAKI, Junichi TAKADA, Takeshi MINOWA, Nobuaki ITO, Seiji FUKUMOTO, Tadashi HASEGAWA, Takuro WADA, Toshihiko YAMASHITA

Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine,Japan.

Address for Correspondence:

Kousuke IBA
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine,Japan.
E-mail: iba@sapmed.ac.jp

Abstract:

Fibroblast growth factor 23 (FGF23), a protein capable of inhibiting renal tubular epithelial phosphate transport, is thought to be the underlying mechanism in tumor-induced- osteomalacia. In this report, we present a case of tumor-induced- osteomalacia associated with an oral soft tissue tumor that caused overexpression of FGF23.

A 35-year-old man suffered from bone pain for 2 years and he presented the difficulty in walking due to severe bone pain and muscle weakness in his lower limbs. Radiography identified old fractures and severe bone atrophy at multiple bones and bone scintigraphy revealed abnormal tracer uptake. Laboratory findings showed that the serum phosphate level was very low (0.8 mg/dl), and FGF23 serum level was elevated (128.7 pg/ml). We diagnosed the patient as FGF 23-producing tumor-induced hypophosphatemic osteomalacia a. About 2 years after the start of our follow-up, a small soft tumor was found behind of the lower lip. After resection of the tumor, the serum phosphate and FGF23 levels rapidly normalized and the severe bone pain markedly improved. Furthermore, the tissue was stained positive using anti-human FGF23 antibody. In this report, we presented the rare case that FGF 23–producing tumor within the oral cavity inducing osteomalacia with severe clinical symptom including bone pain, multiple fragility fractures, muscle weakness and gait disturbance.

J.Orthopaedics 2009;6(4)e11

Keywords:

fibroblast growth factor (FGF 23); tumor-induced osteomalacia; oral soft tumor; bone pain; phosphate

Introduction:

Osteomalacia is a metabolic bone disorder resulting from inadequate mineralization of osteoid in mature bone. One of the most unusual types of osteomalacia is tumor-induced osteomalacia, which is characterized clinically by bone pain, fractures, muscle weakness, gait disturbance, renal phosphate wasting, hypophosphatemia, decreased serum 1, 25-dihydroxyvitamin D levels, and resistance to vitamin D supplementation (1). Recent reports have indicated that fibroblast growth factor 23 (FGF23) is a protein capable of inhibiting renal tubular epithelial phosphate transport (2), which is thought to be the underlying mechanism in tumor-induced- osteomalacia2. FGF23 has been identified as a member of the FGF family and shown to have an important role in phosphate homeostasis (3) Most of the tumors causing osteomalacia are benign and occur in the lower and upper extremities; however, the tumors are frequently very small, making discovery difficult (4, 5).

In this report, we present a case of tumor-induced- osteomalacia associated with an oral soft tissue tumor that caused overexpression of FGF 23, and the rapid normalization of FGF23 levels following removal of the tumor. Subsequently, the normalization of biochemical parameters of mineral metabolism correlated with the improvement in severe bone pain and activities of daily living (ADL).

Case Report:

A 35-year-old man had experienced bone pain in ribs and right hip for 2 years. At 6 months after the onset of pain, he underwent a medical examination to establish the cause of the bone pain in another hospital. However, the origin of the symptoms could not be found, and the patient was followed up with non-steroidal anti-inflammatory drug treatment for over 1.5 years. The symptoms gradually worsened and he presented the difficulty in walking due to severe bone pain and muscle weakness in his lower limbs. The patient was referred to our hospital for further examination because of the unknown origin of the symptoms.

The patient complained of a severe diffuse bone pain all over his body. He was wheelchair bound due to significant pain in hips and knees with a visual analogue scale (VAS) of 8.4, and muscle weakness of lower limbs. He did not have a significant family history of bone diseases or any history of other diseases. Previously he had been healthy and worked as a truck driver with a high level of physical activity. His height, weight, and body mass index was 159.1 cm, 52.6 kg, and 20.8 kg/m², respectively. The muscle strength of the lower limbs was found to be grade 3 on the basis of manual muscle testing. We found no other abnormalities on physical examination. Radiography identified multiple old fractures and severe bone atrophy at spine, ribs, pubis, ischium and lower limbs (data not shown). Bone mineral density (BMD) was markedly decreased at the lumbar spine (L2-L4; 0.512 g/cm², T score -3.8) and femoral neck (0.478 g/cm², T-score -3.6) (QDR4500; Hologic, Waltham, MA, USA). Bone scintigraphy with ^99mTc-methylene diphosphonate revealed abnormal tracer uptake in multiple bones including the spine, ribs, pelvis and femurs, suggesting clinical fractures (Fig. 1). Laboratory findings showed that the serum phosphate (IP, reference range 2.5-4.5 mg/dl) level was very low (0.8 mg/dl), and serum total alkaline phosphatase (ALP, reference range 110-370 IU/l) and bone specific alkaline phosphatase (BAP, reference range 13-33.9 U/l) levels were markedly increased at 1878 IU/l and 312 U/l, respectively. The urinary N-terminal telopeptide of type I collagen (uNTX, reference range, < 66.2 nmol bone collagen equivalent / mmol·creatinine [nMBCE/mM·Cr]) level was 43.7 nMBCE/mM·Cr, and the circulating 1,25-dihydroxyvitamin D (1,25(OH)₂D, reference range, 20-60) level was very low (8 pg/ml) despite the hypophosphatemia. Several serum tumor markers, such as CEA, AFP, CA19-9 and PSA, were within reference ranges. Other laboratory data were also within reference ranges. Thus, we diagnosed the patient as hypophosphatemic osteomalacia, which was confirmed by an iliac bone biopsy. Furthermore, considering that he had been healthy for 33 years prior to the onset of his disease and that the symptoms had worsened during the 2-year- follow-up, tumor-induced- osteomalacia was considered to be the most probable cause of this patient.

However, no significant abnormalities apart from skeletal organs were identified using computed tomography, ultrasonography, ²⁰¹Tl scintigraphy, and endoscopy for the digestive organs. Furthermore, a positron emission tomography (PET) scan failed to reveal any abnormalities in any part of the body. On the basis of a recent report that venous sampling for FGF23 confirms preoperative diagnosis of tumor-induced- osteomalacia (6), we measured FGF23 concentration by ELISA (Kainos, Japan) in subcutaneous venous samples (reference range, 10-50 pg/ml) taken from 6 points in the upper and lower extremities. The FGF23 serum level was elevated in samples from all 6 points, including the bilateral hands (right 181.4, left, 195.5 pg/ml), femurs (right 181.4, left 222.3 pg/ml) and lower legs (right 189.1, left 183.6 pg/ml); however, there were no differences among samples. From these results, we diagnosed the patient as FGF 23-producing tumor-induced hypophosphatemic osteomalacia although no causative tumor was identified. Treatment with alfacalcidol (3.0 µg / day) and sodium acid phosphate (500mg of elemental phosphorus three times daily) was initiated on the basis of the diagnosis. Subsequently, his pain slightly improved, but the patient still suffered from multiple bone pain and presented with the difficulty in walking without aid.

About 2 years after the start of our follow-up, the patient became aware of a small soft tumor behind of the lower lip. Six months later, the tumor size gradually increased until it was 23mm × 14mm × 10mm in size (Fig. 2A) so that the patient underwent resection of the tumor. The pathologic diagnosis of the tumor was consistent with fibroma, and revealed a fibroblastic proliferation with fibrous connective tissues and reactive bone formation without any evidence of malignancy (Fig. 2B). Furthermore, the tissue was stained positive using polyclonal rabbit anti-human FGF23 antibody (FGF23 (FL251)) (1:500 dilution; Santa Cruz Biotechnology, CA, USA) (Fig 2C).

At 5 hours post-surgery, the serum FGF 23 level rapidly decreased to a reference range, and thereafter remained under 10 pg/ml (Fig. 3A). The serum phosphate level rapidly increased and remained within the reference range for more than 9 months post-surgery (fig. 3B). ALP initially rose following tumor removal and then gradually declined. Normalization of the ALP was not achieved until 6 months post-surgery (Fig. 3C). The severe bone pain of the patient gradually decreased although moderate pain remained post-operatively (Fig. 3D). At 6 months post-operatively, the patient was able to walk without any supports and had resumed low-level physical activity. General health was assessed with use of the Short Form-36 (SF-36) (7, 8) and post-operative SF-36 scores were improved compared with pre-operative scores (Fig. 4).

Figure 1  Bone scintigraphy of the patient

Bone scintigraphy with ^99mTc-methylene diphosphonate revealed abnormal tracer uptake in multiple bones including the spine, ribs, pelvis and femurs (arrows).

Figure 2  FGF23 producing tumor within the oral cavity

The soft tumor was located behind the lower lip (tumor size was 23mm × 14mm × 10mm) (A, arrow heads). Pathologic diagnosis of the tumor was consistent with fibroma, and revealed a fibroblastic proliferation with fibrous connective tissues and reactive bone formation without evidence of malignancy (B, Hematoxilin-Eosin stain). The tissue was stained positive using polyclonal rabbit anti-human FGF23 antibody (C, single immunolabeling (peroxidase and DAB).

Figure 3

At 5 hours post-surgery, the serum level of FGF23 rapidly decreased from 128.7 pg/ml to 17.6 pg/ml, and thereafter remained under 10 pg/ml (A). The serum phosphate level rapidly increased to 3.1 mg/dl and remained within the reference range (2.5 – 4.5 mg/dl) for more than 9 months post-surgery (B). ALP initially rose following the tumor removal and then gradually declined. Normalization of the ALP (110 – 370) was not achieved until 6 months post-surgery (ALP, 585 IU/l) (C). The severe bone pain (VAS 8.1) gradually decreased, although moderate pain (VAS 2.1) remained postoperatively (D).

Figure 4  Pre- and 1- and 6-month post-operative SF-36 scores

The scores for the eight subscales of the SF-36 (Physical Function, Role Physical, Bodily pain, General Health, Vitality, Social Function, Role Emotion and Mental Health) were measured prior to the surgery (black bars) and at 1 month (white bars) and 6 months (striped bars) post-surgery

Discussion :

Tumor-induced osteomalacia is an acquired, paraneoplastic syndrome that is characterized by hypophosphatemia due to renal phosphate wasting, osteomalacia, bone pain, proximal muscle weakness, fractures and functional disability (1). The disease shares similar of clinical symptoms with X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR) (9-12). In this case, the patient had no family history so that we preoperatively suspected tumor-induced- osteomalacia rather than genetic diseases such as XLH, ADHR and ARHR. Interestingly, the site of the tumor was within the oral cavity despite the fact that most tumors responsible for tumor-induced- osteomalacia is localized in the lower and upper limbs. To the best of our knowledge, there have been few previous reports of FGF 23–producing tumors within the oral cavity inducing osteomalacia (1, 4, 5).FGF 23 was recently identified as a causative humoral factor for tumor-induced- osteomalacia, and is known to reduce serum phosphate level by inhibiting proximal tubular phosphate reabsorption and decreasing serum 1,25(OH)₂D levels (2, 13). Endo et al. (14) proposed a set of diagnostic criteria based on the serum phosphate and FGF 23 levels as follows; in adults, a serum phosphate level of less than 2.5 mg/dl and a FGF 23 level of more than 30 pg/ml by intact FGF 23 assay indicate the presence of diseases caused by excess FGF 23, such as tumor-induced- osteomalacia and XLH. In our case, the data from the patient met these criteria, with the serum FGF23 level, in particular, greater than 180 pg/ml.

Measurement of serum FGF 23 level in samples obtained from peripheral veins is useful for the diagnosis and post-operative monitoring of patients with tumor-induced- osteomalacia (6). However, we could not locate the responsible tumor in the oral cavity because the FGF23 levels were elevated in the samples from both the upper and lower limbs, and the patient rejected further invasive examination, such as sample collection from all major veins through a catheter inserted through the femoral vein (6). Because the tumor was found in the oral cavity, it is reasonable that FGF23 levels from extremities showed no difference. It is possible that FGF23 was higher if FGF23 levels in jugular veins could be measured.

Various types of mesenchymal tumors associated with tumor-induced- osteomalacia have been reported, including hemangiopericytoma, hemangioma, giant cell tumor and osteoblastoma (4, 5). Weidner and Santa Cruz (4) coined the term “phosphaturic mesenchymal tumor, mixed connective tissue variant” (PMTMCT) to describe these unique lesions, characterized by a distinctive admixture of spindled cells, osteoclast-like giant cells, microcysts, prominent blood vessels, cartilage-like matrix, and metaplastic bone. Although the pathologic diagnosis in our case was fibroma, the histological features could be included into a spectrum of PMTMCT described as the most frequent histology associated with tumor-induced- osteomalacia (4, 5).

In this report, we described a severe case of tumor-induced- osteomalacia associated with a histologically diagnosed fibroma that secreted high levels of FGF23. In most orthopaedic clinics, it is sometimes difficult to distinguish severe osteomalacia from osteoporosis as the clinical symptoms of both, including low BMD, bone pain and multiple fragility fractures are similar. In fact, this case was also diagnosed as a severe osteoporosis before consultation at our hospital. We believe that it is important to consider osteomalacia associated with FGF 23-producing- tumor in the differential diagnosis of patients presenting with the sudden onset of low BMD, bone pain, fragility fractures and hypophosphatemia. The informed consent for the publication of data from the case was received from the patient and the family.

Reference :

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3. Fukumoto S, Yamashita T. FGF23 is a hormone-regulating phosphate metabolism-Unique biological characteristics of FGF23. Bone 2007; 40:1190-1195.

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10. Hyp-Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nature Genetics 1995; 11: 130-136.

11. Lorenz-Depiereux B, Bastepe M, Benet-Pagčs A, Amyere M, Wagenstaller J, Müller-Barth U, et al. DMP1 mutations in autosomal recessive hypophosphatemia implicate a bone matrix protein in the regulation of phosphate homeostasis. Nature Genetics 2006; 38: 1248-1250.

12. Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nature Genetics 2006; 38: 1310-1315.

13. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of Vitamin D metabolism and phosphate homeostasis. Journal of Bone and Mineral Research 2004; 19:429-435.

14. Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D, et al. Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients: Proposal of diagnostic criteria using FGF23 measurement. Bone 2008; 42:1235-1239.

This is a peer reviewed paper 

Please cite as: Kousuke IBA: Improvement of severe bone pain and activities of daily living in a patient with tumor-induced osteomalacia following the resection of a FGF23-producing- tumor in the oral cavity.

J.Orthopaedics 2009;6(4)e11

URL: http://www.jortho.org/2009/6/4/e11

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